67 results on '"Visner GA"'
Search Results
2. Posttransplant monitoring of pediatric lung transplant recipients.
- Author
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Visner GA and Goldfarb SB
- Published
- 2007
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3. Novel action of indoleamine 2,3-dioxygenase attenuating acute lung allograft injury.
- Author
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Liu H, Liu L, Fletcher BS, and Visner GA
- Abstract
RATIONALE: Lung allografts are prone to reperfusion injury and acute rejection, which, in addition to infiltrating lymphocytes, are accompanied by neutrophil infiltration and neutrophil-associated oxidative stress. Indoleamine 2,3-dioxygenase (IDO) is a unique cytosolic enzyme that possesses T-cell-suppressive and antioxidant properties. OBJECTIVES: The purpose of this study was to determine if genetic up-regulation of IDO could ameliorate acute lung allograft injury. METHODS: Lung orthotopic transplants were performed using Lewis donors and Sprague-Dawley rat recipients (allografts) or the same strain (isografts). Plasmid-encoding human IDO was delivered to donor lungs in vivo using a nonviral gene-transfer vector, polyethylenimine. Transplanted lungs were evaluated at 6 d post-transplantation based on pulmonary function, histology, inflammatory responses, and their associated oxidative stress. Basic biology of the IDO-overexpressing lung cells was evaluated in vitro in response to external oxidant. MEASUREMENTS AND MAIN RESULTS: This gene delivery method led to uniform transgene expression in lung tissue distributed in airway, alveolar epithelial, and endothelial cells. IDO overexpression in lung allografts resulted in a significant protective effect with improvement in functional properties (peak airway pressure and oxygenation) and histologic appearance. Although IDO was able to block local T-cell responses, it failed to abrogate neutrophilic infiltration and the inflammation-associated oxidative stress. IDO-enhanced lung cells were resistance to oxidant-induced necrosis and apoptosis by limiting intracellular reactive oxygen species formation. CONCLUSIONS: These results demonstrate that IDO prevents acute lung allograft injury through augmenting the local antioxidant defense system and inhibiting alloreactive T-cell responses. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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4. Heme oxygenase-1 expression in human lungs with cystic fibrosis and cytoprotective effects against Pseudomonas aeruginosa in vitro.
- Author
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Zhou H, Lu F, Latham C, Zander DS, Visner GA, Zhou, Hailan, Lu, Fuhua, Latham, Christopher, Zander, Dani S, and Visner, Gary A
- Abstract
Inflammation and oxidative stress play important roles in cystic fibrosis (CF) lung disease. Inflammatory/oxidant-mediated induction of heme oxygenase-1 (HO-1) is believed to be a cytoprotective response. This study examined HO-1 expression in lung samples from patients with CF using immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. In addition, we evaluated myeloperoxidase staining as a marker of acute inflammation and potentially an increase in oxidant stress and Prussian blue and ferritin staining to assess iron status of the lung. Macrophage HO-1 staining was increased in diseased lungs as compared with normal control subjects and correlated with myeloperoxidase staining. Quantitative reverse transcription-polymerase chain reaction further supported an increase in HO-1 expression in CF lung disease. Although iron staining was minimal, ferritin staining was increased in diseased lungs in concert with HO-1 staining. To determine whether HO-1 induction was cytoprotective, we evaluated a CF airway epithelial cell line, IB3.1, in response to Pseudomonas aeruginosa-induced injury/apoptosis in cells overexpressing HO-1 by either transient or stable transfection of pcDNA3.1/HO-1 construct. Overexpression of HO-1 resulted in protection against P. aeruginosa-induced injury/apoptosis. This suggests that the induction of HO-1 in patients with CF is a cytoprotective event and that augmenting its expression is a potential therapy against bacterial injury. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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5. Role of transbronchial biopsies in pediatric lung diseases.
- Author
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Visner GA, Faro A, and Zander DS
- Abstract
STUDY OBJECTIVE: To evaluate the role of transbronchial biopsies (TBBs) in pediatric lung diseases. DESIGN AND METHODS: We reviewed the records of TBBs performed in pediatric patients at the University of Florida between July 1996 and August 2003. The sample adequacy, diagnostic utility, and procedural complications of the two types of bronchoscopy apparatuses used to collect the samples were assessed and compared. PATIENTS: A total of 429 TBB procedures were performed in 46 patients (age range, 2 months to 21 years) who had received a heart-lung or lung transplant and in 38 non-lung transplant patients (age range, 2 weeks to 18 years). For 86 procedures, the pediatric bronchoscope and forceps that fit in a 1.2-mm channel were used, and a small adult bronchoscope and 2.0-mm forceps were used for the remaining procedures. RESULTS: Adequate tissue samples were obtained in 85% of the procedures using a pediatric bronchoscope and in 97% using an adult bronchoscope. In the non-lung transplant patients, the biopsy findings were considered to be diagnostic in 58% of all procedures (adult bronchoscope, 64%; and pediatric bronchoscope, 50%), contributory in 21%, and noncontributory in 21%. In the lung transplant patients, treatable acute cellular rejection was diagnosed in 24% of the surveillance TBBs and in 47% of the TBBs performed as a result of clinical symptoms. Complications included five pneumothoraces and five episodes of excessive bleeding requiring the discontinuation of the procedure in three of the cases. CONCLUSIONS: Adequate lung tissue for histologic diagnosis can be obtained safely and effectively from pediatric patients of all ages via flexible bronchoscopy with TBB. The performance of bronchoscopy should be considered based on clinical indications, rather than on the age or size of the patient, when a tissue diagnosis is needed. When feasible, the use of an adult bronchoscope is preferable due to the higher diagnostic yield. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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6. Pediatric Lung Transplantation for Pulmonary Vascular Diseases: Recent Advances and Challenges.
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Midyat L, Muise ED, and Visner GA
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- Humans, Child, Stenosis, Pulmonary Vein surgery, Stenosis, Pulmonary Vein therapy, Extracorporeal Membrane Oxygenation, Graft Rejection, Lung Transplantation trends, Lung Transplantation methods, Pulmonary Veno-Occlusive Disease surgery, Pulmonary Veno-Occlusive Disease therapy
- Abstract
Pediatric lung transplantation for pulmonary vascular diseases has seen notable advancements and trends. Medical therapies, surgical options, and bridging techniques like extracorporeal membrane oxygenation and different forms of transplants have expanded treatment possibilities. Current challenges include ensuring patient adherence to post-transplant therapies, addressing complications like primary graft dysfunction and rejection, and conducting further research in less common conditions like pulmonary veno-occlusive disease and pulmonary vein stenosis. In this review article, the authors will explore the advancements, emerging trends, and persistent challenges in pediatric lung transplantation for pulmonary vascular diseases., Competing Interests: Disclosure The other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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7. Exercise-Induced Pulmonary Hypertension in Long-Term Survivors of Congenital Diaphragmatic Hernia.
- Author
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Critser PJ, Buchmiller TL, Gauvreau K, Zalieckas JM, Sheils CA, Visner GA, Shafer KM, Chen MH, and Mullen MP
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- Humans, Retrospective Studies, Female, Male, Adolescent, Child, Young Adult, Child, Preschool, Exercise Test, Exercise physiology, Echocardiography, Prevalence, Hernias, Diaphragmatic, Congenital complications, Hernias, Diaphragmatic, Congenital surgery, Hypertension, Pulmonary etiology, Survivors
- Abstract
Objective: To determine the prevalence of exercise-induced pulmonary hypertension (PH) among long-survivors of congenital diaphragmatic hernia repair., Study Design: This is a single-center, retrospective cohort study of CDH survivors who underwent exercise stress echocardiography (ESE) at Boston Children's Hospital from January 2006 to June 2020. PH severity was assessed by echocardiogram at baseline and after exercise. Patients were categorized by right ventricular systolic pressure (RVSP) after exercise: Group 1 - no or mild PH; and Group 2 - moderate or severe PH (RVSP ≥ 60 mmHg or ≥ ½ systemic blood pressure)., Results: Eighty-four patients with CDH underwent 173 ESE with median age 8.1 (4.8 - 19.1) years at first ESE. Sixty-four patients were classified as Group 1, 11 as Group 2, and 9 had indeterminate RVSP with ESE. Moderate to severe PH after exercise was found in 8 (10%) patients with no or mild PH at rest. Exercise-induced PH was associated with larger CDH defect size, patch repair, use of ECMO, supplemental oxygen at discharge, and higher WHO functional class. Higher VE/VCO2 slope, lower peak oxygen saturation, and lower percent predicted FEV1, and FEV1/FVC ratio were associated with Group 2 classification. ESE changed management in 9/11 Group 2 patients. PH was confirmed in all 5 Group 2 patients undergoing cardiac catheterization after ESE., Conclusions: Among long-term CDH survivors, 10% had moderate-severe exercise-induced PH on ESE, indicating ongoing pulmonary vascular abnormalities. Further studies are needed to optimally define PH screening and treatment for patients with repaired CDH., Competing Interests: Declaration of Competing Interest The authors declare no financial conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)
- Published
- 2024
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8. Outcomes of surgical treatment of tracheobronchomalacia in children.
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Mukharesh L, Krone KA, Hamilton TE, Shieh HF, Smithers CJ, Winthrop ZA, Muise ED, Jennings RW, Mohammed S, Demehri FR, Zendejas B, and Visner GA
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- Humans, Male, Female, Infant, Child, Preschool, Treatment Outcome, Child, Tracheoesophageal Fistula surgery, Tracheoesophageal Fistula complications, Esophageal Atresia surgery, Esophageal Atresia complications, Retrospective Studies, Tracheobronchomalacia surgery, Tracheobronchomalacia complications, Bronchoscopy methods
- Abstract
Background: Tracheobronchomalacia (TBM) is characterized by excessive dynamic airway collapse. Severe TBM can be associated with substantial morbidity. Children with secondary TBM associated with esophageal atresia/tracheoesophageal fistula (EA/TEF) and vascular-related airway compression (VRAC) demonstrate clinical improvement following airway pexy surgery. It is unclear if children with severe primary TBM, without secondary etiologies (EA/TEF, vascular ring, intrinsic pulmonary pathology, or complex cardiac disease) demonstrate clinical improvement following airway pexy surgery., Materials and Methods: The study cohort consisted of 73 children with severe primary TBM who underwent airway pexy surgery between 2013 and 2020 at Boston Children's Hospital. Pre- and postoperative symptoms as well as bronchoscopic findings were compared with Fisher exact test for categorical data and Student's t-test for continuous data., Results: Statistically significant improvements in clinical symptoms were observed, including cough, noisy breathing, prolonged respiratory infections, pneumonias, exercise intolerance, cyanotic spells, brief resolved unexplained events (BRUE), and noninvasive positive pressure ventilation (NIPPV) dependence. No significant differences were seen regarding oxygen dependence, ventilator dependence, or respiratory distress requiring NIPPV. Comparison of pre- and postoperative dynamic bronchoscopy findings revealed statistically significant improvement in the percent of airway collapse in all anatomic locations except at the level of the upper trachea (usually not malacic). Despite some initial improvements, 21 (29%) patients remained symptomatic and underwent additional airway pexies with improvement in symptoms., Conclusion: Airway pexy surgery resulted in significant improvement in clinical symptoms and bronchoscopic findings for children with severe primary TBM; however, future prospective and long-term studies are needed to confirm this benefit., (© 2024 Wiley Periodicals LLC.)
- Published
- 2024
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9. The IPTA Nashville consensus conference on Post-Transplant lymphoproliferative disorders after solid organ transplantation in children: II-consensus guidelines for prevention.
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Green M, Squires JE, Chinnock RE, Comoli P, Danziger-Isakov L, Dulek DE, Esquivel CO, Höcker B, L'Huillier AG, Mazariegos GV, Visner GA, Bollard CM, Dipchand AI, Ferry JA, Gross TG, Hayashi R, Maecker-Kolhoff B, Marks S, Martinez OM, Metes DM, Michaels MG, Preiksaitis J, Smets F, Swerdlow SH, Trappe RU, Wilkinson JD, Allen U, Webber SA, and Dharnidharka VR
- Subjects
- Humans, Child, Immunosuppression Therapy, Chemoprevention, Epstein-Barr Virus Infections complications, Epstein-Barr Virus Infections diagnosis, Lymphoproliferative Disorders diagnosis, Lymphoproliferative Disorders etiology, Lymphoproliferative Disorders prevention & control, Organ Transplantation adverse effects
- Abstract
The International Pediatric Transplant Association (IPTA) convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorder after solid organ transplantation in children. In this report from the Prevention Working Group, we reviewed the existing literature regarding immunoprophylaxis and chemoprophylaxis, and pre-emptive strategies. While the group made a strong recommendation for pre-emptive reduction of immunosuppression at the time of EBV DNAemia (low to moderate evidence), no recommendations for use could be made for any prophylactic strategy or alternate pre-emptive strategy, largely due to insufficient or conflicting evidence. Current gaps and future research priorities are highlighted., (© 2022 Wiley Periodicals LLC.)
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- 2024
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10. A novel ex vivo tracheobronchomalacia model for airway stent testing and in vivo model refinement.
- Author
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Mondal A, Visner GA, Kaza AK, and Dupont PE
- Subjects
- Sheep, Animals, Trachea surgery, Stents, Models, Animal, Bronchoscopy, Tracheobronchomalacia diagnosis, Tracheobronchomalacia surgery
- Abstract
Objectives: We sought to develop an ex vivo trachea model capable of producing mild, moderate, and severe tracheobronchomalacia for optimizing airway stent design. We also aimed to determine the amount of cartilage resection required for achieving different tracheobronchomalacia grades that can be used in animal models., Methods: We developed an ex vivo trachea test system that enabled video-based measurement of internal cross-sectional area as intratracheal pressure was cyclically varied for peak negative pressures of 20 to 80 cm H
2 O. Fresh ovine tracheas were induced with tracheobronchomalacia by single mid-anterior incision (n = 4), mid-anterior circumferential cartilage resection of 25% (n = 4), and 50% per cartilage ring (n = 4) along an approximately 3-cm length. Intact tracheas (n = 4) were used as control. All experimental tracheas were mounted and experimentally evaluated. In addition, helical stents of 2 different pitches (6 mm and 12 mm) and wire diameters (0.52 mm and 0.6 mm) were tested in tracheas with 25% (n = 3) and 50% (n = 3) circumferentially resected cartilage rings. The percentage collapse in tracheal cross-sectional area was calculated from the recorded video contours for each experiment., Results: Ex vivo tracheas compromised by single incision and 25% and 50% circumferential cartilage resection produce tracheal collapse corresponding to clinical grades of mild, moderate, and severe tracheobronchomalacia, respectively. A single anterior cartilage incision produces saber-sheath type tracheobronchomalacia, whereas 25% and 50% circumferential cartilage resection produce circumferential tracheobronchomalacia. Stent testing enabled the selection of stent design parameters such that airway collapse associated with moderate and severe tracheobronchomalacia could be reduced to conform to, but not exceed, that of intact tracheas (12-mm pitch, 0.6-mm wire diameter)., Conclusions: The ex vivo trachea model is a robust platform that enables systematic study and treatment of different grades and morphologies of airway collapse and tracheobronchomalacia. It is a novel tool for optimization of stent design before advancing to in vivo animal models., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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11. Recovery of right ventricular function after bilateral lung transplantation for pediatric pulmonary hypertension.
- Author
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Critser PJ, Boyer D, Visner GA, Collins SL, Fynn-Thompson F, and Mullen MP
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- Child, Heart Ventricles, Humans, Ventricular Function, Right, Hypertension, Pulmonary surgery, Lung Transplantation, Ventricular Dysfunction, Right surgery
- Abstract
Background: Lung transplantation is a therapeutic option for end-stage pediatric pulmonary hypertension (PH). Right ventricular (RV) recovery post-lung transplant in children with PH has not been well-described, and questions persist about the peri-operative course and post-transplant cardiac function after lung transplantation in medically refractory PH patients with baseline RV dysfunction., Methods: A single-center chart review identified patients with childhood PH who subsequently underwent bilateral orthotopic lung transplantation between 2000 and 2020. Twenty-six patients met criteria; three were excluded due to echocardiograms not available for digital review. RV fractional area change (FAC) and left ventricular eccentricity index (LVEI) were determined prior to transplantation, and at 1, 3, 6, and 12-month post-transplantation., Results: Fourteen of 23 patients had baseline RV dysfunction. The median age at transplantation was 16.5 years and 13.9 years for those with and without baseline RV dysfunction, respectively. Of the 14 with baseline RV dysfunction, 12 (86%) were alive 1-year post-transplantation. All patients with baseline RV dysfunction had increased RV-FAC post-transplantation with normalization of RV-FAC in 70% at 3 months and 100% of patients by 12-month post-transplantation. Duration of ventilation (p = .4), intensive care unit (p = .5), or hospital stay (p = .9) was not associated with pre-transplant RV function., Conclusions: Among pediatric patients with PH and RV dysfunction, pre-transplantation RV function was not associated with short-term outcomes. All patients with baseline RV dysfunction had improvement in RV function, justifying consideration of lung transplantation among pediatric patients with end-stage PH and RV dysfunction., (© 2022 Wiley Periodicals LLC.)
- Published
- 2022
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12. Auto-inflammation and auto-immunity pathways are associated with emergence of BOS in pediatric lung transplantation.
- Author
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Conrad CK, Hedlin H, Chin H, Hayes D Jr, Heeger PS, Faro A, Goldfarb S, Melicoff-Portillo E, Thalachallour M, Odim J, Schecter M, Storch GA, Visner GA, Williams NM, Kesler K, Danziger-Isakov L, and Sweet SC
- Subjects
- Adult, Child, Cytokines metabolism, Humans, Inflammation, Interleukin-23, Prospective Studies, Bronchiolitis Obliterans diagnosis, Bronchiolitis Obliterans etiology, Lung Transplantation
- Abstract
Background: Long-term survival after lung transplantation (LTx) is limited by chronic lung allograft dysfunction (CLAD)., Methods: We report an analysis of cytokine profiles in bronchoalveolar lavage samples collected during a prospective multicenter non-interventional trial primarily designed to determine the impact of community-acquired respiratory viral infections (CARV) in outcomes after pediatric LTx. In this analysis, we identify potential biomarkers of auto-inflammation and auto-immunity associated with survival and risk of bronchiolitis obliterans (BOS) after LTx with cytokine analysis of bronchoalveolar lavage fluid (BALF) from 61 pediatric recipients., Results: Higher IL-23 (p = .048) and IL-31 (p = .035) levels were associated with the risk of BOS, and lower levels of epithelial growth factor (EGF) (p = .041) and eotaxin (EOX) (p = .017) were associated with BOS. Analysis using conditional inference trees to evaluate cytokines at each visit associated with survival identified soluble CD30 (p < .001), pro-inflammatory cytokine IL-23 (p = .02), and sTNFRI (p = .01) below cutoff levels as associated with BOS-free survival., Conclusions: Our results indicate that post-LTx survival in children may be linked to activation of alternate pathways of the immune system that affect airway remodeling in addition to activation of "classical" pathways that have been described in adult LTx recipients. These may indicate pathways to target for intervention., (© 2022 Wiley Periodicals LLC.)
- Published
- 2022
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13. miR-21 antagonism reprograms macrophage metabolism and abrogates chronic allograft vasculopathy.
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Usuelli V, Ben Nasr M, D'Addio F, Liu K, Vergani A, El Essawy B, Yang J, Assi E, Uehara M, Rossi C, Solini A, Capobianco A, Rigamonti E, Potena L, Venturini M, Sabatino M, Bottarelli L, Ammirati E, Frigerio M, Castillo-Leon E, Maestroni A, Azzoni C, Loretelli C, Joe Seelam A, Tai AK, Pastore I, Becchi G, Corradi D, Visner GA, Zuccotti GV, Chau NB, Abdi R, Pezzolesi MG, and Fiorina P
- Subjects
- Allografts, Animals, Graft Rejection genetics, Graft Rejection prevention & control, Humans, Macrophages, Mice, Heart Transplantation adverse effects, MicroRNAs genetics
- Abstract
Despite much progress in improving graft outcome during cardiac transplantation, chronic allograft vasculopathy (CAV) remains an impediment to long-term graft survival. MicroRNAs (miRNAs) emerged as regulators of the immune response. Here, we aimed to examine the miRNA network involved in CAV. miRNA profiling of heart samples obtained from a murine model of CAV and from cardiac-transplanted patients with CAV demonstrated that miR-21 was most significantly expressed and was primarily localized to macrophages. Interestingly, macrophage depletion with clodronate did not significantly prolong allograft survival in mice, while conditional deletion of miR-21 in macrophages or the use of a specific miR-21 antagomir resulted in indefinite cardiac allograft survival and abrogated CAV. The immunophenotype, secretome, ability to phagocytose, migration, and antigen presentation of macrophages were unaffected by miR-21 targeting, while macrophage metabolism was reprogrammed, with a shift toward oxidative phosphorylation in naïve macrophages and with an inhibition of glycolysis in pro-inflammatory macrophages. The aforementioned effects resulted in an increase in M2-like macrophages, which could be reverted by the addition of L-arginine. RNA-seq analysis confirmed alterations in arginase-associated pathways associated with miR-21 antagonism. In conclusion, miR-21 is overexpressed in murine and human CAV, and its targeting delays CAV onset by reprogramming macrophages metabolism., (© 2021 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)
- Published
- 2021
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14. Pediatric lung transplant: Correlation of pretransplant condition with post-transplant outcomes.
- Author
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Freiberger D, Gould Delaney A, Forbes P, Manley D, and Visner GA
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- Activities of Daily Living, Adolescent, Child, Child, Preschool, Exercise, Female, Follow-Up Studies, Humans, Male, Mobility Limitation, Outcome Assessment, Health Care, Preoperative Period, Retrospective Studies, Walk Test, Young Adult, Lung Transplantation mortality, Patient Selection, Physical Fitness
- Abstract
Background: It is generally accepted that patients who have greater functional capacity are better candidates for lung transplantation. Accurate assessment of physical condition is important in identifying appropriate candidates for transplant. The focus of this study was to determine which measures of pretransplant physical condition correlate with positive post-transplant outcomes in children undergoing lung transplant., Methods: A retrospective chart review was done on 44 patients, ages 5 to 21 years. The pretransplant data collected included functional status, 6MWT, ambulatory status, and mechanical support. Post-transplant outcome data included time on the ventilator, days in the ICU, length of hospitalization, and 12-month survival., Results: Results were analyzed using Fisher exact and Kruskal-Wallis tests. Patients with limited ambulation had more days in the ICU compared to the most ambulatory group (P = .043). Patients independent or needing some help with ADL had less time on the ventilator compared to patients needing total help. (P = .014). Patients with 6MWT result greater than 500' had fewer ICU days (P = .044) and marginally better 12-month survival (P = .057). The 12-month survival of children needing invasive ventilatory support pretransplant was not significantly worse than those who did not; however, they required significantly more time on the ventilator (P = .004), days in ICU (P = .013), and longer hospitalization., Discussion: This study demonstrated that pretransplant physical condition affects post-transplant outcomes in children. Measures associated with positive post-transplant outcomes were identified and could be beneficial in determining which patients are optimal candidates for lung transplant., (© 2020 Wiley Periodicals LLC.)
- Published
- 2021
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15. Current evaluation and management of plastic bronchitis in the pediatric population.
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Li Y, Williams RJ, Dombrowski ND, Watters K, Daly KP, Irace AL, Visner GA, Rahbar R, and Fynn-Thompson F
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- Asthma complications, Bronchitis complications, Bronchoscopy, Child, Child, Preschool, Female, Heart Transplantation, Humans, Infant, Male, Respiration Disorders complications, Retrospective Studies, Symptom Assessment, Univentricular Heart diagnosis, Univentricular Heart therapy, Bronchitis diagnosis, Bronchitis therapy, Univentricular Heart complications
- Abstract
Objective: To describe a multidisciplinary approach for the treatment of plastic bronchitis (PB) in children., Methods: Retrospective chart review of children with PB between 1997 and 2017. Data regarding clinical presentation, diagnosis, management, and outcomes were analyzed., Results: Of 34 patients presenting with PB, 24 had single ventricle (SV) heart disease, 9 had pulmonary disease, and one had no underlying disease. Median (IQR: interquartile range) age at the time of PB diagnosis was 5.5 years (IQR: 9.0). Presenting symptoms included cough productive of casts (n = 27, 79%), wheezing (n = 5, 15%), dyspnea (n = 18, 53%), hypoxia (n = 31, 91%), and respiratory failure (n = 9, 26%). Diagnosis was made based on clinical evaluation, bronchoscopy findings, and/or pathology of casts. Treatment methods included bronchoscopy for cast removal (25% of SV patients, 91% of non-SV patients), chest physiotherapy (SV: 92%, non-SV: 45%), albuterol (SV: 79%, non-SV: 73%), inhaled steroids (SV: 75%, non-SV: 18%), nebulized hypertonic saline (SV: 29%, non-SV: 9%), nebulized heparin (SV: 8%, non-SV: 55%), nebulized tissue plasminogen activator (tPA; SV: 33%, non-SV: 9%), inhaled Dornase Alfa (SV: 54%, non-SV: 9%), antibiotics (SV: 46%, non-SV: 45%), systemic steroids (SV: 13%, non-SV: 45%), and lymphatic embolization (SV: 8%, non-SV: 45%). Of SV patients, 11 had no recurrence, 5 underwent heart transplantation, one awaits transplant, and 3 died due to cardiac disease. Three patients with respiratory disease had recurrent PB and one died from MRSA pneumonia., Conclusion: PB is a highly morbid disease with limited treatment options. Bronchoscopy and chest physiotherapy for airway clearance are among the most-utilized therapies., Competing Interests: Declaration of competing interest None., (Copyright © 2019. Published by Elsevier B.V.)
- Published
- 2020
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16. Mitochondrial transplantation enhances murine lung viability and recovery after ischemia-reperfusion injury.
- Author
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Moskowitzova K, Orfany A, Liu K, Ramirez-Barbieri G, Thedsanamoorthy JK, Yao R, Guariento A, Doulamis IP, Blitzer D, Shin B, Snay ER, Inkster JAH, Iken K, Packard AB, Cowan DB, Visner GA, Del Nido PJ, and McCully JD
- Subjects
- Acute Lung Injury metabolism, Acute Lung Injury physiopathology, Animals, Apoptosis physiology, Bronchoalveolar Lavage Fluid, Chemokines metabolism, Cytokines metabolism, Disease Models, Animal, Lung metabolism, Male, Mice, Mice, Inbred C57BL, Mitochondria metabolism, Neutrophil Infiltration physiology, Reperfusion Injury metabolism, Respiratory Function Tests methods, Lung physiopathology, Mitochondria physiology, Reperfusion Injury physiopathology
- Abstract
The most common cause of acute lung injury is ischemia-reperfusion injury (IRI), during which mitochondrial damage occurs. We have previously demonstrated that mitochondrial transplantation is an efficacious therapy to replace or augment mitochondria damaged by IRI, allowing for enhanced muscle viability and function in cardiac tissue. Here, we investigate the efficacy of mitochondrial transplantation in a murine lung IRI model using male C57BL/6J mice. Transient ischemia was induced by applying a microvascular clamp on the left hilum for 2 h. Upon reperfusion mice received either vehicle or vehicle-containing mitochondria either by vascular delivery (Mito V) through the pulmonary artery or by aerosol delivery (Mito Neb) via the trachea (nebulization). Sham control mice underwent thoracotomy without hilar clamping and were ventilated for 2 h before returning to the cage. After 24 h recovery, lung mechanics were assessed and lungs were collected for analysis. Our results demonstrated that at 24 h of reperfusion, dynamic compliance and inspiratory capacity were significantly increased and resistance, tissue damping, elastance, and peak inspiratory pressure (Mito V only) were significantly decreased ( P < 0.05) in Mito groups as compared with their respective vehicle groups. Neutrophil infiltration, interstitial edema, and apoptosis were significantly decreased ( P < 0.05) in Mito groups as compared with vehicles. No significant differences in cytokines and chemokines between groups were shown. All lung mechanics results in Mito groups except peak inspiratory pressure in Mito Neb showed no significant differences ( P > 0.05) as compared with Sham. These results conclude that mitochondrial transplantation by vascular delivery or nebulization improves lung mechanics and decreases lung tissue injury.
- Published
- 2020
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17. Descending Aortopexy and Posterior Tracheopexy for Severe Tracheomalacia and Left Mainstem Bronchomalacia.
- Author
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Shieh HF, Smithers CJ, Hamilton TE, Zurakowski D, Visner GA, Manfredi MA, Jennings RW, and Baird CW
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- Bronchomalacia diagnostic imaging, Bronchomalacia physiopathology, Bronchoscopy, Child, Preschool, Female, Humans, Infant, Male, Recovery of Function, Retrospective Studies, Sternotomy, Thoracotomy, Tracheomalacia diagnostic imaging, Tracheomalacia physiopathology, Treatment Outcome, Aorta surgery, Bronchomalacia surgery, Suture Techniques, Tracheomalacia surgery, Vascular Surgical Procedures
- Abstract
Posterior descending aortopexy can relieve posterior intrusion of the left mainstem bronchus that may limit the effectiveness of posterior tracheobronchopexy. We review outcomes of patients undergoing both descending aortopexy and posterior tracheopexy for severe tracheobronchomalacia with posterior intrusion and left mainstem compression to determine if there were resolution of clinical symptoms and bronchoscopic evidence of improvement in airway collapse. All patients who underwent both descending aortopexy and posterior tracheopexy from October 2012 to October 2016 were retrospectively reviewed. Clinical symptoms, tracheomalacia scores based on standardized dynamic airway evaluation by anatomical region, and persistent airway intrusion requiring reoperation were collected. Data were analyzed by Wald and Wilcoxon signed-rank tests. Thirty-two patients underwent descending aortopexy and posterior tracheopexy at median age of 18 months (interquartile range 6-40 months). Median follow-up was 3 months (interquartile range 1-7 months). There were statistically significant improvements in clinical symptoms postoperatively, including cough, noisy breathing, prolonged and recurrent respiratory infections, ventilator dependence, blue spells, and brief resolved unexplained events (all P < 0.001), as well as exercise intolerance (P = 0.033), transient respiratory distress requiring positive pressure (P = 0.003), and oxygen dependence (P = 0.007). Total tracheomalacia scores improved significantly (P < 0.001), with significant segmental improvements in the middle (P = 0.003) and lower (P < 0.001) trachea, and right (P = 0.011) and left (P < 0.001) mainstem bronchi. Two patients (6%) had persistent airway intrusion requiring reoperation with anterior aortopexy or tracheopexy. Descending aortopexy and posterior tracheopexy are effective in treating severe tracheobronchomalacia and left mainstem intrusion with significant improvements in clinical symptoms and degree of airway collapse on bronchoscopy., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2019
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18. Mitochondrial transplantation prolongs cold ischemia time in murine heart transplantation.
- Author
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Moskowitzova K, Shin B, Liu K, Ramirez-Barbieri G, Guariento A, Blitzer D, Thedsanamoorthy JK, Yao R, Snay ER, Inkster JAH, Orfany A, Zurakowski D, Cowan DB, Packard AB, Visner GA, Del Nido PJ, and McCully JD
- Subjects
- Animals, Disease Models, Animal, Male, Mice, Mice, Inbred C57BL, Microscopy, Electron, Transmission, Mitochondria, Heart ultrastructure, Cold Ischemia adverse effects, Heart Transplantation, Mitochondria, Heart transplantation, Organ Preservation methods
- Abstract
Background: Cold ischemia time (CIT) causes ischemia‒reperfusion injury to the mitochondria and detrimentally effects myocardial function and tissue viability. Mitochondrial transplantation replaces damaged mitochondria and enhances myocardial function and tissue viability. Herein we investigated the efficacy of mitochondrial transplantation in enhancing graft function and viability after prolonged CIT., Methods: Heterotopic heart transplantation was performed in C57BL/6J mice. Upon heart harvesting from C57BL/6J donors, 0.5 ml of either mitochondria (1 × 10
8 in respiration buffer; mitochondria group) or respiration buffer (vehicle group) was delivered antegrade to the coronary arteries via injection to the coronary ostium. The hearts were excised and preserved for 29 ± 0.3 hours in cold saline (4°C). The hearts were then heterotopically transplanted. A second injection of either mitochondria (1 × 108 ) or respiration buffer (vehicle) was delivered antegrade to the coronary arteries 5 minutes after transplantation. Grafts were analyzed for 24 hours. Beating score, graft function, and tissue injury were measured., Results: Beating score, calculated ejection fraction, and shortening fraction were significantly enhanced (p < 0.05), whereas necrosis and neutrophil infiltration were significantly decreased (p < 0.05) in the mitochondria group as compared with the vehicle group at 24 hours of reperfusion. Transmission electron microscopy showed the presence of contraction bands in vehicle but not in mitochondria grafts., Conclusions: Mitochondrial transplantation prolongs CIT to 29 hours in the murine heart transplantation model, significantly enhances graft function, and decreases graft tissue injury. Mitochondrial transplantation may provide a means to reduce graft failure and improve transplantation outcomes after prolonged CIT., (Copyright © 2018 Elsevier Ltd. All rights reserved.)- Published
- 2019
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19. Purinergic P2X4 receptors and mitochondrial ATP production regulate T cell migration.
- Author
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Ledderose C, Liu K, Kondo Y, Slubowski CJ, Dertnig T, Denicoló S, Arbab M, Hubner J, Konrad K, Fakhari M, Lederer JA, Robson SC, Visner GA, and Junger WG
- Subjects
- Adenosine Triphosphate genetics, Animals, Autocrine Communication genetics, CD4-Positive T-Lymphocytes cytology, Humans, Inflammation genetics, Inflammation immunology, Jurkat Cells, Mice, Mice, Inbred BALB C, Mitochondria genetics, Receptors, Purinergic P2X4 genetics, Adenosine Triphosphate immunology, Autocrine Communication immunology, CD4-Positive T-Lymphocytes immunology, Cell Movement immunology, Mitochondria immunology, Receptors, Purinergic P2X4 immunology
- Abstract
T cells must migrate in order to encounter antigen-presenting cells (APCs) and to execute their varied functions in immune defense and inflammation. ATP release and autocrine signaling through purinergic receptors contribute to T cell activation at the immune synapse that T cells form with APCs. Here, we show that T cells also require ATP release and purinergic signaling for their migration to APCs. We found that the chemokine stromal-derived factor-1α (SDF-1α) triggered mitochondrial ATP production, rapid bursts of ATP release, and increased migration of primary human CD4+ T cells. This process depended on pannexin-1 ATP release channels and autocrine stimulation of P2X4 receptors. SDF-1α stimulation caused localized accumulation of mitochondria with P2X4 receptors near the front of cells, resulting in a feed-forward signaling mechanism that promotes cellular Ca2+ influx and sustains mitochondrial ATP synthesis at levels needed for pseudopod protrusion, T cell polarization, and cell migration. Inhibition of P2X4 receptors blocked the activation and migration of T cells in vitro. In a mouse lung transplant model, P2X4 receptor antagonist treatment prevented the recruitment of T cells into allograft tissue and the rejection of lung transplants. Our findings suggest that P2X4 receptors are therapeutic targets for immunomodulation in transplantation and inflammatory diseases.
- Published
- 2018
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20. Anellovirus loads are associated with outcomes in pediatric lung transplantation.
- Author
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Blatter JA, Sweet SC, Conrad C, Danziger-Isakov LA, Faro A, Goldfarb SB, Hayes D Jr, Melicoff E, Schecter M, Storch G, Visner GA, Williams NM, and Wang D
- Subjects
- Adolescent, Anelloviridae immunology, Biomarkers, Child, Child, Preschool, Female, Follow-Up Studies, Graft Rejection immunology, Humans, Immune Tolerance, Immunosuppression Therapy, Infant, Infant, Newborn, Kaplan-Meier Estimate, Male, Outcome Assessment, Health Care, Reoperation statistics & numerical data, Retrospective Studies, Anelloviridae isolation & purification, Graft Rejection virology, Lung Transplantation mortality, Viral Load
- Abstract
Anelloviruses are DNA viruses ubiquitously present in human blood. Due to their elevated levels in immunosuppressed patients, anellovirus levels have been proposed as a marker of immune status. We hypothesized that low anellovirus levels, reflecting relative immunocompetence, would be associated with adverse outcomes in pediatric lung transplantation. We assayed blood samples from 57 patients in a multicenter study for alpha- and betatorquevirus, two anellovirus genera. The primary short-term outcome of interest was acute rejection, and longer-term outcomes were analyzed individually and as "composite" (death, chronic rejection, or retransplant within 2 years). Patients with low alphatorquevirus levels at 2 weeks post-transplantation were more likely to develop acute rejection within 3 months after transplant (P = .013). Low betatorquevirus levels at 6 weeks and 6 months after transplant were associated with death (P = .047) and the composite outcome (P = .017), respectively. There was an association between low anellovirus levels and adverse outcomes in pediatric lung transplantation. Alphatorquevirus levels were associated with short-term outcomes (ie, acute rejection), while betatorquevirus levels were associated with longer-term outcomes (ie, death, or composite outcome within 2 years). These observations suggest that anelloviruses may serve as useful biomarkers of immune status and predictors of adverse outcomes., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2018
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21. Posterior Tracheopexy for Severe Tracheomalacia Associated with Esophageal Atresia (EA): Primary Treatment at the Time of Initial EA Repair versus Secondary Treatment.
- Author
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Shieh HF, Smithers CJ, Hamilton TE, Zurakowski D, Visner GA, Manfredi MA, Baird CW, and Jennings RW
- Abstract
Purpose: We review outcomes of posterior tracheopexy for tracheomalacia in esophageal atresia (EA) patients, comparing primary treatment at the time of initial EA repair versus secondary treatment., Methods: All EA patients who underwent posterior tracheopexy from October 2012 to September 2016 were retrospectively reviewed. Clinical symptoms, tracheomalacia scores, and persistent airway intrusion were collected. Indication for posterior tracheopexy was the presence of clinical symptoms, in combination with severe tracheomalacia as identified on bronchoscopic evaluation, typically defined as coaptation in one or more regions of the trachea. Secondary cases were usually those with chronic respiratory symptoms who underwent bronchoscopic evaluation, whereas primary cases were those found to have severe tracheomalacia on routine preoperative dynamic tracheobronchoscopy at the time of initial EA repair., Results: A total of 118 patients underwent posterior tracheopexy: 18 (15%) primary versus 100 (85%) secondary cases. Median (interquartile range) age was 2 months (1-4 months) for primary (22% type C) and 18 months (8-40 months) for secondary (87% type C) cases ( p < 0.001). There were statistically significant improvements in most clinical symptoms postoperatively for primary and secondary cases, with no significant differences in any postoperative symptoms between the two groups ( p > 0.1). Total tracheomalacia scores improved significantly in primary ( p = 0.013) and secondary ( p < 0.001) cases. Multivariable Cox regression analysis indicated no differences in persistent airway intrusion requiring reoperation between primary and secondary tracheopexy adjusting for imbalances in age and EA type ( p = 0.67)., Conclusion: Posterior tracheopexy is effective in treating severe tracheomalacia with significant improvements in clinical symptoms and degree of airway collapse on bronchoscopy. With no significant differences in outcomes between primary and secondary treatment, posterior tracheopexy should be selectively considered at the time of initial EA repair.
- Published
- 2018
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22. Transplant center volume and outcomes in lung transplantation for cystic fibrosis.
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Hayes D Jr, Sweet SC, Benden C, Kopp BT, Goldfarb SB, Visner GA, Mallory GB, Tobias JD, and Tumin D
- Subjects
- Adolescent, Adult, Child, Female, Humans, Lung surgery, Male, Middle Aged, Multivariate Analysis, Proportional Hazards Models, Registries, Retrospective Studies, Risk Factors, Survival Analysis, Transplants, Treatment Outcome, United States, Young Adult, Cystic Fibrosis surgery, Hospitals statistics & numerical data, Lung Transplantation
- Abstract
Transplant volume represents lung transplant (LTx) expertise and predicts outcomes, so we sought to determine outcomes related to center volumes in cystic fibrosis (CF). United Network for Organ Sharing data were queried for patients with CF in the United States (US) receiving bilateral LTx from 2005 to 2015. Multivariable Cox regression was used to model survival to 1 year and long-term (>1 year) survival, conditional on surviving at least 1 year. A total of 2025 patients and 67 centers were included in the analysis. The median annual LTx volumes were three in CF [interquartile range (IQR): 2, 6] and 17 in non-CF (IQR: 8, 33). Multivariable Cox regression in cases with complete data and surviving at least 1 year (n = 1510) demonstrated that greater annual CF LTx volume (HR per 10 LTx = 0.66; 95% CI: 0.49, 0.89; P = 0.006) but not greater non-CF LTx volume (HR = 1.00; 95% CI: 0.96, 1.05; P = 0.844) was associated with improved long-term survival in LTx recipients with CF. A Wald interaction test confirmed that CF LTx volume was more strongly associated with long-term outcomes than non-CF LTx volume (P = 0.012). In a US cohort, center volume was not associated with 1-year survival. CF-specific expertise predicted improved long-term outcomes of LTx for CF, whereas general LTx expertise was unassociated with CF patients' survival., (© 2016 Steunstichting ESOT.)
- Published
- 2017
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23. Paracorporeal lung assist device in infants and toddlers: Coming of age?
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Visner GA and Fynn-Thompson F
- Subjects
- Child, Preschool, Heart-Assist Devices, Humans, Infant, Extracorporeal Membrane Oxygenation, Lung
- Published
- 2016
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24. Inhibition of the purinergic pathway prolongs mouse lung allograft survival.
- Author
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Liu K, Vergani A, Zhao P, Ben Nasr M, Wu X, Iken K, Jiang D, Su X, Fotino C, Fiorina P, and Visner GA
- Subjects
- Adenosine Triphosphate pharmacology, Allografts, Animals, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Graft Rejection immunology, Graft Rejection metabolism, Graft Rejection pathology, Histocompatibility, Lung immunology, Lung metabolism, Lung pathology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Receptors, Purinergic P2X7 metabolism, Time Factors, Adenosine Triphosphate analogs & derivatives, Graft Rejection prevention & control, Graft Survival drug effects, Immunosuppressive Agents pharmacology, Lung drug effects, Lung Transplantation adverse effects, Purinergic P2X Receptor Antagonists pharmacology, Receptors, Purinergic P2X7 drug effects, Signal Transduction drug effects, Suramin pharmacology
- Abstract
Lung transplantation has limited survival with current immunosuppression. ATP is released from activated T cells, which act as costimulatory molecules through binding to the purinergic receptor P2XR7. We investigated the role of blocking the ATP/purinergic pathway, primarily P2XR7, using its inhibitor oxidized ATP (oATP) in modulating rejection of mouse lung allografts. Mouse lung transplants were performed using mice with major histocompatibility complex mismatch, BALB/c to C57BL6. Recipients received suramin or oATP, and lung allografts were evaluated 15 to ≥ 60 days after transplantation. Recipients were also treated with oATP after the onset of moderate to severe rejection to determine its ability to rescue lung allografts. Outcomes measures included lung function, histology, thoracic imaging, and allo-immune responses. Blocking purinergic receptors with the nonselective inhibitor suramin or with the P2XR7-selective inhibitor oATP reduced acute rejection and prolonged lung allograft survival for ≥ 60 days with no progression in severity. There were fewer inflammatory cells within lung allografts, less rejection, and improved lung function, which was maintained over time. CD4 and CD8 T cells were reduced within lung allografts with impaired activation with prolonged impairment of CD8 responses. In vitro, oATP reduced CD8 activation of Th1 inflammatory cytokines IFN-γ and TNF-α and cytolytic machinery, granzyme B. Cotreatment with immunosuppressive agents, cyclosporine, rapamycin, or CTLA-4Ig resulted in no additive benefits, and oATP alone resulted in better outcomes than cyclosporine alone. This study illustrates a potential new pathway to target in hopes of prolonging survival of lung transplant recipients.
- Published
- 2014
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25. Indoleamine 2,3-dioxygenase and metabolites protect murine lung allografts and impair the calcium mobilization of T cells.
- Author
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Iken K, Liu K, Liu H, Bizargity P, Wang L, Hancock WW, and Visner GA
- Subjects
- 3-Hydroxyanthranilic Acid pharmacology, Animals, Antigens, CD metabolism, Cells, Cultured, Coculture Techniques, Cytokines metabolism, Graft Rejection enzymology, Graft Rejection immunology, Immunosuppressive Agents pharmacology, Indoleamine-Pyrrole 2,3,-Dioxygenase genetics, Lung enzymology, Lung metabolism, Lung pathology, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Receptors, Antigen, T-Cell antagonists & inhibitors, Receptors, Antigen, T-Cell metabolism, Recombinant Proteins biosynthesis, Recombinant Proteins genetics, T-Lymphocytes metabolism, Transplantation, Homologous, 3-Hydroxyanthranilic Acid therapeutic use, Calcium Signaling, Graft Rejection prevention & control, Immunosuppressive Agents therapeutic use, Indoleamine-Pyrrole 2,3,-Dioxygenase biosynthesis, Lung Transplantation, T-Lymphocytes immunology
- Abstract
The enzyme indoleamine 2,3-dioxygenase (IDO) converts tryptophan into kynurenine metabolites that suppress effector T-cell function. In this study, we investigated IDO and its metabolite, 3-hydroxyanthranilic acid (3HAA), in regulating lung allograft rejection, using a murine orthotopic lung transplant model with a major mismatch (BALB/c donor and C57BL6 recipient). IDO was overexpressed in murine donor lungs, using an established nonviral (polyethylenimine carrier)-based gene transfer approach, whereas 3HAA was delivered daily via intraperitoneal injection. Increased IDO expression or its metabolite, 3HAA, resulted in a remarkable therapeutic effect with near normal lung function and little acute rejection, approximately A1, compared with A3 in untreated allografts (grading based on International Society for Heart and Lung Transplantation guidelines). We found that a high IDO environment for 7 days in lung allografts resulted in impaired T-cell activation, the production of multiple effector cytokines (IL-2, IL-4, IL-5, IL-6, IFN-γ, TNF-α, IL-12, and IL-13), and the generation of effector memory T cells (CD62L(lo)CD44(hi) phenotype). In isolated murine splenocytes, we observed that IDO/3HAA impaired T-cell receptor (TCR)-mediated T-cell activation, and more importantly, a decrease of intracellular calcium, phospholipase C-γ1 phosphorylation, and mitochondrial mass was evident. This work further illustrates the potential role of a high IDO environment in lung transplantation, and that the high IDO environment directly impairs TCR activation via the disruption of calcium signaling.
- Published
- 2012
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26. Inhibitory effects of pirfenidone on dendritic cells and lung allograft rejection.
- Author
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Bizargity P, Liu K, Wang L, Hancock WW, and Visner GA
- Subjects
- Animals, Cell Communication drug effects, Cytokines biosynthesis, Dendritic Cells immunology, Dendritic Cells physiology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, T-Lymphocytes drug effects, Transplantation, Homologous, Dendritic Cells drug effects, Graft Rejection prevention & control, Lung Transplantation adverse effects, Pyridones pharmacology
- Abstract
Background: Pirfenidone (PFD) is an antifibrotic agent with beneficial effects on proinflammatory disorders. In this study, we further investigated PFD and long-acting form, "deuterated PFD," immune-modulating properties by evaluating their effects on mouse dendritic cells (DCs)., Methods: The effects of PFD on DCs were examined in vivo using an orthotopic mouse lung transplant model and in vitro using isolated bone marrow-derived DCs in response to lipopolysaccharide and allogeneic stimulation., Results: In mouse lung transplants, PFD and deuterated PFD treatment improved allograft lung function based on peak airway pressure, less infiltrates/consolidation on micro-computed tomography scan imaging, and reduced lung rejection/injury. DC activation from lung allografts was suppressed with PFD, and there seemed to be a greater effect of PFD on CD11c(+)CD11b(-)CD103(+) lung DCs. In addition, PFD reduced the expression of several proinflammatory cytokines/chemokines from lung allografts. In vitro, DCs treated with PFD showed decreased expression of major histocompatibility complex class II and costimulatory molecules and the capacity of these DCs to stimulate T-cell activation was impaired, although antigen uptake was preserved. PFD directly inhibited the release of inflammatory cytokines from isolated DCs, was associated with a reduction of stress protein kinases, and attenuated lipopolysaccharide-dependent mitogen-activated protein kinase p38 phosphorylation., Conclusions: PFD has lung allograft protective properties, and in addition to its known effects on T-cell biology, PFD immune-modulating activities encompass inhibitory effects on DC activation and function.
- Published
- 2012
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27. Pirfenidone inhibits T-cell activation, proliferation, cytokine and chemokine production, and host alloresponses.
- Author
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Visner GA, Liu F, Bizargity P, Liu H, Liu K, Yang J, Wang L, and Hancock WW
- Subjects
- Adoptive Transfer, Animals, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes immunology, Cells, Cultured, Drug Therapy, Combination, Graft Rejection immunology, Histocompatibility drug effects, Isoantigens immunology, Lymphocyte Culture Test, Mixed, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Sirolimus pharmacology, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets transplantation, T-Lymphocytes, Regulatory drug effects, T-Lymphocytes, Regulatory immunology, Time Factors, Cell Proliferation drug effects, Chemokines metabolism, Cytokines metabolism, Graft Rejection prevention & control, Heart Transplantation, Immunosuppressive Agents pharmacology, Lymphocyte Activation drug effects, Pyridones pharmacology, T-Lymphocyte Subsets drug effects
- Abstract
Background: We previously showed that pirfenidone, an anti-fibrotic agent, reduces lung allograft injury or rejection. In this study, we tested the hypothesis that pirfenidone has immune modulating activities and evaluated its effects on the function of T-cell subsets, which play important roles in allograft rejection., Method: We first evaluated whether pirfenidone alters T-cell proliferation and cytokine release in response to T-cell receptor (TCR) activation, and whether pirfenidone alters regulatory T cells (CD4CD25) suppressive effects using an in vitro assay. Additionally, pirfenidone effects on alloantigen-induced T-cell proliferation in vivo were assessed by adoptive transfer of carboxyfluorescein diacetate succinimidyl ester-labeled T cells across a parent->F1 major histocompatibility complex mismatch, as well as using a murine heterotopic cardiac allograft model (BALB/c->C57BL/6)., Results: Pirfenidone was found to inhibit the responder frequency of TCR-stimulated CD4 cell total proliferation in vitro and in vivo, whereas both CD4 and CD8 proliferation index were reduced by pirfenidone. Additionally, pirfenidone inhibited TCR-induced production of multiple pro-inflammatory cytokines and chemokines. Interestingly, there was no change on transforming growth factor-beta production by purified T cells, and pirfenidone had no effect on the suppressive properties of naturally occurring regulatory T cells. Pirfenidone alone showed a small but significant (P<0.05) effect on the in vivo allogeneic response, whereas the combination of pirfenidone and low dose rapamycin had more remarkable effect in reducing the alloantigen response with prolonged graft survival., Conclusion: Pirfenidone may be an important new agent in transplantation, with particular relevance to combating chronic rejection by inhibiting both fibroproliferative and alloimmune responses.
- Published
- 2009
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28. Reduced cytotoxic function of effector CD8+ T cells is responsible for indoleamine 2,3-dioxygenase-dependent immune suppression.
- Author
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Liu H, Liu L, Liu K, Bizargity P, Hancock WW, and Visner GA
- Subjects
- Animals, Cell Proliferation, Cell Survival, Electron Transport Complex I, Humans, Immunity, Indoleamine-Pyrrole 2,3,-Dioxygenase administration & dosage, Indoleamine-Pyrrole 2,3,-Dioxygenase genetics, Lung Transplantation immunology, Rats, Rats, Inbred Lew, Rats, Sprague-Dawley, Rats, Transgenic, T-Lymphocytes, Cytotoxic cytology, Transgenes, Cytotoxicity, Immunologic, Indoleamine-Pyrrole 2,3,-Dioxygenase immunology, T-Lymphocytes, Cytotoxic immunology
- Abstract
Indoleamine 2,3-dioxygenase (IDO), a potent immunosuppressive enzyme, contributes to tumoral escape, immune tolerance, and protection against allograft injury. In this paper, we report that inhibition of CD8(+) T cell-mediated cytotoxic function is an important mechanism behind IDO's immune-modulating property. The experimental rat lung allograft proved attractive for evaluating effector CD8(+) T cells. Enhanced IDO activity achieved by using a lung-tissue-targeted nonviral human IDO gene transfer approach reduced, but did not eliminate, infiltrating CD8(+) T cells. Although CD8(+) T cells existed in the IDO-high lung allografts, CD8(+) T cells remained viable and could proliferate for an extended period. However, cells lost their ability to attack allogeneic donor lung cells in vivo and allogeneic target cells in vitro. The impaired cytotoxic function seen in the IDO-treated CD8(+) T cells was accompanied by defects in production of granule cytotoxic proteins, including perforin and granzyme A and B. Furthermore, we discovered that IDO leads to an impaired bioenergetic condition in active CD8(+) T cells via selective inhibition of complex I in the mitochondrial electron transfer chain. These intriguing findings provide a base for establishing a novel mode of IDO's immune-suppressing action. Additionally, donor lung IDO delivery, a direct and/or leukocyte passenger effect, impaired CD8(+) effector cell function.
- Published
- 2009
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29. Nonviral gene delivery with indoleamine 2,3-dioxygenase targeting pulmonary endothelium protects against ischemia-reperfusion injury.
- Author
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Liu H, Liu L, and Visner GA
- Subjects
- Animals, Blood Urea Nitrogen, Lung Transplantation pathology, Male, Plasmids, Polymerase Chain Reaction, Rats, Rats, Inbred Lew, Transfection methods, Endothelium, Vascular enzymology, Indoleamine-Pyrrole 2,3,-Dioxygenase genetics, Lung Transplantation physiology, Pulmonary Circulation physiology, Reperfusion Injury prevention & control
- Abstract
Pulmonary endothelial dysfunction induced by inflammation and inflammation-associated reactive oxygen species is a central component in the pathophysiology of lung transplant ischemia-reperfusion (IR) injury. Indoleamine-2,3-dioxygenase (IDO) is a unique cytosolic enzyme possessing both immune modulating and antioxidant properties. This study investigated whether enhanced pulmonary endothelial IDO activity by a targeted nonviral gene transfer approach ameliorates lung IR injury. Orthotopic syngeneic lung transplants were performed in Lewis rats. A human IDO (hIDO)-expressing plasmid driven by an endothelial cell-specific endothelin-1 promoter was generated and intravenously delivered to donor lung using cationic polymer polyethylenimine. This nonviral gene transfer approach augmented hIDO expression specifically in endothelial cells within lung grafts. Importantly, enhanced IDO activity induced by the hIDO transgene prevented endothelial cell apoptosis, reduced vascular permeability and leukocyte extravasation, and consequently improved graft function and histologic appearance. Furthermore, our in vitro studies showed that increased IDO activity in endothelial cells protected its mitochondrial function and ultrastructure from oxidative stress through stabilization of intracellular redox status. The approach used in these experiments has properties that could eliminate the inherent side effects associated with viral vectors and/or antibody-directed targeted therapy, and thus may represent a potential therapeutic strategy against lung IR injury in patients.
- Published
- 2007
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30. Applications of Sleeping Beauty transposons for nonviral gene therapy.
- Author
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Liu H and Visner GA
- Subjects
- Genetic Vectors genetics, Genetic Vectors metabolism, Humans, Transposases genetics, Transposases metabolism, DNA Transposable Elements, Genetic Therapy methods
- Abstract
Virus-based gene therapy has advanced to clinical trials; however, this approach may result in serious adverse events including oncogenesis and the possibility of triggering fatal immune responses. Nonviral gene delivery approaches have a better safety profile, but their in vivo application has been largely limited in the past due to their inefficient delivery into cells and lack of stable chromosomal integration that is necessary for long-term therapeutic benefit. However, recent advances suggest that the use of Sleeping Beauty transposons, a novel integrating nonviral vector system, are capable of achieving long-lasting therapeutic levels of transgene expression in preclinical settings. These observations and other ongoing relevant studies may unlock the therapeutic potential of nonviral gene therapy for human diseases.
- Published
- 2007
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31. Sleeping Beauty-based gene therapy with indoleamine 2,3-dioxygenase inhibits lung allograft fibrosis.
- Author
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Liu H, Liu L, Fletcher BS, and Visner GA
- Subjects
- Animals, Animals, Genetically Modified, DNA Transposable Elements, Humans, Rats, Transplantation, Homologous pathology, Fibrosis prevention & control, Genetic Therapy methods, Indoleamine-Pyrrole 2,3,-Dioxygenase genetics, Indoleamine-Pyrrole 2,3,-Dioxygenase therapeutic use, Lung Neoplasms pathology, Transposases genetics
- Abstract
Sleeping Beauty (SB) transposon is a natural nonviral gene transfer system that can mediate long-term transgene expression. Its potential utility in treating organ transplantation-associated long-term complications has not yet been explored. In the present study we generated an improved SB transposon encoding the human gene indoleamine-2,3-dioxygenase (hIDO), an enzyme that possesses both T cell-suppressive and antioxidant properties and selectively delivered the SB transposon in combination with a hyperactive transposase plasmid to donor lung using the cationic polymer polyethylenimine (PEI) as transfection reagent. This nonviral gene therapeutic approach led to persistent and uniform transgene expression in the rat lung tissue without noticeable toxicity and inflammation. Importantly, IDO activity produced by hIDO transgene showed a remarkable therapeutic response, as evident by near normal pulmonary function (peak airway pressure and oxygenation), histological appearance, and reduced collagen content in lung allografts. In addition, we established a hIDO-overexpressing type II cell line using the SB-based gene transfer system and found that hIDO-overexpressing lung cells effectively inhibited transforming growth factor-beta-stimulated fibroblast proliferation in vitro. In summary, the SB-based gene therapy with hIDO represents a new strategy for treating lung transplantation-associated chronic complications, e.g., obliterative bronchiolitis.
- Published
- 2006
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32. Bone marrow stem cells as a vehicle for delivery of heme oxygenase-1 gene.
- Author
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Zhou H, Ramiya VK, and Visner GA
- Subjects
- Adenoviridae chemistry, Adult, Animals, Bone Marrow Cells, Cell Differentiation, Fluoresceins chemistry, Heme Oxygenase-1 genetics, Humans, Male, Mesenchymal Stem Cells metabolism, Rats, Rats, Inbred Lew, Succinimides chemistry, Adenoviridae metabolism, Adipogenesis genetics, Heme Oxygenase-1 metabolism, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells physiology
- Abstract
Bone marrow-derived mesenchymal stem cells (MSCs) are readily accessible adult stem cells that are capable of self-renewal and multilineage differentiation. Human MSCs have been well described and used in xenogenic models for investigation, but rodent MSCs, if available, would eliminate problems associated with transplantation across a species barrier. Here we describe an effective method to generate rat MSCs and use these cells to target gene delivery in vivo. MSCs that were capable of retaining their differentiation potential after several population doublings in culture were generated from rat bone marrow. Marrow-derived MSCs were enriched and infected with an adenoviral vector carrying the heme oxygenase gene (Ad5/HO-1). Transfected rodent MSCs retained their differentiation potential, even after 10 passages, as determined by their ability to differentiate into adipocytes. Western analyses clearly indicated that Ad5/HO-1-transfected rodent MSCs exhibited increased HO-1 expression. Trafficking of fluorescent rat MSCs was evaluated 24 and 48 h after MSC infusion. Most of the infused cells accumulated in the lungs of recipients where they expressed HO-1. Thus, bone marrow-derived MSCs are useful for gene delivery replacement of the products of deficient genes. These cells may be useful for potentiation of wound healing because they retain their pluripotential differentiation ability.
- Published
- 2006
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33. Heme oxygenase-1 mediates the protective effects of rapamycin in monocrotaline-induced pulmonary hypertension.
- Author
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Zhou H, Liu H, Porvasnik SL, Terada N, Agarwal A, Cheng Y, and Visner GA
- Subjects
- Animals, Blotting, Northern, Cell Cycle, Cell Proliferation, Hypertension, Pulmonary enzymology, Hypertension, Pulmonary pathology, Male, Rats, Rats, Sprague-Dawley, Sirolimus pharmacology, Heme Oxygenase (Decyclizing) metabolism, Hypertension, Pulmonary drug therapy, Monocrotaline toxicity, Sirolimus therapeutic use
- Abstract
Rapamycin inhibits the development and progression of vascular disease. We previously showed that rapamycin induces the cytoprotective protein, heme oxygenase-1 (HO-1), and more importantly, chemically inhibiting HO-1 blocked the antiproliferative actions of rapamycin. In this study, we evaluated whether HO-1 is required for the vascular protective effects of rapamycin in vivo using a rat monocrotaline-induced pulmonary hypertension model. Rats were exposed to monocrotaline with or without rapamycin and HO activity was altered using the chemical inhibitor, tin protoporphyrin or the inducer, cobalt protoporphyrin. We also evaluated possible mechanisms of rapamycin-dependent induction of HO-1, and how HO-1 mediates growth factor-dependent antiproliferative actions of rapamycin. Proliferation and cell cycle progression were examined in smooth muscle cells derived from both wild-type and HO-1 knockout (HO-1-/-) mice in response to growth factors and rapamycin. Similar to our previous findings in vitro, rapamycin induced HO-1 in rat lung. Rapamycin also inhibited the development of monocrotaline-induced pulmonary hypertension, and this protective effect was blocked with the addition of tin protoporphyrin. In addition, treatment with cobalt protoporphyrin resulted in a substantial protection in this model of pulmonary hypertension. Rapamycin induction of HO-1 was dependent upon a transcriptional event; however, it was not mediated through an altered redox state or mammalian targets of rapamycin inhibition. Unlike wild-type cells, the growth of HO-1-/- mouse aortic smooth muscle cells was not inhibited or cell cycle arrested in G1 in response to rapamycin. This study demonstrates that HO-1 is critical for the antiproliferative and vascular protective effects of rapamycin in vitro and in vivo in monocrotaline-induced pulmonary hypertension.
- Published
- 2006
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34. Pirfenidone inhibits obliterative airway disease in mouse tracheal allografts.
- Author
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Zhou H, Latham CW, Zander DS, Margolin SB, and Visner GA
- Subjects
- Administration, Oral, Animals, Chronic Disease, Cyclosporine administration & dosage, Disease Models, Animal, Female, Graft Rejection blood, Immunosuppressive Agents administration & dosage, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Sirolimus administration & dosage, Transforming Growth Factor beta blood, Anti-Inflammatory Agents, Non-Steroidal administration & dosage, Graft Rejection prevention & control, Pyridones administration & dosage, Trachea transplantation
- Abstract
Background: Obliterative bronchiolitis (OB) is the histologic correlate of chronic airway rejection, which remains the most significant cause of death in long-term survivors of lung transplantation. Using an established murine heterotopic tracheal transplant model of chronic airway rejection, the effects of the oral anti-fibrotic agent pirfenidone on development of the OB-like lesion were evaluated., Methods: Tracheas from BALB/c mice were implanted into the sub-cutaneous tissue of C57BL/6 mice, and the allografts were evaluated morphologically for airway rejection changes and immunohistochemically for transforming growth factor (TGF)-beta at 16 or 28 days after transplantation. In addition, the potential additive effects of pirfenidone in combination with 2 immunosuppressive agents, cyclosporine or rapamycin, was evaluated., Results: Compared with untreated controls, pirfenidone-fed mice showed less epithelial cell injury and luminal granulation tissue and fibrosis. Plasma TGF-beta levels and local TGF-beta expression based on immunohistochemistry were decreased in the pirfenidone-treated animals. Pirfenidone given on Day 9 or 16 post-transplant through Day 28 resulted in no significant improvement compared with controls. There was no significant additive effect of pirfenidone in combination with cyclosporine, whereas pirfenidone plus rapamycin demonstrated additive protection against the development of the obstructive airway lesion., Conclusions: In aggregate, these results show that the anti-fibrotic agent pirfenidone inhibits the development of the OB-like lesion in this mouse model of human chronic airway rejection, and that these effects may be mediated by TGF-beta. The results also suggest that pirfenidone may be worthy of investigation in human lung transplant recipients at high risk of developing OB.
- Published
- 2005
- Full Text
- View/download PDF
35. Pirfenidone inhibits inflammatory responses and ameliorates allograft injury in a rat lung transplant model.
- Author
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Liu H, Drew P, Cheng Y, and Visner GA
- Subjects
- Animals, Graft Rejection pathology, Iron analysis, Lung metabolism, Lung pathology, Male, Neutrophil Infiltration, Oxidative Stress, Peroxidase analysis, Rats, Rats, Sprague-Dawley, Tumor Necrosis Factor-alpha analysis, Lung Transplantation, Pyridones pharmacology, Tumor Necrosis Factor-alpha antagonists & inhibitors
- Abstract
Objective: Tumor necrosis factor alpha is a proinflammatory cytokine that has been proved to play a crucial role in inducing posttransplantation lung injury. The present study was performed to determine whether pirfenidone, a new nonpeptide drug with potent anti-tumor necrosis factor alpha activity, promotes protection against acute allograft injury through inhibiting pulmonary inflammatory responses in a rat model of orthotopic lung transplantation., Methods: Three transplant groups were formed: isografts, untreated allografts, and allografts treated with pirfenidone (0.5% chow starting on day 1 after transplantation). The implants were harvested on day 21 after transplantation. Acute cellular rejection grade and degree of allograft injury were evaluated on the basis of hematoxylin-and-eosin staining. The pulmonary inflammatory response and inflammation-induced oxidative stress were assessed on the basis of neutrophil accumulation (myeloperoxidase immunoreactivity and enzymatic activity) and iron deposition (Prussian blue staining). In addition, circulating levels of tissue necrosis factor alpha in all animals were measured., Results: The degree of allograft injury was significantly reduced in pirfenidone-treated allografts relative to untreated allografts (P < .01). The beneficial effect of pirfenidone was associated with decreased lung myeloperoxidase immunoreactivity (P < .05) and enzymatic activity (P < .01). Moreover, the untreated allografts contained a high concentration of iron, which was strikingly reduced by pirfenidone. Treatment with pirfenidone resulted in a lower level of plasma tissue necrosis factor alpha, which correlated positively with lung myeloperoxidase enzymatic activity (P < .0001)., Conclusion: These results suggest that pirfenidone, with its anti-tissue necrosis factor alpha activity, reduced neutrophil recruitment and iron accumulation, hence limiting the acute lung allograft injury.
- Published
- 2005
- Full Text
- View/download PDF
36. Bone marrow-derived stem-cell repopulation contributes minimally to the Type II pneumocyte pool in transplanted human lungs.
- Author
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Zander DS, Baz MA, Cogle CR, Visner GA, Theise ND, and Crawford JM
- Subjects
- Adolescent, Adult, Chromosomes, Human, X, Chromosomes, Human, Y, Female, Humans, In Situ Hybridization, Fluorescence, Male, Middle Aged, Retrospective Studies, Tissue Donors, Lung Transplantation pathology, Lung Transplantation physiology, Stem Cell Transplantation, Transplantation Chimera
- Abstract
Background: Lung transplant recipients are vulnerable to immunologic, infectious, ischemic, and toxic pulmonary injuries. The authors investigated whether type II pneumocytes in the lungs of cross-gender lung transplant patients show genotypic evidence to support repopulation of the lung by stem cells of bone marrow origin, and whether the degree of repopulation was related to rejection history., Methods: Recut sections were obtained from lung biopsy specimens from seven male recipients of transplanted lungs from female donors. Sequential immunohistochemistry and fluorescence in situ hybridization was performed on each section to evaluate for Y-chromosome-containing type II pneumocytes., Results: Y-chromosome-containing type II pneumocytes were found in 9 of 25 biopsy specimens from 5 of 7 gender-mismatched male lung transplant recipients, and accounted for 0% to 0.553% of type II pneumocytes. There was no evidence of polyploidy to suggest cell-cell fusion. The number of type II pneumocytes of male karyotype showed a statistically significant relationship to the cumulative number of episodes of acute cellular rejection., Conclusions: Lung transplant recipients develop low levels of pneumocyte repopulation by bone marrow-derived stem cells or their progeny. These cells contribute minimally to the type II pneumocyte proliferation that is often present in these patients as a sequela to alveolar injury.
- Published
- 2005
- Full Text
- View/download PDF
37. Pirfenidone inhibits lung allograft fibrosis through L-arginine-arginase pathway.
- Author
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Liu H, Drew P, Gaugler AC, Cheng Y, and Visner GA
- Subjects
- Animals, Cells, Cultured, Collagen metabolism, Down-Regulation, Gene Expression Regulation, Graft Rejection immunology, Graft Rejection metabolism, Graft Rejection pathology, Male, Nitric Oxide Synthase metabolism, Nitric Oxide Synthase Type II, Pulmonary Fibrosis metabolism, Pulmonary Fibrosis pathology, Rats, Rats, Inbred Lew, Rats, Sprague-Dawley, Transforming Growth Factor beta metabolism, Transforming Growth Factor beta1, Transplantation, Homologous, Tumor Necrosis Factor-alpha antagonists & inhibitors, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Arginase metabolism, Arginine metabolism, Lung Transplantation pathology, Pulmonary Fibrosis prevention & control, Pyridones therapeutic use, Signal Transduction
- Abstract
Transplant-related lung fibrosis is characterized by excessive fibro-collagenous deposition. Induction of arginase, an enzyme that metabolizes L-arginine to urea and L-ornithine, is vital for collagen synthesis. Pirfenidone is an investigational anti-fibrotic agent shown to be effective in blocking pulmonary fibrosis. The purpose of this study was to determine if pirfenidone was protective against the development of fibro-collagenous injury in rat lung orthotopic transplants through altering L-arginine-arginase metabolic pathways. Lung transplants were performed using Lewis donors and Sprague-Dawley recipients (allografts) or the same strain (isografts). Recipients were given pirfenidone (0.5% chow) 1-21-day post-transplantation. A significantly increased peak airway pressure (PawP) with excessive collagen deposition was found in untreated lung allografts. Pirfenidone treatment decreased PawP and collagen content in lung allografts. The beneficial effects were associated with downregulation of arginase protein expression and activity. In addition, pirfenidone decreased endogenous transforming growth factor (TGF)-beta level in lung allografts, and TGF-beta stimulated arginase activity in a dose-dependent manner in both lung tissue and fibroblasts. These results suggest that pirfenidone inhibits local arginase activity possibly through suppression of endogenous TGF-beta, hence, limiting the development of fibrosis in lung allografts.
- Published
- 2005
- Full Text
- View/download PDF
38. Heme-oxygenase-1 expression correlates with severity of acute cellular rejection in lung transplantation.
- Author
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Bonnell MR, Visner GA, Zander DS, Mandalapu S, Kazemfar K, Spears L, and Beaver TM
- Subjects
- Animals, Heme Oxygenase-1, Humans, Immunohistochemistry, Male, Membrane Proteins, Oxidative Stress, Peroxidase biosynthesis, Rats, Rats, Inbred Lew, Rats, Sprague-Dawley, Reperfusion Injury enzymology, Graft Rejection enzymology, Heme Oxygenase (Decyclizing) biosynthesis, Lung Transplantation immunology
- Abstract
Background: Heme-oxygenase-1 (HO-1) has been shown to play an important role in oxidative stress, and recent studies indicate that it is a graft survival protein in cardiac and liver transplant models. Our laboratory previously found HO-1 to be increased in human lung allografts with acute cellular rejection (ACR) and in active obliterative bronchiolitis. To better understand the role of HO-1 in ACR we studied the relationship between HO-1 expression and ACR in a rodent model of lung transplantation., Study Design: Orthotopic left lung transplantation was performed from Lewis (donor) to Sprague-Dawley (recipient) rats, and ACR (Grade A0 to A4) was evaluated at days 3, 5, and 7. HO-1 expression was assessed by immunohistochemistry and Western analysis, and compared with the degree of ACR. Myeloperoxidase staining was evaluated as an indirect measure of oxidant stress. Donors and recipients were also treated with either an inhibitor of HO activity, tin protoporphyrin or an inducer, cobalt protoporphyrin, and the severity of ACR was compared with that in untreated allografts., Results: HO-1 expression was elevated in transplanted versus native lungs or isografts, and the degree of elevation was closely correlated with ACR grade (p < 0.001). Similarly, myeloperoxidase expression increased with time and severity of ACR. Administration of the metalloporphyrins, tin protoporphyrin and cobalt protoporphyrin, produced no significant difference in the degree of ACR, but did alter the severity of ischemia-reperfusion injury., Conclusions: Similar to what occurs in human lung transplantation, HO-1 expression is increased in a rodent lung transplant model of ACR and correlates with the severity of rejection. Altering its expression does not appear to affect the degree of ACR.
- Published
- 2004
- Full Text
- View/download PDF
39. Graft protective effects of heme oxygenase 1 in mouse tracheal transplant-related obliterative bronchiolitis.
- Author
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Visner GA, Lu F, Zhou H, Latham C, Agarwal A, and Zander DS
- Subjects
- Animals, Collagen metabolism, Graft Rejection, Heme Oxygenase (Decyclizing) analysis, Heme Oxygenase-1, In Situ Nick-End Labeling, Interleukin-10 physiology, Membrane Proteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Trachea enzymology, Transplantation, Homologous, Bronchiolitis Obliterans prevention & control, Heme Oxygenase (Decyclizing) physiology, Trachea transplantation
- Abstract
Background: Heme oxygenase (HO)-1, long believed to be a cytoprotective protein, has recently been identified as a graft survival gene. This study evaluates the role of HO-1 in a murine heterotopic tracheal allograft model for obliterative bronchiolitis., Methods: Mice with deficient or experimentally enhanced HO-1 expression underwent subcutaneous implantation of murine tracheal isografts and allografts. Grafts were excised after 9, 16, or 21 days and evaluated by histologic examination, immunohistochemistry for HO-1 and interleukin (IL)-10 proteins, and terminal deoxynucleotide transferase-mediated dUTP nick-end labeling. To evaluate the relationships between IL-10 and HO-1, the effects of modulation of HO-1 expression on IL-10 expression were evaluated and HO-1 expression was examined in tracheal transplants from IL-10 null mice., Results: Isografts demonstrated normal histology with minimal HO-1 staining, whereas allografts showed features of human airway rejection (loss of respiratory epithelium, luminal granulation tissue, lymphocytic tracheitis) with increased HO-1 staining in macrophages and mesenchymal cells. HO-1-deficient mice demonstrated a more rapid progression of the tracheal allograft injury as compared with control allografts, and this was associated with a decrease in the anti-inflammatory cytokine, IL-10. Tracheal transplants using IL-10-deficient mice also resulted in a more severe injury, and this was accompanied by a decrease in HO-1 staining., Conclusions: HO-1 protein expression is increased in murine heterotopic airway rejection, and deficiency of HO-1 accelerates the development of the obliterative bronchiolitis-like lesion. IL-10 protein expression parallels expression of HO-1, suggesting that IL-10 may participate in the genesis of HO-1's effects on the inflammatory processes triggered by allotransplantation.
- Published
- 2003
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40. Toxic serum trough concentrations after administration of nebulized tobramycin.
- Author
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Kahler DA, Schowengerdt KO, Fricker FJ, Mansfield M, Visner GA, and Faro A
- Subjects
- Administration, Inhalation, Adult, Female, Humans, Nebulizers and Vaporizers, Tobramycin administration & dosage, Tobramycin adverse effects, Tobramycin blood
- Abstract
The goal of administering nebulized antibiotics is to provide patients with a high concentration of drug at the infection site with minimal systemic effects. In two studies in which nebulized tobramycin 300 mg twice/day was administered, systemic peak concentrations were below 0.2 and 3.62 microg/ml, and trough concentrations were undetectable, making toxicity from this route of administration negligible. A 19-year-old woman who received a heart transplant was administered tobramycin inhalation solution for Acinetobacter baumanii pneumonia; her serum trough concentrations were found to be toxic (> 2.0 microg/ml). Her risk factors for experiencing these toxic concentrations were renal failure and administration of the drug by positive pressure ventilation. Although nebulized tobramycin is safe under routine circumstances, clinicians must be aware of its potential for toxicity in patients with renal dysfunction or in those receiving positive pressure ventilation.
- Published
- 2003
- Full Text
- View/download PDF
41. Rapamycin induces heme oxygenase-1 in human pulmonary vascular cells: implications in the antiproliferative response to rapamycin.
- Author
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Visner GA, Lu F, Zhou H, Liu J, Kazemfar K, and Agarwal A
- Subjects
- Androstadienes pharmacology, Blotting, Northern, Cell Division drug effects, Cells, Cultured, Dose-Response Relationship, Drug, Endothelium, Vascular cytology, Endothelium, Vascular drug effects, Enzyme Induction drug effects, Enzyme Inhibitors pharmacology, Heme Oxygenase (Decyclizing) antagonists & inhibitors, Heme Oxygenase (Decyclizing) genetics, Heme Oxygenase-1, Humans, Immunosuppressive Agents pharmacology, Membrane Proteins, Metalloporphyrins pharmacology, Muscle, Smooth, Vascular cytology, Muscle, Smooth, Vascular drug effects, Phosphatidylinositol 3-Kinases metabolism, Phosphoinositide-3 Kinase Inhibitors, Platelet-Derived Growth Factor pharmacology, Protein Kinase Inhibitors, Protein Kinases metabolism, Protoporphyrins pharmacology, Pulmonary Artery cytology, RNA, Messenger metabolism, TOR Serine-Threonine Kinases, Wortmannin, Endothelium, Vascular enzymology, Heme Oxygenase (Decyclizing) metabolism, Muscle, Smooth, Vascular enzymology, Pulmonary Artery enzymology, Sirolimus pharmacology
- Abstract
Background: Rapamycin is an immunosuppressive agent with antiproliferative properties against not only lymphocytes but also vascular endothelial and smooth muscle cells, and it reduces the fibroproliferative response to vascular injury. Heme oxygenase-1 (HO-1) has also been shown to have graft protective effects and to inhibit vascular remodeling. In this study, we evaluated whether there is an interaction between rapamycin and HO-1., Methods and Results: In human pulmonary artery endothelial or smooth muscle cells, HO-1 expression was evaluated in response to rapamycin or wortmannin, an inhibitor of the upstream modulator of mammalian target of rapamycin (mTOR) PI-3K. We also evaluated whether the inhibitory actions of rapamycin on platelet-derived growth factor-dependent proliferation was mediated by HO using the chemical inhibitor tin protoporphyrin. Rapamycin induced HO-1 expression in both pulmonary endothelial and smooth muscle cells, whereas no to little increase was seen in response to another immunosuppressive agent, cyclosporin A. HO-1 expression was also increased in response to wortmannin, suggesting that the PI-3K-mTOR pathway is required for this induction. Inhibition of HO activity resulted in a loss of the antiproliferative activity of rapamycin in growth factor-stimulated smooth muscle cells., Conclusions: The induction of HO-1 expression by rapamycin and, more importantly, the effects of tin protoporphyrin, an inhibitor of HO activity, on the antiproliferative actions of rapamycin suggest that the effects of rapamycin may be, at least in part, modulated by its actions on HO-1.
- Published
- 2003
- Full Text
- View/download PDF
42. Increased expression of heme oxygenase-1 in human lung transplantation.
- Author
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Lu F, Zander DS, and Visner GA
- Subjects
- Ferritins metabolism, Heme Oxygenase-1, Humans, Iron metabolism, Membrane Proteins, Transplantation, Homologous, Bronchiolitis Obliterans enzymology, Graft Rejection enzymology, Heme Oxygenase (Decyclizing) metabolism, Lung Transplantation physiology
- Abstract
Heme oxygenase-1 (HO-1) has been found to be a cytoprotective protein, and has recently been identified as a graft survival gene. This study demonstrates that HO-1 expression is increased in human lung allografts with acute cellular rejection and obliterative bronchiolitis. HO-1 expression was correlated with increased tissue iron and/or ferritin expression and increased inflammatory/oxidant load as measured by myeloperoxidase expression. Although the trigger for increased HO-1 expression in this setting is unknown, it may be related to hemorrhage and/or oxidative stress associated with rejection.
- Published
- 2002
- Full Text
- View/download PDF
43. Analysis of early deaths after isolated lung transplantation.
- Author
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Zander DS, Baz MA, Visner GA, Staples ED, Donnelly WH, Faro A, and Scornik JC
- Subjects
- Adolescent, Adult, Bacterial Infections etiology, Bacterial Infections mortality, Female, Graft Rejection mortality, Humans, Hypoxia-Ischemia, Brain etiology, Hypoxia-Ischemia, Brain mortality, Lung Diseases diagnosis, Male, Middle Aged, Postoperative Complications diagnosis, Reperfusion Injury mortality, Retrospective Studies, Time Factors, Lung Transplantation mortality, Postoperative Complications mortality
- Abstract
Study Objectives: To determine the causes of death in patients dying within 30 days after lung transplantation at the University of Florida, to assess the importance of several diagnostic modalities for determining the causes of their decline, and to construct an algorithm for the evaluation of patients with severe respiratory compromise occurring early after lung transplantation., Design: Retrospective review of medical records and pathology slides from all patients dying within 30 days after lung transplantation, and biopsy specimen diagnoses from all lung allograft recipients at the University of Florida., Patients: Nine deaths occurred during the first 30 days after transplantation among 117 patients undergoing 123 isolated lung transplantation operations., Results: Infections accounted for the greatest number of deaths (bacterial pneumonia, four patients; catheter-related bacteremia, one patient). Persistent pneumonia confirmed by biopsy specimen was usually accompanied by histologic manifestations of acute cellular rejection and was associated with poor patient outcome (ie, death or subsequent development of bronchiolitis obliterans syndrome). In two patients, antibody-mediated rejection either was the immediate cause of death (hyperacute rejection, one patient) or preceded a fatal case of pneumonia (accelerated antibody-mediated rejection, one patient). Other causes of death included hypoxic-ischemic encephalopathy secondary to an intraoperative cardiac arrest (one patient), pulmonary venous thrombosis with bacterial colonization of the thrombotic material (one patient), and ischemic reperfusion injury (one patient). In most patients, more than one type of diagnostic technique was needed to ascertain the cause of the catastrophic decline., Conclusions: The causes of early posttransplant death in our patient group included infections, antibody-mediated rejection, hypoxic-ischemic encephalopathy secondary to cardiac arrest, pulmonary venous thrombosis, and ischemic reperfusion injury. Because these processes often demonstrate overlapping clinical and morphologic features requiring multiple diagnostic techniques for resolution, a systematic multimodality approach to diagnosis is advantageous for determining the causes of decline in individual patients and for estimating the incidences of the different causes of early graft and patient loss in the lung transplant population.
- Published
- 2001
- Full Text
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44. Geneticin induces endogenous heme oxygenase-1 expression: implication in transfection studies.
- Author
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Shiraishi F, Visner GA, Nick HS, and Agarwal A
- Subjects
- Anti-Bacterial Agents pharmacology, Cells, Cultured, DNA, Complementary metabolism, Dose-Response Relationship, Drug, Epithelial Cells metabolism, Heme Oxygenase (Decyclizing) genetics, Heme Oxygenase-1, Humans, Kidney cytology, Membrane Proteins, Oxidation-Reduction, RNA, Messenger metabolism, Time Factors, Transfection, Gentamicins pharmacology, Heme Oxygenase (Decyclizing) metabolism
- Published
- 2001
- Full Text
- View/download PDF
45. Smad7-dependent regulation of heme oxygenase-1 by transforming growth factor-beta in human renal epithelial cells.
- Author
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Hill-Kapturczak N, Truong L, Thamilselvan V, Visner GA, Nick HS, and Agarwal A
- Subjects
- Cells, Cultured, DNA-Binding Proteins genetics, Dose-Response Relationship, Drug, Epithelial Cells enzymology, Heme Oxygenase (Decyclizing) genetics, Heme Oxygenase-1, Humans, Membrane Proteins, RNA, Messenger analysis, Smad6 Protein, Smad7 Protein, Trans-Activators genetics, DNA-Binding Proteins physiology, Gene Expression Regulation, Enzymologic drug effects, Heme Oxygenase (Decyclizing) biosynthesis, Kidney Tubules, Proximal enzymology, Trans-Activators physiology, Transforming Growth Factor beta pharmacology
- Abstract
Heme oxygenase-1 (HO-1), a 32-kDa microsomal enzyme, is induced as a beneficial and adaptive response in cells/tissues exposed to oxidative stress. Transforming growth factor-beta1 (TGF-beta1) is a regulatory cytokine that has been implicated in a variety of renal diseases where it promotes extracellular matrix deposition and proinflammatory events. We hypothesize that the release of TGF-beta1 via autocrine and/or paracrine pathways may induce HO-1 and serve as a protective response in renal injury. To understand the molecular mechanism of HO-1 induction by TGF-beta1, we exposed confluent human renal proximal tubule cells to TGF-beta1 and observed a significant induction of HO-1 mRNA at 4 h with a maximal induction at 8 h. This induction was accompanied by increased expression of HO-1 protein. TGF-beta1 treatment in conjunction with actinomycin D or cycloheximide demonstrated that induction of HO-1 mRNA requires de novo transcription and, in part, protein synthesis. Exposure to TGF-beta1 resulted in marked induction of Smad7 mRNA with no effect on Smad6 expression. Overexpression of Smad7, but not Smad6, inhibited TGF-beta1-mediated induction of endogenous HO-1 gene expression. We speculate that the induction of HO-1 in the kidney is an adaptive response to the inflammatory effects of TGF-beta1 and manipulations of the Smad pathway to alter HO-1 expression may serve as a potential therapeutic target.
- Published
- 2000
- Full Text
- View/download PDF
46. Heme oxygenase-1 gene ablation or expression modulates cisplatin-induced renal tubular apoptosis.
- Author
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Shiraishi F, Curtis LM, Truong L, Poss K, Visner GA, Madsen K, Nick HS, and Agarwal A
- Subjects
- Acute Kidney Injury chemically induced, Acute Kidney Injury genetics, Acute Kidney Injury pathology, Animals, Apoptosis genetics, Cells, Cultured, Enzyme Induction drug effects, Gene Expression, Gene Targeting, Heme Oxygenase (Decyclizing) biosynthesis, Heme Oxygenase-1, Hemin pharmacology, Humans, Kidney Tubules metabolism, Membrane Proteins, Mice, Mice, Knockout, Mice, Transgenic, Microscopy, Electron, Apoptosis drug effects, Cisplatin toxicity, Heme Oxygenase (Decyclizing) genetics, Kidney Tubules drug effects, Kidney Tubules pathology
- Abstract
Heme oxygenase-1 (HO-1) is a 32-kDa microsomal enzyme that catalyzes the conversion of heme to biliverdin, releasing iron and carbon monoxide. Induction of HO-1 occurs as a protective response in cells/tissues exposed to a wide variety of oxidant stimuli. The chemotherapeutic effects of cis-diamminedichloroplatinum(II) (cisplatin), a commonly used anticancer drug, are limited by significant nephrotoxicity, which is characterized by varying degrees of renal tubular apoptosis and necrosis. The purpose of this study was to evaluate the functional significance of HO-1 expression in cisplatin-induced renal injury. Our studies demonstrate that transgenic mice deficient in HO-1 (-/-), develop more severe renal failure and have significantly greater renal injury compared with wild-type (+/+) mice treated with cisplatin. In vitro studies in human renal proximal tubule cells demonstrate that hemin, an inducer of HO-1, significantly attenuated cisplatin-induced apoptosis and necrosis, whereas inhibition of HO-1 enzyme activity reversed the cytoprotective effect. Overexpression of HO-1 resulted in a significant reduction in cisplatin-induced cytotoxicity. These studies provide a basis for future studies using targeted gene expression of HO-1 as a therapeutic and preventive modality in high-risk settings of acute renal failure.
- Published
- 2000
- Full Text
- View/download PDF
47. Transcriptional regulation and structural organization of the human cytosolic phospholipase A(2) gene.
- Author
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Dolan-O'Keefe M, Chow V, Monnier J, Visner GA, and Nick HS
- Subjects
- Cell Line, Cytokines pharmacology, Dose-Response Relationship, Drug, Drug Synergism, Epithelial Cells metabolism, Fibroblasts metabolism, Gene Deletion, Gene Expression drug effects, Glucocorticoids pharmacology, Humans, Interleukin-1 pharmacology, Kinetics, Lung cytology, Lung metabolism, Phospholipases A antagonists & inhibitors, Phospholipases A metabolism, Promoter Regions, Genetic genetics, RNA, Messenger metabolism, Tumor Necrosis Factor-alpha pharmacology, Cytosol enzymology, Phospholipases A genetics, Transcription, Genetic physiology
- Abstract
Cytokines are established regulators of the arachidonic acid cascade in lung cells. The levels of various arachidonic metabolites distinguish the normal and pathogenic states of the human lung. Arachidonyl-selective cytosolic phospholipase A(2) (cPLA(2)) is ubiquitously present in human lung and is most likely the rate-limiting step in eicosanoid generation. We therefore studied the regulation of this pivotal gene in human lung fibroblasts and epithelial cells by proinflammatory cytokines. We demonstrate a dose- and time-dependent induction of human cPLA(2) mRNA by interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma as well as the abrogation of this induction by glucocorticoids. Nuclear runoff studies demonstrate that de novo transcription of the cPLA(2) gene is required for cytokine induction. We have characterized the human cPLA(2) gene, which is encoded by 18 exons and spans in excess of 137 kb. Deletion analysis of a 3.4-kb fragment of the human promoter identified two regions responsible for basal expression of the cPLA(2) gene. Conversely, a CA-dinucleotide repeat in the proximal promoter appears to repress overall promoter activity. Understanding the molecular mechanisms associated with cytokine-dependent expression of the cPLA(2) gene should provide further insight into regulating the level of proinflammatory mediators in pulmonary diseases.
- Published
- 2000
- Full Text
- View/download PDF
48. Iron regulates hyperoxia-dependent human heme oxygenase 1 gene expression in pulmonary endothelial cells.
- Author
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Fogg S, Agarwal A, Nick HS, and Visner GA
- Subjects
- Cathepsins genetics, Cell Nucleus metabolism, Cells, Cultured, Endothelium, Vascular cytology, Gene Expression Regulation, Enzymologic drug effects, Genes, Reporter, Heme Oxygenase-1, Humans, Hyperoxia, Kinetics, Membrane Proteins, Oxygen toxicity, Pulmonary Artery, RNA, Messenger genetics, Recombinant Proteins biosynthesis, Transfection, Endothelium, Vascular enzymology, Gene Expression Regulation, Enzymologic physiology, Heme Oxygenase (Decyclizing) genetics, Iron pharmacology, Transcription, Genetic drug effects
- Abstract
The endothelium of the lung is sensitive to the toxic effects of oxygen, and early evidence of toxicity is characterized by protein leak and extravasation of red blood cells. The overproduction of oxygen free radicals plays a critical role in the pathophysiology of a hyperoxic lung injury. Recently, heme oxygenase 1 (HO-1), the rate-limiting enzyme in the metabolism of heme, has been found to have a protective role in oxidant injury. Our laboratory and others have identified HO-1 as a hyperoxia-inducible protein. In this study, we characterized HO-1 expression and evaluated its regulation in human pulmonary endothelial cells. Hyperoxia results in a relatively small increase in HO-1 expression; however, this induction is potentiated by heme and dramatically potentiated in the presence of free iron. This is probably more reflective of the in vivo situation in which there is extravasation of heme and iron products. We also found that HO-1 expression depended on chelatable iron. The iron chelator desferrioxamine not only inhibited the iron- dependent potentiation of HO-1 in response to hyperoxia but also inhibited both hyperoxia and basal expression. On the basis of inhibitor studies and nuclear run-on assays, we demonstrated that this induction is transcriptionally dependent. We also evaluated 4.5 kb of the human HO-1 promoter region and demonstrated that this region has promoter activity to the stimulus heme; however, there was no evidence of promoter activity to either iron or hyperoxia. This diversity of promoter activity to heme, heavy metals, and hyperoxia is unique to the human HO-1 gene.
- Published
- 1999
- Full Text
- View/download PDF
49. Linoleyl hydroperoxide transcriptionally upregulates heme oxygenase-1 gene expression in human renal epithelial and aortic endothelial cells.
- Author
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Agarwal A, Shiraishi F, Visner GA, and Nick HS
- Subjects
- Aorta cytology, Cells, Cultured, Endothelium, Vascular cytology, Enzyme Activation physiology, Epithelial Cells physiology, Heme Oxygenase-1, Humans, Kidney cytology, Lysophosphatidylcholines pharmacology, Membrane Proteins, RNA, Messenger biosynthesis, Transcriptional Activation, Aorta physiology, Endothelium, Vascular physiology, Gene Expression Regulation physiology, Heme Oxygenase (Decyclizing) genetics, Kidney physiology, Linoleic Acids genetics, Lipid Peroxides genetics, Transcription, Genetic physiology
- Abstract
Atherogenic lipoproteins such as oxidized LDL are implicated in the pathogenesis of atherosclerosis and renal disease. Fatty acid hydroperoxides and phospholipids such as linoleyl hydroperoxide (LAox or 13-HPODE) and lysophosphatidylcholine (lyso-PC), abundant components of oxidized LDL, mediate the effects of atherogenic lipids. Oxidized LDL has been shown to induce heme oxygenase-1 (HO-1), a microsomal enzyme that is involved in heme detoxification and is a major endogenous source of carbon monoxide. HO-1 is also induced by many other stimuli that shift cellular redox. To identify the constituents and molecular mechanisms of oxidized LDL-mediated HO-1 induction, human renal epithelial cells and aortic endothelial cells were exposed to LAox and lyso-PC. Exposure to LAox (25 microM) showed an approximately 16-fold induction of HO-1 mRNA, whereas exposure to lyso-PC (25 microM) showed only an approximate 2.6-fold increase. Treatment with actinomycin-D (4 microM), a transcriptional inhibitor, as well as nuclear run-on assays, demonstrated that LAox-mediated HO-1 gene induction is dependent on de novo transcription. Cycloheximide did not affect LAox-mediated HO-1 mRNA induction, suggesting that new protein synthesis is not required for transcriptional induction. Transfection of a human HO-1 promoter-reporter gene construct showed that LAox upregulation of HO-1 occurs via mechanisms different from those of known inducers, heme and cadmium. These studies are the first demonstration that LAox induces HO-1 by transcriptional mechanisms and may have implications in the pathogenesis of cell injury in atherosclerosis and progressive renal disease.
- Published
- 1998
- Full Text
- View/download PDF
50. Thrombin regulation of endothelin-1 gene in isolated human pulmonary endothelial cells.
- Author
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Golden CG, Nick HS, and Visner GA
- Subjects
- Endothelium, Vascular cytology, Humans, Promoter Regions, Genetic physiology, Pulmonary Artery cytology, Pulmonary Artery physiology, Transcription, Genetic, Endothelin-1 physiology, Endothelium, Vascular physiology, Gene Expression Regulation physiology, Thrombin physiology
- Published
- 1998
- Full Text
- View/download PDF
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