33 results on '"Scozzi, Davide"'
Search Results
2. Avoid being trapped by your liver: ischemia-reperfusion injury in liver transplant triggers SIP-mediated NETosis
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Scozzi, Davide and Gelman, Andrew E.
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Health care industry - Abstract
Liver transplantation can be a life-saving treatment for end-stage hepatic disease. Unfortunately, some recipients develop ischemia-reperfusion injury (IRI) that leads to poor short- and long-term outcomes. Recent work has shown neutrophils contribute to IRI by undergoing NETosis, a form of death characterized by DNA ejection resulting in inflammatory extracellular traps. In this issue of the JCI, Hirao and Kojima et al. report that sphingosine-1-phosphate (S1P) expression induced by liver transplant-mediated IRI triggers NETosis. They also provide evidence that neutrophil expression of the carcinoembryonic antigen-related cell adhesion molecule-1 (CC1) long isoform inhibited NETosis by controlling S1P receptor-mediated autophagic flux. These findings suggest stimulating regulatory mechanisms that suppress NETosis could be used to prevent IRI., CC1-L restrains IRI and NETosis Liver transplantation remains the only life-saving option for patients with end-stage hepatic disease. A common postoperative complication, ischemia-reperfusion injury (IRI), is the predominant driver of [...]
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- 2023
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3. Lung transplant outcomes are influenced by severity of neutropenia and granulocyte colony-stimulating factor treatment
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Tague, Laneshia Karee, Scozzi, Davide, Wallendorf, Michael, Gage, Brian F., Krupnick, Alexander S., Kreisel, Daniel, Byers, Derek, Hachem, Ramsey R., and Gelman, Andrew E.
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- 2020
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4. Reprogramming alveolar macrophage responses to TGF-[beta]] reveals [CCR2.sup.+] monocyte activity that promotes bronchiolitis obliterans syndrome
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Liu, Zhiyi, Liao, Fuyi, Zhu, Jihong, Zhou, Dequan, Heo, Gyu Seong, Leuhmann, Hannah P., Scozzi, Davide, Parks, Antanisha, Hachem, Ramsey, Byers, Derek E., Tague, Laneshia K., Kulkarni, Hrishikesh S., Cano, Marlene, Wong, Brian W., Li, Wenjun, Haung, Howard J., Krupnick, Alexander S., Kreisel, Daniel, Liu, Yongjian, and Gelman, Andrew E.
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Transplantation of organs, tissues, etc. -- Patient outcomes ,Bronchiolitis -- Diagnosis -- Care and treatment ,Immunotherapy -- Patient outcomes ,Macrophages -- Analysis ,Transforming growth factors -- Analysis ,Health care industry - Abstract
Bronchiolitis obliterans syndrome (BOS) is a major impediment to lung transplant survival and is generally resistant to medical therapy. Extracorporeal photophoresis (ECP) is an immunomodulatory therapy that shows promise in stabilizing BOS patients, but its mechanisms of action are unclear. In a mouse lung transplant model, we show that ECP blunts alloimmune responses and inhibits BOS through lowering airway TGF-[beta] bioavailability without altering its expression. Surprisingly, ECP-treated leukocytes were primarily engulfed by alveolar macrophages (AMs), which were reprogrammed to become less responsive to TGF-[beta] and reduce TGF-[beta] bioavailability through secretion of the TGF-[beta] antagonist decorin. In untreated recipients, high airway TGF-[beta] activity stimulated AMs to express CCL2, leading to [CCR2.sup.+] monocyte-driven BOS development. Moreover, we found TGF-[beta] receptor 2-dependent differentiation of [CCR2.sup.+] monocytes was required for the generation of monocyte-derived AMs, which in turn promoted BOS by expanding tissue-resident memory CD8* T cells that inflicted airway injury through Blimp-1-mediated granzyme B expression. Thus, through studying the effects of ECP, we have identified an AM functional plasticity that controls a TGF-[beta]-dependent network that couples [CCR2.sup.+] monocyte recruitment and differentiation to alloimmunity and BOS., Introduction Bronchiolitis obliterans syndrome (BOS) is the most common form of chronic lung allograft dysfunction (CLAD) and the leading cause of rejection after the first year of transplantation (1). The [...]
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- 2022
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5. Mitochondrial damage–associated molecular patterns released by lung transplants are associated with primary graft dysfunction
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Scozzi, Davide, Ibrahim, Mohsen, Liao, Fuyi, Lin, Xue, Hsiao, Hsi-Min, Hachem, Ramsey, Tague, Laneshia K., Ricci, Alberto, Kulkarni, Hrishikesh S., Huang, Howard J., Sugimoto, Seiichiro, Krupnick, Alexander S., Kreisel, Daniel, and Gelman, Andrew E.
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- 2019
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6. Neutrophil extracellular trap fragments stimulate innate immune responses that prevent lung transplant tolerance
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Scozzi, Davide, Wang, Xingan, Liao, Fuyi, Liu, Zhiyi, Zhu, Jihong, Pugh, Katy, Ibrahim, Mohsen, Hsiao, Hsi-Min, Miller, Mark J., Yizhan, Guo, Mohanakumar, Thalachallour, Krupnick, Alexander S., Kreisel, Daniel, and Gelman, Andrew E.
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- 2019
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7. Spleen-derived classical monocytes mediate lung ischemia-reperfusion injury through IL-i[beta]
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Hsiao, Hsi-Min, Fernandez, Ramiro, Tanaka, Satona, Li, Wenjun, Spahn, Jessica H., Chiu, Stephen, Akbarpour, Mahzad, Ruiz-Perez, Daniel, Wu, Qiang, Turam, Cem, Scozzi, Davide, Takahashi, Tsuyoshi, Luehmann, Hannah P., Puri, Varun, Budinger, G.R. Scott, Krupnick, Alexander S., Misharin, Alexander V., Lavine, Kory J., Liu, Yongjian, Gelman, Andrew E., Bharat, Ankit, and Kreisel, Daniel
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Mortality -- Risk factors ,Reperfusion injury -- Drug therapy -- Genetic aspects -- Research ,Interleukin-2 -- Research ,Health care industry - Abstract
Ischemia-reperfusion injury, a form of sterile inflammation, is the leading risk factor for both short-term mortality following pulmonary transplantation and chronic lung allograft dysfunction. While it is well recognized that neutrophils are critical mediators of acute lung injury, processes that guide their entry into pulmonary tissue are not well understood. Here, we found that [CCR2.sup.+] classical monocytes are necessary and sufficient for mediating extravasation of neutrophils into pulmonary tissue during ischemia-reperfusion injury following hilar clamping or lung transplantation. The classical monocytes were mobilized from the host spleen, and splenectomy attenuated the recruitment of classical monocytes as well as the entry of neutrophils into injured lung tissue, which was associated with improved graft function. Neutrophil extravasation was mediated by MyD88-dependent IL-1[beta] production by graft-infiltrating classical monocytes, which downregulated the expression of the tight junction-associated protein ZO-2 in pulmonary vascular endothelial cells. Thus, we have uncovered a crucial role for classical monocytes, mobilized from the spleen, in mediating neutrophil extravasation, with potential implications for targeting of recipient classical monocytes to ameliorate pulmonary ischemia-reperfusion injury in the clinic., Introduction Ischemia-reperfusion injury (IRI) following solid organ transplantation is mediated by host neutrophils that, upon extravasation, initiate NETosis and induce allograft damage (1, 2). Following lung transplantation, IRI leads to [...]
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- 2018
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8. Modified expression of peripheral blood lymphocyte muscarinic cholinergic receptors in asthmatic children
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Cherubini, Emanuela, Tabbì, Luca, Scozzi, Davide, Mariotta, Salvatore, Galli, Elena, Carello, Rossella, Avitabile, Simona, Tayebati, Seyed Koshrow, Amenta, Francesco, De Vitis, Claudia, Mancini, Rita, and Ricci, Alberto
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- 2015
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9. Mechanisms of graft rejection after lung transplantation
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Hsiao, Hsi-Min, Scozzi, Davide, Gauthier, Jason M., and Kreisel, Daniel
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- 2017
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10. The role of neutrophil extracellular traps in acute lung injury.
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Scozzi, Davide, Liao, Fuyi, Krupnick, Alexander S., Kreisel, Daniel, and Gelman, Andrew E.
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LUNG injuries ,NEUTROPHILS ,THERAPEUTICS - Abstract
Acute lung injury (ALI) is a heterogeneous inflammatory condition associated with high morbidity and mortality. Neutrophils play a key role in the development of different forms of ALI, and the release of neutrophil extracellular traps (NETs) is emerging as a common pathogenic mechanism. NETs are essential in controlling pathogens, and their defective release or increased degradation leads to a higher risk of infection. However, NETs also contain several pro-inflammatory and cytotoxic molecules than can exacerbate thromboinflammation and lung tissue injury. To reduce NETmediated lung damage and inflammation, DNase is frequently used in preclinical models of ALI due to its capability of digesting NET DNA scaffold. Moreover, recent advances in neutrophil biology led to the development of selective NET inhibitors, which also appear to reduce ALI in experimental models. Here we provide an overview of the role of NETs in different forms of ALI discussing existing gaps in our knowledge and novel therapeutic approaches to modulate their impact on lung injury. [ABSTRACT FROM AUTHOR]
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- 2022
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11. Necroptosis triggers spatially restricted neutrophil-mediated vascular damage during lung ischemia reperfusion injury.
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Wenjun Li, Terada, Yuriko, Tyurina, Yulia Y., Tyurin, Vladimir A., Bery, Amit I., Gauthier, Jason M., Higashikubo, Ryuji, Tong, Alice Y., Zhou, Dequan, Nunez-Santana, Felix, Lecuon, Emilia, Hassan, Adil, Hashimoto, Kohei, Scozzi, Davide, Puri, Varun, Nava, Ruben G., Krupnick, Alexander S., Lavine, Kory J., Gelman, Andrew E., and Miller, Mark J.
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REPERFUSION injury ,VASCULAR endothelial cells ,PLANNING techniques ,REMANUFACTURING ,NADPH oxidase ,CELL death ,LUNGS - Abstract
Ischemia reperfusion injury represents a common pathological condition that is triggered by the release of endogenous ligands. While neutrophils are known to play a critical role in its pathogenesis, the tissue-specific spatiotemporal regulation of ischemia-reperfusion injury is not understood. Here, using oxidative lipidomics and intra-vital imaging of transplanted mouse lungs that are subjected to severe ischemia reperfusion injury, we discovered that necroptosis, a nonapoptotic form of cell death, triggers the recruitment of neu- trophils. During the initial stages of inflammation, neutrophils traffic predominantly to subpleural vessels, where their aggregation is directed by chemoattractants produced by nonclassical monocytes that are spatially restricted in this vascular compartment. Subse- quent neutrophilic disruption of capillaries resulting in vascular leakage is associated with impaired graft function. We found that TLR4 signaling in vascular endothelial cells and downstream NADPH oxidase 4 expression mediate the arrest of neutrophils, a step upstream of their extravasation. Neutrophil extracellular traps formed in injured lungs and their disruption with DNase prevented vascular leakage and ameliorated primary graft dysfunction. Thus, we have uncovered mechanisms that regulate the initial recruitment of neutrophils to injured lungs, which result in selective damage to subpleural pulmonary vessels and primary graft dys function. Our findings could lead to the development of new therapeutics that protect lungs from ischemia reperfusion injury. [ABSTRACT FROM AUTHOR]
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- 2022
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12. Pericardial Mitochondrial DNA Levels Are Associated With Atrial Fibrillation After Cardiac Surgery.
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Manghelli, Joshua L., Kelly, Meghan O., Carter, Daniel I., Gauthier, Jason M., Scozzi, Davide, Lancaster, Timothy S., MacGregor, Robert M., Khiabani, Ali J., Schuessler, Richard B., Gelman, Andrew E., Damiano, Ralph J., and Melby, Spencer J.
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Postoperative atrial fibrillation (POAF) is the most common complication after cardiac surgery, and is associated with increased morbidity and mortality. Inflammation has been implicated as an etiology of POAF. Mitochondrial DNA (mtDNA) has been shown to initiate inflammation. This study analyzed inflammatory mechanisms of POAF by evaluating mtDNA, neutrophils, and cytokines/chemokines in the pericardial fluid and blood after cardiac surgery. Blood and pericardial fluid from patients who underwent coronary artery bypass or heart valve surgery, or both, were collected intraoperatively and at 4, 12, 24, and 48 hours postoperatively. Real-time polymerase chain reaction was used to quantify mtDNA in the pericardial fluid and blood. A Luminex (Luminex Corp, Austin, TX) assay was used to study cytokine and chemokine levels. Flow cytometry was used to analyze neutrophil infiltration and activation in the pericardial fluid. Samples from 100 patients were available for analysis. Postoperatively, mtDNA and multiple cytokine levels were higher in the pericardial fluid versus blood. Patients who had POAF had significantly higher levels of mtDNA in the pericardial fluid compared with patients who did not (P <.001, area under the curve 0.74). There was no difference in the mtDNA concentration in the blood between the POAF group and non-POAF group (P =.897). Neutrophil concentration increased in the pericardial fluid over time from a baseline of 0.8% to 56% at 48 hours (P <.01). The pericardial space has a high concentration of inflammatory mediators postoperatively. Mitochondrial DNA in the pericardial fluid was strongly associated with the development of POAF. This finding provides insight into a possible mechanism of inflammation that may contribute to POAF, and may offer novel therapeutic targets. [ABSTRACT FROM AUTHOR]
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- 2021
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13. Full-Length TrkB Variant in NSCLC Is Associated with Brain Metastasis.
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Lombardi, Mariangela, D'Ascanio, Michela, Scarpino, Stefania, Scozzi, Davide, Giordano, Marco, Costarelli, Leopoldo, Raj, Enrico Rathina, Mancini, Rita, Cardillo, Giuseppe, Cardaci, Vittorio, Innammorato, Marta, Vecchione, Andrea, and Ricci, Alberto
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RISK of metastasis ,BRAIN ,CELL lines ,GENE expression ,IMMUNOHISTOCHEMISTRY ,LUNG cancer ,PROTEIN-tyrosine kinases ,BRAIN-derived neurotrophic factor - Abstract
Despite remarkable therapeutic advances have been made in the last few decades, non-small cell lung cancer (NSCLC) is still one of the leading causes of death worldwide. Brain metastases are a common complication of a wide range of human malignancies and in particular NSCLC. Brain-derived neurotrophic factor (BDNF), binding its high-affinity tyrosine kinase B receptor, has been shown to promote cancer progression and metastasis. We hereby investigated the expression of the BDNF and its TrkB receptor in its full-length and truncated isoform T1, in samples from primary adenocarcinomas (ADKs) of the lung and in their metastasis to evaluate if their expression was related to preferential tumor entry into the central nervous system (CNS). By immunohistochemistry, 80% of the ADKs that metastasize to central nervous system expressed TrkB receptor compared to 33% expressing of ADKs without CNS metastasis. Moreover, ADKs with CNS metastasis showed an elevated expression of the full-length TrkB receptor. The TrkB receptor FL/T1 ratio was statistically higher in primary ADKs with brain metastasis compared to ADKs without brain metastasis. Our data indicate that TrkB full-length isoform expression in primary ADK cells may be associated with higher risk to develop brain metastasis. Therefore, TrkB receptor may possess prognostic and therapeutic implications in lung ADK. [ABSTRACT FROM AUTHOR]
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- 2020
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14. Protective role of brain derived neurotrophic factor (BDNF) in obstructive sleep apnea syndrome (OSAS) patients.
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Flores, Krisstopher Richard, Viccaro, Fausta, Aquilini, Mauro, Scarpino, Stefania, Ronchetti, Francesco, Mancini, Rita, Di Napoli, Arianna, Scozzi, Davide, and Ricci, Alberto
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SLEEP apnea syndromes ,COGNITION disorders ,MONTREAL Cognitive Assessment ,NERVOUS system ,GROWTH factors - Abstract
Obstructive sleep apnea syndrome (OSAS) is a common disorder characterized by repeated episodes of upper airways collapse during the sleep. The following intermittent hypoxia triggers a state of chronic inflammation, which also interests the nervous system leading to neuronal damage and increased risk of cognitive impairment. Brain derived neurotrophic factor (BDNF) is a growth factor often associated with neuroplasticity and neuroprotection whose levels increase in several condition associated with neuronal damage. However, whether patients affected by OSAS have altered BDNF levels and whether such alteration may be reflective of their cognitive impairment is still controversial. Here we show that, when compared to healthy control volunteers, OSAS patients have increased serum levels of BDNF. Moreover, OSAS patients with the higher levels of BDNF also have reduced neurocognitive impairment as measured by The Montreal Cognitive Assessment (MoCA) questionnaire. Treatment with standard non-invasive mechanical ventilation (CPAP) also was able to ameliorate the level of cognitive impairment. Altogether our results indicate that BDNF levels represent a neuroprotective response to intermittent hypoxia in OSAS patients. [ABSTRACT FROM AUTHOR]
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- 2020
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15. Naive CD4+ T Cells Carrying a TLR2 Agonist Overcome TGF-β-Mediated Tumor Immune Evasion.
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Ibrahim, Mohsen, Scozzi, Davide, Toth, Kelsey A., Ponti, Donatella, Kreisel, Daniel, Menna, Cecilia, De Falco, Elena, D'Andrilli, Antonio, Rendina, Erino A., Calogero, Antonella, Krupnick, Alexander S., and Gelman, Andrew E.
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T cells , *CD4 antigen , *TOLL-like receptors , *CELL death , *TRANSFORMING growth factors , *CELLULAR therapy - Abstract
TLR agonists are effective at treating superficial cancerous lesions, but their use internally for other types of tumors remains challenging because of toxicity. In this article, we report that murine and human naive CD4+T cells that sequester Pam3Cys4 (CD4+ TPam3) become primed for Th1 differentiation. CD4+ TPam3 cells encoding the OVA-specific TCR OT2, when transferred into mice bearing established TGF-b-OVA-expressing thymomas, produce high amounts of IFN-g and sensitize tumors to PD-1/programmed cell death ligand 1 blockade-induced rejection. In contrast, naive OT2 cells without Pam3Cys4 cargo are prone to TGFb- dependent inducible regulatory Foxp3+ CD4+ T cell conversion and accelerate tumor growth that is largely unaffected by PD-1/programmed cell death ligand 1 blockade. Ex vivo analysis reveals that CD4+ TPam3 cells are resistant to TGF-β-mediated gene expression through Akt activation controlled by inputs from the TCR and a TLR2-MyD88-dependent PI3K signaling pathway. These data show that CD4+ TPam3 cells are capable of Th1 differentiation in the presence of TGF-β, suggesting a novel approach to adoptive cell therapy. [ABSTRACT FROM AUTHOR]
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- 2018
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16. BDNF/TrkB axis activation promotes epithelial-mesenchymal transition in idiopathic pulmonary fibrosis.
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Cherubini, Emanuela, Mariotta, Salvatore, Scozzi, Davide, Mancini, Rita, Osman, Giorgia, D'Ascanio, Michela, Bruno, Pierdonato, Cardillo, Giuseppe, and Ricci, Alberto
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NEUROTROPHINS ,IDIOPATHIC pulmonary fibrosis ,METALLOPROTEINASES ,BRAIN-derived neurotrophic factor ,TRANSCRIPTION factors - Abstract
Background: Neurotrophins (NT) belongs to a family of growth factors which promotes neurons survival and differentiation. Increasing evidence show that NT and their receptor are expressed in lung tissues suggesting a possible role in lung health and disease. Here we investigated the expression and functional role of the TrkB/BDNF axis in idiopathic pulmonary fibrotic lung (myo)fibroblasts.Methods: Lung fibroblast were isolated from IPF patients and characterized for the expression of mesenchymal markers in comparison to normal lung fibroblasts isolated from non-IPF controls.Results: BDNF treatment promoted mesenchymal differentiation and this effect was counteracted by the TrkB inhibitor K252a. In this regard, we showed that K252a treatment was able to control the expression of transcription factors involved in epithelial to mesenchymal transition (EMT). Accordingly, K252a treatment reduced matrix metalloproteinase-9 enzyme activity and E-cadherin expression while increased cytoplasmic β-catenin expression.Conclusions: Our results suggest that BDNF/TrkB axis plays a role in EMT promoting the acquisition of (myo)fibroblast cell phenotype in IPF. Targeting BDNF/TrkB seems to represent a viable approach in order to prevent EMT dependent lung fibrosis. [ABSTRACT FROM AUTHOR]- Published
- 2017
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17. Mechanisms of graft rejection after lung transplantation.
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Hsi-Min Hsiao, Scozzi, Davide, Gauthier, Jason M., and Kreisel, Daniel
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- 2017
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18. Genetic Polymorphism of CHRM2 in COPD: Clinical Significance and Therapeutic Implications.
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Cherubini, Emanuela, Esposito, Maria Cristina, Scozzi, Davide, Terzo, Fabrizio, Osman, Giorgia Amira, Mariotta, Salvatore, Mancini, Rita, Bruno, Pierdonato, and Ricci, Alberto
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OBSTRUCTIVE lung diseases ,OBSTRUCTIVE lung disease treatment ,GENETIC polymorphisms ,BRONCHODILATOR agents ,SYMPATHOMIMETIC agents ,PREVENTION - Abstract
Chronic Obstructive Pulmonary Disease (COPD) is a common preventable and treatable disease, characterized by persistent airflow limitation not fully reversible. However, a number of patients with COPD respond to bronchodilator agents. Some studies have shown polymorphisms in the b2-adrenergic (ADRb2) and muscarinic M2 and M3 receptors (CHRM) that may participate in the modulation of the receptor responses. This study was designed to investigate the existence and the role of adrenergic and muscarinic receptor polymorphisms and their functional impact in COPD. Eighty-two patients with COPD and 17 healthy smokers were recruited and screened for ADRb2 (T164I and R175R), for CHRM2 (rs1824024) and for CHRM3 (−513C/A and −492C/T). Among the polymorphisms studied our results was not able to demonstrate statistically significant association between the polymorphisms studied and COPD risk. Contrarily, we identified, in our COPD population, a significant association with the CHRM2 (rs1824024) polymorphism and disease severity, with lower lung function test values, frequent exacerbations, and poor response to anti-cholinergic drugs. These results suggest the potential role of receptor polymorphism assessment to discriminate newly COPD phenotypes. J. Cell. Physiol. 231: 1745-1751, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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19. Decreased expression of autophagic beclin 1 protein in idiopathic pulmonary fibrosis fibroblasts.
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Ricci, Alberto, Cherubini, Emanuela, Scozzi, Davide, Pietrangeli, Vittorio, Tabbì, Luca, Raffa, Salvatore, Leone, Laura, Visco, Vincenzo, Torrisi, Maria Rosaria, Bruno, Pierdonato, Mancini, Rita, Ciliberto, Gennaro, Terzano, Claudio, and Mariotta, Salvatore
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AUTOPHAGY ,IDIOPATHIC pulmonary fibrosis ,FIBROBLASTS ,CELL culture ,CELLULAR control mechanisms ,ORGANELLES ,MOLECULAR biology - Abstract
Autophagy is the main cellular pathway for degradation of long-lived proteins and organelles and regulates cell fate in response to stress. Beclin 1 is a key regulator of this process. In some settings autophagy and apoptosis seem to be interconnected. Recent reports indicate that fibroblasts in idiopathic pulmonary fibrosis (IPF) acquire resistance to apoptosis. Here, we examined the expression of beclin 1, and of the anti apoptotic protein Bcl-2 in human IPF fibroblasts using immunohistochemistry and molecular biology in bioptic sections, in primary cultures of fibroblasts taken from patients with IPF and in fibroblast cell lines. Expression of beclin 1 in fibroblasts from IPF was down-regulated in comparison with fibroblasts from normal lungs while the anti-apoptotic protein Bcl-2 expression was over-expressed. Treatment of fibroblast cell cultures with cisplatin induced a significant increase in beclin 1 and caspase 3 protein levels but a reduction in Bcl-2 expression. These observations were confirmed by the analysis of acid compartments and transmission electron microscopy. Our results demonstrate a modified expression of the apoptotic beclin 1 Bcl-2 proteins in human IPF fibroblasts suggesting the existence of an autophagy/apoptosis system dysfunction. J. Cell. Physiol. 228: 1516-1524, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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20. Homeodomain-interacting protein kinase2 in human idiopathic pulmonary fibrosis.
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Ricci, Alberto, Cherubini, Emanuela, Ulivieri, Alessandra, Lavra, Luca, Sciacchitano, Salvatore, Scozzi, Davide, Mancini, Rita, Ciliberto, Gennaro, Bartolazzi, Armando, Bruno, Pierdonato, Graziano, Paolo, and Mariotta, Salvatore
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PROTEIN kinases ,IDIOPATHIC pulmonary fibrosis ,GENETIC toxicology ,CELL cycle ,APOPTOSIS ,CELL proliferation - Abstract
Homeodomain-interacting protein kinase 2 (Hipk2) is an emerging player in cell response to genotoxic agents that contributes to the cell's decision between cell cycle arrest or apoptosis. HIPK2 acts as co-regulator of an increasing number of transcription factors and modulates many different basic cellular processes such as apoptosis, proliferation, DNA damage response, differentiation. Idiopathic pulmonary fibrosis (IPF) is characterized by an anatomical disarrangement of the lung due to fibroblast proliferation, extracellular matrix deposition and lung function impairment. Although the role of inflammation is still debated, attention has been focused on lung cell functions as fibroblast phenotype and activity. Aim of the present study was to analyze the loss of heterozygosity (LOH) at HIPK2 locus 7q32.34 in human lung fibroblasts and the HIPK2 expression in 15 IPF samples and in four primary fibroblast cell cultures isolated from IPF biopsies using semi-quantitative RT-PCR, Western blots and immunohistochemistry. We demonstrated a frequency of LOH in IPF fibroblasts of 46% for the internal D7S6440 microsatellite and 26.6% for the external D7S2468 microsatellite. Furthermore, we demonstrated low HIPK2 protein expression in those fibroblasts from IPF patients that present the HIPK2 LOH. The restoration of HIPK2 expression in IPF derived cells induced a significant reduction of chemoresistance after treatment with cisplatin. The results obtained allow us to hypothesize that HIPK2 dysfunction may play a role in fibroblasts behavior and in IPF pathogenesis. HIPK2 may be considered as a novel potential target for anti-fibrosis therapy. J. Cell. Physiol. 228: 235-241, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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21. Recent advances into the role of pattern recognition receptors in transplantation.
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Kulkarni, Hrishikesh S., Scozzi, Davide, and Gelman, Andrew E.
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PATTERN perception receptors , *PEPTIDE receptors , *TOLL-like receptors , *TRANSPLANTATION of organs, tissues, etc. - Abstract
Pattern recognition receptors (PRRs) are germline-encoded sensors best characterized for their critical role in host defense. However, there is accumulating evidence that organ transplantation induces the release or display of molecular patterns of cellular injury and death that trigger PRR-mediated inflammatory responses. There are also new insights that indicate PRRs are able to distinguish between self and non-self, suggesting the existence of non-clonal mechanisms of allorecognition. Collectively, these reports have spurred considerable interest into whether PRRs or their ligands can be targeted to promote transplant survival. This review examines the mounting evidence that PRRs play in transplant-mediated inflammation. Given the large number of PRRs, we will focus on members from four families: the complement system, toll-like receptors, the formylated peptide receptor, and scavenger receptors through examining reports of their activity in experimental models of cellular and solid organ transplantation as well as in the clinical setting. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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22. Abstract 16046: Elevated Mitochondrial DNA Levels in the Pericardial Fluid Are Associated With Postoperative Atrial Fibrillation After Cardiac Surgery.
- Author
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Manghelli, Joshua L, Carter, Daniel I, Scozzi, Davide, Khiabani, Ali J, Schuessler, Richard B, Gelman, Andrew E, Damiano, Ralph J, and Melby, Spencer J
- Published
- 2018
23. Reprogramming alveolar macrophage responses to TGF-β reveals CCR2+ monocyte activity that promotes bronchiolitis obliterans syndrome.
- Author
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Zhiyi Liu, Fuyi Liao, Jihong Zhu, Dequan Zhou, Gyu Seong Heo, Leuhmann, Hannah P., Scozzi, Davide, Parks, Antanisha, Hachem, Ramsey, Byers, Derek E., Tague, Laneshia K., Kulkarni, Hrishikesh S., Cano, Marlene, Wong, Brian W., Wenjun Li, Huang, Howard J., Krupnick, Alexander S., Kreisel, Daniel, Yongjian Liu, and Gelman, Andrew E.
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BRONCHIOLITIS obliterans syndrome , *LUNG transplantation , *GROWTH factors , *ANIMAL experimentation , *PROTEOLYTIC enzymes , *MACROPHAGES , *CELL receptors , *GLYCOPROTEINS , *RESEARCH funding , *MICE , *MONOCYTES - Abstract
Bronchiolitis obliterans syndrome (BOS) is a major impediment to lung transplant survival and is generally resistant to medical therapy. Extracorporeal photophoresis (ECP) is an immunomodulatory therapy that shows promise in stabilizing BOS patients, but its mechanisms of action are unclear. In a mouse lung transplant model, we show that ECP blunts alloimmune responses and inhibits BOS through lowering airway TGF-β bioavailability without altering its expression. Surprisingly, ECP-treated leukocytes were primarily engulfed by alveolar macrophages (AMs), which were reprogrammed to become less responsive to TGF-β and reduce TGF-β bioavailability through secretion of the TGF-β antagonist decorin. In untreated recipients, high airway TGF-β activity stimulated AMs to express CCL2, leading to CCR2+ monocyte-driven BOS development. Moreover, we found TGF-β receptor 2-dependent differentiation of CCR2+ monocytes was required for the generation of monocyte-derived AMs, which in turn promoted BOS by expanding tissue-resident memory CD8+ T cells that inflicted airway injury through Blimp-1-mediated granzyme B expression. Thus, through studying the effects of ECP, we have identified an AM functional plasticity that controls a TGF-β-dependent network that couples CCR2+ monocyte recruitment and differentiation to alloimmunity and BOS. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
24. Spleen-derived classical monocytes mediate lung ischemia-reperfusion injury through IL-1β.
- Author
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Hsi-Min Hsiao, Fernandez, Ramiro, Satona Tanaka, Wenjun Li, Spahn, Jessica H., Stephen Chiu, Akbarpour, Mahzad, Ruiz-Perez, Daniel, Qiang Wu, Turam, Cem, Scozzi, Davide, Tsuyoshi Takahashi, Luehmann, Hannah P., Puri, Varun, Scott Budinger, G. R., Krupnick, Alexander S., Misharin, Alexander V., Lavine, Kory J., Yongjian Liu, and Gelman, Andrew E.
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REPERFUSION injury , *LUNG transplantation , *MONOCYTES , *LEUCOCYTES , *ISCHEMIA , *HOMOGRAFTS - Abstract
Ischemia-reperfusion injury, a form of sterile inflammation, is the leading risk factor for both short-term mortality following pulmonary transplantation and chronic lung allograft dysfunction. While it is well recognized that neutrophils are critical mediators of acute lung injury, processes that guide their entry into pulmonary tissue are not well understood. Here, we found that CCR2+ classical monocytes are necessary and sufficient for mediating extravasation of neutrophils into pulmonary tissue during ischemia-reperfusion injury following hilar clamping or lung transplantation. The classical monocytes were mobilized from the host spleen, and splenectomy attenuated the recruitment of classical monocytes as well as the entry of neutrophils into injured lung tissue, which was associated with improved graft function. Neutrophil extravasation was mediated by MyD88-dependent IL-1β production by graft-infiltrating classical monocytes, which downregulated the expression of the tight junction-associated protein ZO-2 in pulmonary vascular endothelial cells. Thus, we have uncovered a crucial role for classical monocytes, mobilized from the spleen, in mediating neutrophil extravasation, with potential implications for targeting of recipient classical monocytes to ameliorate pulmonary ischemia-reperfusion injury in the clinic. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
25. WT1 CpG islands methylation in human lung cancer: A pilot study
- Author
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Bruno, Pierdonato, Gentile, Giovanna, Mancini, Rita, De Vitis, Claudia, Esposito, Maria Cristina, Scozzi, Davide, Mastrangelo, Mario, Ricci, Alberto, Mohsen, Ibrahim, Ciliberto, Gennaro, Simmaco, Maurizio, and Mariotta, Salvatore
- Subjects
- *
CPG nucleotides , *LUNG cancer & genetics , *PROMOTERS (Genetics) , *EPIGENETICS , *GENE silencing , *METHYLATION , *TUMOR suppressor proteins , *CELLULAR signal transduction - Abstract
Abstract: Background: CpG island hypermethylation of gene promoters and regulatory regions is a well-known mechanism of epigenetic silencing of tumor suppressors and is directly linked to carcinogenesis. Wilm’s tumor gene (WT1) is a tumor suppressor protein involved in the regulation of human cell growth and differentiation and a modulator of oncogenic K Ras signaling in lung cancer. Changes in the pattern of methylation of the WT1 gene have not yet been studied in detail in human lung cancer. In this study we compared the methylation profile of WT1 gene in samples of neoplastic and non-neoplastic lung tissue taken from the same patients. Methods: DNA was extracted from neoplastic and normal lung tissue obtained from 16 patients with non small cell lung cancer (NSCLC). The methylation status of 29 CpG islands in the 5′ region of WT1 was determined by pyrosequencing. Statistical analysis was carried out by T test and Mann Whitney test. Results: The mean percentage of methylation, considering all CpG islands of WT1 in the neoplastic tissues of the 16 NSCLC patients, was 16.2±3.4, whereas in the normal lung tissue from the same patients it was 5.6±1.7 (p <0.001). Adenocarcinomas presented higher methylation levels than squamous cell carcinomas (p <0,001). Conclusions: Methylation of WT1 gene is significantly increased in NSCLC. Both histotype and exposure to cigarette smoke heavily influence the pattern of CpG islands which undergo hypermethylation. [Copyright &y& Elsevier]
- Published
- 2012
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26. Downregulation of Tumor Suppressor Gene LKB1 During Severe Primary Graft Dysfunction After Human Lung Transplantation: Implication for the Development of Chronic Lung Allograft Dysfunction.
- Author
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Rahman M, Scozzi D, Eguchi N, Klein R, Sankpal NV, Sureshbabu A, Fleming T, Hachem R, Smith M, Bremner R, and Mohanakumar T
- Abstract
Background: Severe primary graft dysfunction (PGD) after lung transplantation (LTx) is a significant risk factor for the development of bronchiolitis obliterans syndrome (BOS). Recent data from our group demonstrated that small extracellular vesicles (sEVs) isolated from the plasma of LTx recipients with BOS have reduced levels of tumor suppressor gene liver kinase B1 (LKB1) and promote epithelial-to-mesenchymal transition (EMT) and fibrosis. Here, we hypothesized that early inflammatory responses associated with severe PGD (PGD2/3) can downregulate LKB1 levels in sEVs, predisposing to the development of chronic lung allograft dysfunction (CLAD)., Methods: sEVs were isolated from the plasma of human participants by Exosome Isolation Kit followed by 0.20-µm filtration and characterized by NanoSight and immunoblotting analysis. Lung self-antigens (K alpha 1 tubulin, Collagen V), LKB1, nuclear factor kappa B, and EMT markers in sEVs were compared by densitometry analysis between PGD2/3 and no-PGD participants. Neutrophil-derived factors and hypoxia/reperfusion effects on LKB1 levels and EMT were analyzed in vitro using quantitative real-time polymerase chain reaction and Western blotting., Results: LKB1 was significantly downregulated in PGD2/3 sEVs compared with no-PGD sEVs. Within PGD2/3 participants, lower post-LTx LKB1 was associated with CLAD development. Hypoxia/reperfusion downregulates LKB1 and is associated with markers of EMT in vitro. Finally, lower LKB1 levels in PGD2/3 are associated with increased markers of EMT., Conclusions: Our results suggest that in post-LTx recipients with PGD2/3, downregulation of LKB1 protein levels in sEVs is associated with increased EMT markers and may result in the development of CLAD. Our results also suggest that ischemia/reperfusion injury during LTx may promote CLAD through the early downregulation of LKB1., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2024
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27. Necroptosis triggers spatially restricted neutrophil-mediated vascular damage during lung ischemia reperfusion injury.
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Li W, Terada Y, Tyurina YY, Tyurin VA, Bery AI, Gauthier JM, Higashikubo R, Tong AY, Zhou D, Nunez-Santana F, Lecuona E, Hassan A, Hashimoto K, Scozzi D, Puri V, Nava RG, Krupnick AS, Lavine KJ, Gelman AE, Miller MJ, Kagan VE, Bharat A, and Kreisel D
- Subjects
- Animals, Endothelium, Vascular injuries, Humans, Lung blood supply, Mice, Mice, Knockout, Reperfusion Injury genetics, Toll-Like Receptor 4 genetics, Toll-Like Receptor 4 metabolism, Endothelium, Vascular metabolism, Lung metabolism, Necroptosis, Neutrophil Infiltration, Neutrophils metabolism, Reperfusion Injury metabolism
- Abstract
Ischemia reperfusion injury represents a common pathological condition that is triggered by the release of endogenous ligands. While neutrophils are known to play a critical role in its pathogenesis, the tissue-specific spatiotemporal regulation of ischemia-reperfusion injury is not understood. Here, using oxidative lipidomics and intravital imaging of transplanted mouse lungs that are subjected to severe ischemia reperfusion injury, we discovered that necroptosis, a nonapoptotic form of cell death, triggers the recruitment of neutrophils. During the initial stages of inflammation, neutrophils traffic predominantly to subpleural vessels, where their aggregation is directed by chemoattractants produced by nonclassical monocytes that are spatially restricted in this vascular compartment. Subsequent neutrophilic disruption of capillaries resulting in vascular leakage is associated with impaired graft function. We found that TLR4 signaling in vascular endothelial cells and downstream NADPH oxidase 4 expression mediate the arrest of neutrophils, a step upstream of their extravasation. Neutrophil extracellular traps formed in injured lungs and their disruption with DNase prevented vascular leakage and ameliorated primary graft dysfunction. Thus, we have uncovered mechanisms that regulate the initial recruitment of neutrophils to injured lungs, which result in selective damage to subpleural pulmonary vessels and primary graft dysfunction. Our findings could lead to the development of new therapeutics that protect lungs from ischemia reperfusion injury.
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- 2022
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28. Circulating mitochondrial DNA is an early indicator of severe illness and mortality from COVID-19.
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Scozzi D, Cano M, Ma L, Zhou D, Zhu JH, O'Halloran JA, Goss C, Rauseo AM, Liu Z, Sahu SK, Peritore V, Rocco M, Ricci A, Amodeo R, Aimati L, Ibrahim M, Hachem R, Kreisel D, Mudd PA, Kulkarni HS, and Gelman AE
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- Aged, Aged, 80 and over, Biomarkers blood, COVID-19 mortality, COVID-19 therapy, COVID-19 virology, Female, Follow-Up Studies, Hospital Mortality, Humans, Intensive Care Units statistics & numerical data, Male, Middle Aged, Prospective Studies, ROC Curve, Renal Replacement Therapy statistics & numerical data, Respiration, Artificial statistics & numerical data, Risk Factors, SARS-CoV-2 isolation & purification, Vasoconstrictor Agents therapeutic use, COVID-19 diagnosis, Cell-Free Nucleic Acids blood, DNA, Mitochondrial blood, Severity of Illness Index
- Abstract
BackgroundMitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether circulating cell-free MT-DNA quantitation could be used to predict the risk of poor COVID-19 outcomes remains undetermined.MethodsWe measured circulating MT-DNA levels in prospectively collected, cell-free plasma samples from 97 subjects with COVID-19 at hospital presentation. Our primary outcome was mortality. Intensive care unit (ICU) admission, intubation, vasopressor, and renal replacement therapy requirements were secondary outcomes. Multivariate regression analysis determined whether MT-DNA levels were independent of other reported COVID-19 risk factors. Receiver operating characteristic and area under the curve assessments were used to compare MT-DNA levels with established and emerging inflammatory markers of COVID-19.ResultsCirculating MT-DNA levels were highly elevated in patients who eventually died or required ICU admission, intubation, vasopressor use, or renal replacement therapy. Multivariate regression revealed that high circulating MT-DNA was an independent risk factor for these outcomes after adjusting for age, sex, and comorbidities. We also found that circulating MT-DNA levels had a similar or superior area under the curve when compared against clinically established measures of inflammation and emerging markers currently of interest as investigational targets for COVID-19 therapy.ConclusionThese results show that high circulating MT-DNA levels are a potential early indicator for poor COVID-19 outcomes.FundingWashington University Institute of Clinical Translational Sciences COVID-19 Research Program and Washington University Institute of Clinical Translational Sciences (ICTS) NIH grant UL1TR002345.
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- 2021
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29. Circulating Mitochondrial DNA is an Early Indicator of Severe Illness and Mortality from COVID-19.
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Scozzi D, Cano M, Ma L, Zhou D, Zhu JH, O'Halloran JA, Goss C, Rauseo AM, Liu Z, Peritore V, Rocco M, Ricci A, Amodeo R, Aimati L, Ibrahim M, Hachem R, Kreisel D, Mudd PA, Kulkarni HS, and Gelman AE
- Abstract
Mitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether the appearance of cell-free MT-DNA is linked to poor COVID-19 outcomes remains undetermined. Here, we quantified circulating MT-DNA in prospectively collected, cell-free plasma samples from 97 subjects with COVID-19 at the time of hospital presentation. Circulating MT-DNA were sharply elevated in patients who eventually died, required ICU admission or intubation. Multivariate regression analysis revealed that high circulating MT-DNA levels is an independent risk factor for all of these outcomes after adjusting for age, sex and comorbidities. Additionally, we found that circulating MT-DNA has a similar or superior area-under-the curve when compared to clinically established measures of systemic inflammation, as well as emerging markers currently of interest as investigational targets for COVID-19 therapy. These results show that high circulating MT-DNA levels is a potential indicator for poor COVID-19 outcomes.
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- 2020
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30. An obligatory role for club cells in preventing obliterative bronchiolitis in lung transplants.
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Liu Z, Liao F, Scozzi D, Furuya Y, Pugh KN, Hachem R, Chen DL, Cano M, Green JM, Krupnick AS, Kreisel D, Perl AKT, Huang HJ, Brody SL, and Gelman AE
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- Animals, Bronchioles immunology, Bronchiolitis Obliterans pathology, CD8-Positive T-Lymphocytes immunology, Cells, Cultured, Coculture Techniques, Disease Models, Animal, Graft Rejection pathology, Humans, Mice, Primary Cell Culture, Respiratory Mucosa cytology, Respiratory Mucosa immunology, Transplantation, Homologous adverse effects, Bronchioles cytology, Bronchiolitis Obliterans immunology, Epithelial Cells immunology, Graft Rejection immunology, Lung Transplantation adverse effects
- Abstract
Obliterative bronchiolitis (OB) is a poorly understood airway disease characterized by the generation of fibrotic bronchiolar occlusions. In the lung transplant setting, OB is a pathological manifestation of bronchiolitis obliterans syndrome (BOS), which is a major impediment to long-term recipient survival. Club cells play a key role in bronchiolar epithelial repair, but whether they promote lung transplant tolerance through preventing OB remains unclear. We determined if OB occurs in mouse orthotopic lung transplants following conditional transgene-targeted club cell depletion. In syngeneic lung transplants club cell depletion leads to transient epithelial injury followed by rapid club cell-mediated repair. In contrast, allogeneic lung transplants develop severe OB lesions and poorly regenerate club cells despite immunosuppression treatment. Lung allograft club cell ablation also triggers the recognition of alloantigens, and pulmonary restricted self-antigens reported associated with BOS development. However, CD8+ T cell depletion restores club cell reparative responses and prevents OB. In addition, ex-vivo analysis reveals a specific role for alloantigen-primed effector CD8+ T cells in preventing club cell proliferation and maintenance. Taken together, we demonstrate a vital role for club cells in maintaining lung transplant tolerance and propose a new model to identify the underlying mechanisms of OB.
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- 2019
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31. Naive CD4 + T Cells Carrying a TLR2 Agonist Overcome TGF-β-Mediated Tumor Immune Evasion.
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Ibrahim M, Scozzi D, Toth KA, Ponti D, Kreisel D, Menna C, De Falco E, D'Andrilli A, Rendina EA, Calogero A, Krupnick AS, and Gelman AE
- Subjects
- Animals, Antigen-Presenting Cells immunology, Antigen-Presenting Cells metabolism, Cell Differentiation genetics, Cell Differentiation immunology, Gene Expression, Interferon-gamma genetics, Interferon-gamma metabolism, Ligands, Lymphocyte Activation immunology, Mice, Mice, Knockout, Models, Biological, Myeloid Differentiation Factor 88 metabolism, Neoplasms genetics, Neoplasms pathology, Proto-Oncogene Proteins c-akt metabolism, Receptors, Antigen, T-Cell metabolism, Signal Transduction, Toll-Like Receptor 2 genetics, Tumor Microenvironment genetics, Tumor Microenvironment immunology, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Neoplasms immunology, Neoplasms metabolism, Toll-Like Receptor 2 agonists, Transforming Growth Factor beta metabolism, Tumor Escape immunology
- Abstract
TLR agonists are effective at treating superficial cancerous lesions, but their use internally for other types of tumors remains challenging because of toxicity. In this article, we report that murine and human naive CD4
+ T cells that sequester Pam3 Cys4 (CD4+ TPam3 ) become primed for Th 1 differentiation. CD4+ TPam3 cells encoding the OVA-specific TCR OT2, when transferred into mice bearing established TGF-β-OVA-expressing thymomas, produce high amounts of IFN-γ and sensitize tumors to PD-1/programmed cell death ligand 1 blockade-induced rejection. In contrast, naive OT2 cells without Pam3 Cys4 cargo are prone to TGF-β-dependent inducible regulatory Foxp3+ CD4+ T cell conversion and accelerate tumor growth that is largely unaffected by PD-1/programmed cell death ligand 1 blockade. Ex vivo analysis reveals that CD4+ TPam3 cells are resistant to TGF-β-mediated gene expression through Akt activation controlled by inputs from the TCR and a TLR2-MyD88-dependent PI3K signaling pathway. These data show that CD4+ TPam3 cells are capable of Th 1 differentiation in the presence of TGF-β, suggesting a novel approach to adoptive cell therapy., (Copyright © 2018 by The American Association of Immunologists, Inc.)- Published
- 2018
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32. The Role of Neutrophils in Transplanted Organs.
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Scozzi D, Ibrahim M, Menna C, Krupnick AS, Kreisel D, and Gelman AE
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- Animals, Humans, Graft Rejection immunology, Immunity, Innate immunology, Neutrophils immunology, Organ Transplantation
- Abstract
Neutrophils are often viewed as nonspecialized effector cells whose presence is a simple indicator of tissue inflammation. There is new evidence that neutrophils exist in subsets and have specialized effector functions that include extracellular trap generation and the stimulation of angiogenesis. The application of intravital imaging to transplanted organs has revealed novel requirements for neutrophil trafficking into graft tissue and has illuminated direct interactions between neutrophils and other leukocytes that promote alloimmunity. Paradoxically, retaining some neutrophilia may be important to induce or maintain tolerance. Neutrophils can stimulate anti-inflammatory signals in other phagocytes and release molecules that inhibit T cell activation. In this article, we will review the available evidence of how neutrophils regulate acute and chronic inflammation in transplanted organs and discuss the possibility of targeting these cells to promote tolerance., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)
- Published
- 2017
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33. Reliability of direct sequencing of EGFR: comparison between cytological and histological samples from the same patient.
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Bruno P, Mariotta S, Ricci A, Duranti E, Scozzi D, Noto A, Mancini R, Giarnieri E, and Giovagnoli MR
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- Adult, Aged, Biopsy, Needle, Bronchoalveolar Lavage, Bronchoscopy methods, Cytological Techniques, Exons, Female, Histological Techniques, Humans, Lung Neoplasms genetics, Male, Middle Aged, Reproducibility of Results, ErbB Receptors genetics, Sequence Analysis, DNA
- Abstract
The results of a recent study have shown the superiority of treatment with gefitinib or erlotinib in lung tumors positive for epidermal growth factor receptor (EGFR) mutation. As a consequence, the complete diagnosis of lung cancer cannot be limited to histotype classification, but should include a series of molecular biology analyses. In most cases, the diagnosis of lung cancer is performed on cytological specimens; therefore, there is a need to obtain a complete and reliable molecular diagnosis on cytologic specimens. Brushing, transbronchial needle aspiration (TBNA) and broncho alveolar lavage during fibro-bronchoscopy allow the sampling of the lung and the mediastinal lymph node. The aim of this study was to demonstrate that direct sequencing of exons 19 and 21 of EGFR in lung tumors, carried out on the cytological samples obtained through fibro-bronchoscopy, is as reliable as the same analysis carried out on a histological surgical sample obtained from the same individual. We considered 50 patients with a histological diagnosis of lung adenocarcinoma whose cytological samples, obtained by fibro-bronchoscopy and histological samples, obtained by surgical resection were available. A comparison of the sensitivity and reliability of the molecular biology analyses carried out on histological and cytological samples of the same patient was carried out. The combined mutation percentage of exons 19 and 21 of EGFR was 10%. The results of the analyses carried out on cytological samples matched those obtained from the histological samples. The feasibility of EGFR analysis on cytological samples has already been demonstrated in previous studies, however these studies referred to the method of fluorescence in situ hybridization, or did not perform any comparison between histological samples from the same patient; our work, on the other hand, shows that direct sequencing of exons 19 and 21 of the EGFR gene is feasible on fibro-bronchoscopy cytological samples with the same reliability offered by the histological samples obtained from the same patient.
- Published
- 2011
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