Search

Background: Chronic lung allograft dysfunction (CLAD) and its obstructive form, the obliterative bronchiolitis (OB), are the main long-term complications related to high mortality rate postlung transplantation. CLAD treatment lacks a significant success in survival. Here, we investigated a new strategy through inhibition of the proinflammatory mitogen- and stress-activated kinase 1 (MSK1) kinase., Methods: MSK1 expression was assessed in a mouse OB model after heterotopic tracheal allotransplantation. Pharmacological inhibition of MSK1 (H89, fasudil, PHA767491) was evaluated in the murine model and in a translational model using human lung primary fibroblasts in proinflammatory conditions. MSK1 expression was graded over time in biopsies from a cohort of CLAD patients., Results: MSK1 mRNA progressively increased during OB (6.4-fold at D21 posttransplantation). Inhibition of MSK1 allowed to counteract the damage to the epithelium (56% restoration for H89), and abolished the recruitment of MHCII+ (94%) and T cells (100%) at the early inflammatory phase of OB. In addition, it markedly decreased the late fibroproliferative obstruction in allografts (48%). MSK1 inhibitors decreased production of IL-6 (whose transcription is under the control of MSK1) released from human lung fibroblasts (96%). Finally, we confirmed occurrence of a 2.9-fold increased MSK1 mRNA expression in lung biopsies in patients at 6 months before CLAD diagnosis as compared to recipients with stable lung function., Conclusions: These findings suggest the overall interest of the MSK1 kinase either as a marker or as a potential therapeutic target in lung dysfunction posttransplantation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Localization of inflammatory stimuli may direct lung allografts to different phenotypes of chronic dysfunction, such as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). We hypothesized that airway stimulation with lipopolysaccharide (LPS) in rats leads to airway-centered inflammation similar to human BOS., Methods: Rat left lung transplantation was conducted (donor: Brown Norway, recipient: Lewis). Allotransplant recipients received cyclosporine A (CsA) until postoperative day 56 with airway instillation of LPS (Allo-LPS, n = 8), phosphate buffered saline (Allo-PBS, n = 5) from days 35 to 46 (3 times a wk), or no further treatment (n = 4). Some allotransplant recipients received CsA until day 14 and were immunosuppression free after day 15 until day 56. Bronchial and pleural fibrosis were semiquantified; alveolar fibrosis was evaluated with a histological scale., Results: The Allo-LPS group had significantly increased International Society for Heart and Lung Transplantation rejection grades (grade A, P = 0.005; grade B, P = 0.004), bronchial obstructive proportion (0.34 ± 0.04% [Allo-LPS] versus 0.11 ± 0.04% [Allo-PBS], P = 0.006), and airway resistance (3.05 ± 1.78 cm H2O·s/mL [Allo-LPS] versus 0.83 ± 0.58 cm H2O·s/mL [Allo-PBS], P = 0.007) compared with other groups. Allotransplant recipients that underwent a short course of CsA developed RAS-like fibrosis involving the airways, alveoli, and pleura., Conclusions: Airway instillation of LPS in allografts under immunosuppression resulted in BOS-like airway-centered inflammation and fibrosis distinct from RAS-like diffuse fibrosis, which was induced by a shortened course of immunosuppression. We propose novel animal models for BOS and RAS after lung transplantation.

Background: Dysregulated airway epithelial repair following injury is a proposed mechanism driving posttransplant bronchiolitis obliterans (BO), and its clinical correlate bronchiolitis obliterans syndrome (BOS). This study compared gene and cellular characteristics of injury and repair in large (LAEC) and small (SAEC) airway epithelial cells of transplant patients., Methods: Subjects were recruited at the time of routine bronchoscopy posttransplantation and included patients with and without BOS. Airway epithelial cells were obtained from bronchial and bronchiolar brushing performed under radiological guidance from these patients. In addition, bronchial brushings were also obtained from healthy control subjects comprising of adolescents admitted for elective surgery for nonrespiratory-related conditions. Primary cultures were established, monolayers wounded, and repair assessed (±) azithromycin (1 µg/mL). In addition, proliferative capacity as well as markers of injury and dysregulated repair were also assessed., Results: SAEC had a significantly dysregulated repair process postinjury, despite having a higher proliferative capacity than large airway epithelial cells. Addition of azithromycin significantly induced repair in these cells; however, full restitution was not achieved. Expression of several genes associated with epithelial barrier repair (matrix metalloproteinase 7, matrix metalloproteinase 3, the integrins β6 and β8, and β-catenin) were significantly different in epithelial cells obtained from patients with BOS compared to transplant patients without BOS and controls, suggesting an intrinsic defect., Conclusions: Chronic airway injury and dysregulated repair programs are evident in airway epithelium obtained from patients with BOS, particularly with SAEC. We also show that azithromycin partially mitigates this pathology.

Objective: To evaluate the diagnostic value of function volume/morphological volume ratio calculated from ventilation/perfusion single-photon emission computed tomography/computed tomography in distinguishing the lungs with bronchiolitis obliterans syndrome (BOS) from the lungs without this syndrome after lung transplantation and to assess its relationship with spirometry parameters., Materials and Methods: We retrospectively identified 84 consecutive lung transplant recipients and 13 donors who underwent ventilation/perfusion single-photon emission computed tomography/computed tomography. Differences in the function volume/morphological volume ratio of unilateral lungs were tested for significance between the lungs with and without BOS. Receiver operating characteristics and correlations between function volume/morphological volume ratios of bilateral lungs and forced expiratory volume in 1 s, forced vital capacity, and total lung capacity were analyzed., Results: The function volume/morphological volume ratios of ventilation and perfusion images of unilateral lungs were significantly lower in lungs with BOS (each P<0.0001). The area under the curve values of ventilation and perfusion images were 0.97 and 0.99, respectively. Significant correlations were identified between the function volume/morphological volume ratios of ventilation and perfusion images and forced expiratory volume in 1 s (r=0.54, P<0.0001 and r=0.45, P<0.0001, respectively). The function volume/morphological volume ratio of ventilation image had a significantly weak correlation with forced vital capacity., Conclusion: The function volume/morphological volume ratio enables a semiquantitative assessment of ventilation and perfusion lung functions and is useful for diagnosing BOS after lung transplantation.

Purpose of Review: Lung transplantation (LTx) can be a life saving treatment in end-stage pulmonary diseases, but survival after transplantation is still limited. Posttransplant development of chronic lung allograft dysfunction with bronchiolits obliterans syndrome (BOS) as the major subphenotype, is the main cause of morbidity and mortality. Early identification of high-risk patients for BOS is a large unmet clinical need. In this review, we discuss gene polymorphisms and gene expression related to the development of BOS., Recent Findings: Candidate gene studies showed that donor and recipient gene polymorphisms affect transplant outcome and BOS-free survival after LTx. Both selective and nonselective gene expression studies revealed differentially expressed fibrosis and apoptosis-related genes in BOS compared with non-BOS patients. Significantly, recent microarray expression analysis of blood and broncho-alveolar lavage suggest a role for B-cell and T-cell responses prior to the development of BOS. Furthermore, 6 months prior to the development of BOS differentially expressed genes were identified in peripheral blood cells., Summary: Genetic polymorphisms and gene expression changes are associated with the development of BOS. Future genome wide studies are needed to identify easily accessible biomarkers for prediction of BOS toward precision medicine.

Background: Immunosuppression therapy after lung transplantation fails to prevent bronchiolitis obliterans syndrome (BOS) in many patients, primarily a disease of the small airways. We have reported that BOS is associated with a lack of suppression of cytotoxic mediators, and proinflammatory cytokines, in peripheral blood T, NKT-like (particularly CD8+) and NK cells. We also showed a loss of glucocorticoid receptor (GCR) in proinflammatory lymphocytes after transplant. It is unknown whether these proinflammatory lymphocytes target the small and/or large airways in BOS., Methods: Blood, bronchoalveolar lavage, large proximal, and small distal airway brushings were collected from patients with BOS (n = 10), stable lung transplant patients (n = 18), and healthy aged-matched controls (n = 10). Intracellular cytotoxic mediators (perforin/granzyme B), proinflammatory cytokines (IFNγ/TNFα), and expression of GCR were determined in lymphocytes subsets from cultured blood using flow cytometry., Results: Increases in CD8 T cells, NKT-like cells, and NK cells were found in the small distal airways in BOS compared with stable patients and controls. An increase in perforin, granzyme B, IFNγ, TNFα, and a loss of GCR from these lymphocyte subsets was also found in BOS. GCR expression by CD8+ T cells from small airways correlated with FEV1 (R = 0.834, P = 0.039). Many of these changes significantly differed from those in the large airways., Conclusions: BOS is associated with increased cytotoxic/proinflammatory CD8+ T, NKT-like, and NK cells in the small airways. Treatments that increase GCR in these lymphocyte subsets may improve graft survival.

Background: Bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx) results from bronchial epithelial cell (BECs) damages, thought to be orchestrated by T cells primed by antigen-presenting cell presenting alloantigens. In this cell cross-talk, BECs are also suspected to play a pivotal immunosuppressive role in T cell alloreactivity. We studied the immunomodulating role of BECs in a human ex vivo model of allogeneic T cell response, both in healthy subjects and LTx recipients., Methods: BECs from 35 LTx recipients (n = 22 stable, n = 13 BOS) and healthy controls (n = 25) were cultured as primary cell cultures. Their inhibitory capacities through the involvement of tolerogenic molecules (HLA-G, TGF-β, and IL-10) were tested on a mixed lymphocyte reaction between antigen-presenting cells and recipient T cells., Results: Control BECs inhibited T cell alloproliferation by a mean of 53 ± 7%. This inhibitory effect of BECs was significantly reduced in the stable LTx group (24 ± 8%, P = 0.009), but not in the BOS TxP group (53 ± 10%, P = 0.97). Neutralization of HLA-G, TGF-β, and IL-10 partially restored T cell alloproliferation, arguing for their involvement in the immunosuppressive effect of BECs. BECs culture supernatant from stable LTx patients with impaired BEC properties showed a skewed Th2-type secretion profile (high IL-4/IFN-γ ratio)., Conclusions: The inhibitory properties of BECs are dysregulated in stable LTx recipients, which could suggest their instrumental role in the initiation of BOS process and potential targeted therapies.

Background: Chronic lung allograft dysfunction (CLAD), presenting as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS) is the major limiting factor of long-term survival in lung transplantation. Its pathogenesis is still obscure. In BOS, persistent alloimmune injury and chronic airway inflammation are suggested. One of the main tasks of the lymphatic vessel (LV) system is the promotion of immune cell trafficking. The formation of new LVs has been shown to trigger chronic allograft rejection in kidney transplants. We therefore sought to address the role of lymphangiogenesis in CLAD., Methods: Formalin-fixed paraffin-embedded tissue samples of 22 patients receiving a lung retransplantation due to BOS or RAS were collected. Lymphatic vessel density (LVD) was determined by immunohistochemical staining for podoplanin. Lung tissue obtained from 13 non-CLAD patients served as control. The impact of LVD on graft survival was assessed., Results: Lymphatic vessel density in CLAD patients did not differ from those in control subjects (median number of LVs per bronchiole: 4.75 (BOS), 6.47 (RAS), 4.25 (control), P = 0.97). Moreover, the number of LVs was not associated with regions of cellular infiltrates (median number of LVs per bronchiole: with infiltrates, 5.00 (BOS), 9.00 (RAS), 4.00 (control), P = 0.62; without infiltrates, 4.5 (BOS), 0.00 (RAS), 4.56 (control), P = 0.74). Lymphatic vessel density did not impact the time to development of BOS or RAS in lung transplantation (low vs high LVD: 38.5 vs 86.0 months, P = 0.15 [BOS]; 60.5 vs 69.5 months, P = 0.80 [RAS])., Conclusions: Unlike chronic organ failure in kidney transplantation, lymphangiogenesis is not altered in CLAD patients. Our findings highlight unique immunological processes leading to BOS and RAS.

Background: The long-term outcome of lung transplantation is impeded by the development of obliterative bronchiolitis (OB). We sought to investigate the relationship between the apoptosis of tracheal epithelial cells and bone marrow-derived myofibroblasts in the process of OB., Methods: The mouse orthotopic tracheal transplant model was established. The allografts and syngrafts were harvested at 1, 2, 3, and 4 weeks after tracheal transplant. The percentage of tracheal lumen occlusion was assayed via histology and morphometry. Immunofluorescence staining was used to detect the apoptotic epithelial cells and recipient-derived myofibroblasts. The expression of SDF-1α and TGF-β and the infiltrations of CD4 and CD8 T cells in the grafts were detected using immunohistochemical staining., Results: We found that there were more apoptotic epithelia in the allograft group than in the syngraft group and that the level of tracheal lumen occlusion was higher at different time points. Moreover, the increase in the apoptosis of the tracheal epithelium occurred earlier than that of occlusion of the tracheal lumen. There were more myofibroblasts derived from the recipient's bone marrow and more CD4 and CD8 T cells in the allografts. The expression of SDF-1α and TGF-β was higher in the epithelium from allografts than in those of the syngrafts., Conclusions: Our study indicated that the apoptotic tracheal epithelia in the OB model might increase the amount of myofibroblasts derived from the recipient's bone marrow. Therapeutic methods aimed at preventing apoptosis of the tracheal epithelium may improve the outcome of lung transplantation.

Pulmonary chronic graft-versus-host disease (cGvHD) is one of the most common causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (aHSCT). Herein, we describe a patient with severe restrictive lung defect secondary to cGvHD. A 21-year-old male patient was admitted to our pediatric intensive care unit (PICU) with pneumonia and respiratory distress. He had a history of aHSCT for chronic myelogeneous leukemia at the age of 17 years. Six months after undergoing aHSCT, he had developed cGvHD involving skin, mouth, eye, lung, liver, and gastrointestinal tract. At the time of PICU admission he had respiratory distress and required ventilation support. Thorax high-resolution computed tomography was consistent with bronchiolitis obliterans. Although bronchiolitis obliterans is an obstructive lung defect, a restrictive pattern became prominent in the clinical course because of the sclerotic chest wall skin. The activity of cGvHD kept increasing despite the therapy and we lost the patient because of severe respiratory distress and massive hemoptysis secondary to bronchiectasis. In conclusion, pulmonary cGvHD can present with restrictive changes related with the advanced sclerosis of the chest wall skin. Performing a fasciotomy or a scar revision for the rigid chest wall in selected patients may improve the patients ventilation.

Background: The IL-17 axis is implicated in pathogenesis of chronic rejection after human lung transplantation. Using a murine model of obliterative airway disease (OAD), we recently demonstrated that Abs to MHC class I antigens can induce immune responses to self-antigens that contributes to immunopathogenesis of chronic rejection. Using a murine model of OAD, we determined the role of IL-17 family members in induction of autoimmunity leading to OAD after ligation of MHC class I., Methods: Anti-MHC class I or control antibodies (Abs) were administered intrabronchially to wild-type (WT) and IL-17a knock out (IL-17A-/-) C57BL/6., Results: By day 30, anti-MHC I administered endobronchially in IL-17A-/- mice demonstrated significant reduction in cellular infiltration, a 36.8% reduction in CD4 T cells, 62.7% in CD11b macrophages, 37.5% in degree of fibrosis, 1.94 fold and 2.17 fold decrease in anti-KAT and anti-Col-V, respectively, when compared with wild-type mice. Analysis of lung infiltrating cells in anti-MHC I WT revealed increase in IL-17A (KAT:92+21,Col-V:103+19spm) and IL-17F (KAT:5.03%,Col-V:2.75%) secreting CD4+ T cells. However, administration of anti-MHC I in IL-17A-/- demonstrated increase only in IL-17F for KAT (13.70%) and Col-V (7.08%). Anti-IL-17(A-F) mAb administration after anti-MHC I abrogated OAD in both WT and IL-17A-/-., Conclusion: Our findings indicate that IL-17A and IL-17F secreted by CD4+Th17 cells specific to lung self-antigens are critical mediators of autoimmunity leading to the pathogenesis of OAD.

Background: The calcium-activated potassium channel KCa3.1 is critically involved in T-cell activation as well as in the proliferation of smooth muscle cells and fibroblasts. We sought to investigate whether KCa3.1 contributes to the pathogenesis of obliterative airway disease (OAD) and whether knockout or pharmacologic blockade would prevent the development of OAD., Methods: Tracheas from CBA donors were heterotopically transplanted into the omentum of C57Bl/6J wild-type or KCa3.1 mice. C57Bl/6J recipients were either left untreated or received the KCa3.1 blocker TRAM-34 (120 mg/kg/day). Histopathology and immunologic assays were performed on postoperative day 5 or 28., Results: Subepithelial T-cell and macrophage infiltration on postoperative day 5, as seen in untreated allografts, was significantly reduced in the KCa3.1 and TRAM-34 groups. Also, systemic Th1 activation was significantly and Th2 mildly reduced by KCa3.1 knockout or blockade. After 28 days, luminal obliteration of tracheal allografts was reduced from 89%±21% in untreated recipients to 53%±26% (P=0.010) and 59%±33% (P=0.032) in KCa3.1 and TRAM-34-treated animals, respectively. The airway epithelium was mostly preserved in syngeneic grafts, mostly destroyed in the KCa3.1 and TRAM-34 groups, and absent in untreated allografts. Allografts triggered an antibody response in untreated recipients, which was significantly reduced in KCa3.1 animals. KCa3.1 was detected in T cells, airway epithelial cells, and myofibroblasts. TRAM-34 dose-dependently suppressed proliferation of wild-type C57B/6J splenocytes but did not show any effect on KCa3.1 splenocytes., Conclusions: Our findings suggest that KCa3.1 channels are involved in the pathogenesis of OAD and that KCa3.1 blockade holds promise to reduce OAD development.

Background: Obliterative bronchiolitis after lung transplantation is associated with intrapulmonary lymphoid neogenesis. The purpose of this study was to examine the role of lymphoid neogenesis, especially its relationship with secondary lymphoid organs (SLOs) in allograft airway rejection., Methods: A murine intrapulmonary tracheal transplant model and a conventional subcutaneous tracheal transplant model were tested using wild-type control mice and splenectomized lymphotoxin α knockout (LT) mice deficient in SLOs as recipients., Results: In both subcutaneous and intrapulmonary tracheal transplant models using wild-type animals, tracheal isografts remained open without rejection, whereas allografts showed progressive luminal obliteration after transplantation. Lymphoid neogenesis containing alloreactive T cells was observed in the lungs, which received an intrapulmonary tracheal allograft. Despite a lack of SLOs, intrapulmonary allografts in splenectomized LT mice were rejected and obliterated by day 28, but the rejection of subcutaneous allografts was significantly delayed. Extensive lymphoid neogenesis was observed in the lungs of both intrapulmonary and subcutaneous allograft LT recipients. Increased proliferation of CD4 T cells and B220 B cells was observed in the lungs but not in the thymus or bone marrow., Conclusions: Intrapulmonary lymphoid neogenesis is capable of mounting alloimmune responses without SLOs. Tracheal allograft rejection occurs as efficiently as in wild-type animals when it is placed in the lungs. Tracheal allograft rejection in the subcutaneous tissue occurs in a delayed manner without SLO in association with intrapulmonary lymphoid neogenesis.

Background: Bronchiolitis obliterans syndrome (BOS) has an incidence of 57% at 5 years after lung transplantation, accounts for 30% of all deaths 3 years posttransplant and because treatment options are extremely limited, it constitutes a significant health care problem. Adult mesenchymal stem cells (MSCs) play a role in lung turnover; however, their role in BOS remains unknown., Methods: MSCs were isolated from bronchoalveolar lavage (BAL) in 101 lung allograft recipients. BAL was screened by protein array and MSCs were analyzed by real-time polymerase chain reaction, proliferation, migration, and enzyme linked immunosorbent assays., Results: Multipotent MSCs were isolated from BAL of lung recipients independent of BOS presence. However, MSCs from BOS patients proliferated at higher rates (P<0.001) and were associated with higher α-smooth muscle actin (P = 0.03) but lower surfactant protein B (P = 0.02) compared with those from no-BOS patients. Histological analysis revealed that MSCs are abundant in lung tissue of BOS patients. MSCs from BOS patients produced higher endothelin-1 (ET-1) amounts (P<0.001) compared with those from no-BOS; and ET-1 stimulated whereas ET-1 blockade suppressed MSC proliferation, migration, and differentiation., Conclusions: These results indicate that MSCs are associated with BOS and are governed by ET-1. Targeting MSCs by ET-1 blockade might be useful in BOS treatment.

Background: Community-acquired respiratory viral infections (RVIs) are common in lung transplant patients and may be associated with acute rejection and bronchiolitis obliterans syndrome (BOS). The use of sensitive molecular methods that can simultaneously detect a large panel of respiratory viruses may help better define their effects., Methods: Lung transplant recipients undergoing serial surveillance and diagnostic bronchoalveolar lavages (BALs) during a period of 3 years were enrolled. BAL samples underwent multiplex testing for a panel of 19 respiratory viral types/subtypes using the Luminex xTAG respiratory virus panel assay., Results: Demographics, symptoms, and forced expiratory volume in 1 sec were prospectively collected for 93 lung transplant recipients enrolled. Mean number of BAL samples was 6.2+/-3.1 per patient. A respiratory virus was isolated in 48 of 93 (51.6%) patients on at least one BAL sample. Of 81 positive samples, the viruses isolated included rhinovirus (n=46), parainfluenza 1 to 4 (n=17), coronavirus (n=11), influenza (n=4), metapneumovirus (n=4), and respiratory syncytial virus (n=2). Biopsy-proven acute rejection (> or =grade 2) or decline in forced expiratory volume in 1 sec > or =20% occurred in 16 of 48 (33.3%) patients within 3 months of RVI when compared with 3 of 45 (6.7%) RVI-negative patients within a comparable time frame (P=0.001). No significant difference was seen in incidence of acute rejection between symptomatic and asymptomatic patients. Biopsy-proven obliterative bronchiolitis or BOS was diagnosed in 10 of 16 (62.5%) patients within 1 year of infection., Conclusion: Community-acquired RVIs are frequently detected in BAL samples from lung transplant patients. In a significant percentage of patients, symptomatic or asymptomatic viral infection is a trigger for acute rejection and obliterative bronchiolitis/BOS.

Collagen vascular disease is one of the most common causes of chronic infiltrative lung disease. Patterns of lung injury from collagen vascular disease include nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia, organizing pneumonia, bronchiectasis, obliterative bronchiolitis, and pulmonary arterial hypertension. The prevalence of each entity varies according to the specific disease entity. NSIP and pulmonary hypertension are common in scleroderma, whereas usual interstitial pneumonia, bronchiectasis, and obliterative bronchiolitis are commonly found in rheumatoid arthritis. In systemic lupus erythematosus, pleural effusions and pulmonary hemorrhage are the salient features. In polymyositis, a combination of organizing pneumonia and NSIP is characteristic. Sjögren syndrome is characterized by bronchiectasis and lymphoid interstitial pneumonia, often associated with thin-walled cysts. Ankylosing spondylitis is associated with upper lobe fibrosis, and may be complicated by mycetoma.

Background: Obliterative airway disease (OAD) has been a major obstacle to long-term survival after lung or tracheal transplantations, but the role of airflow has not been examined in the orthotopic or the heterotopic tracheal transplantation models., Methods: Sixty mice were assigned to two experimental groups. Two C57BL/6 tracheal segments were surgically prepared and then orthotopically transplanted into allogeneic BALB/c recipients. In group A mice, both segments were left patent, whereas in group B mice, one of the donor tracheas was occluded with a silk knot to obstruct airflow. Histology, quantitative OAD measurements, electron microscopy, immunohistochemical staining, and apoptosis measurement of the epithelium were performed., Results: Gross examination at harvest showed patent lumens of all tracheal segments. Group A allografts (ventilating tracheas) showed a markedly higher proportion of ciliated epitheliums and less lymphocyte infiltration in the lamina propria, whereas the epithelium appeared metaplastic in group B, with a higher proportion of flattened attenuated epithelium and loss of the normal ciliate architecture. Quantitative morphometric measurements suggested more prominent OAD manifestations in the nonventilating allografts of group B than were present in group A, although recipient-derived epithelium was observed in all allografts under immunohistochemical staining. The apoptotic indexes of the epithelium were 12.1% in allografts with adequate ventilation (group A) and 66.2% in ventilation-occluded allotracheas (group B)., Conclusions: OAD severity and the epithelial repopulation process are closely related to the physiologic environment of airflow. Further research is warranted to explore the underlying mechanisms of this phenomenon.

Background: A retrospective review of pediatric lung transplant recipients at 14 centers in North America and Europe was conducted to characterize the epidemiology and the risk factors for cytomegalovirus (CMV) and to explore the impact of preventative antiviral therapy., Methods: Data were recorded for 1 year posttransplant. Associations between CMV and continuous and categorical risk factors were assessed using Wilcoxon rank sum and chi-square tests, respectively. Associations between time to CMV and risk factors or survival were assessed by multivariable Cox proportional hazards models., Results: Within 12 months posttransplant, 172 of 577 subjects (29.8%) developed 218 CMV episodes (90 asymptomatic infection, 25 syndrome, and 103 disease). Forty-one subjects developed more than one episode of CMV. Donor or recipient CMV seropositivity was associated with increased risk of CMV episodes. Except for decreased prophylaxis in CMV D-/R- subjects, duration of prophylaxis did not vary by D/R serostatus. For CMV D+ subjects, not being on prophylaxis at the time of CMV episode increased the risk of CMV (D+/R+ hazard ratio 3.5, 95% confidence interval 1.4-8.4; D+/R- 1.9, 1.02-3.7). CMV was associated with increased mortality within the first posttransplant year among those with donor or recipient CMV seropositivity (hazard ratio 2.0: 95% confidence interval 1.1-3.6; P=0.024)., Conclusions: CMV remains a serious complication after pediatric lung transplant, and the impact of prophylaxis is complex.

Background: Posttransplant lymphoproliferative disease (PTLD) is a serious complication after lung transplantation and its relation with Epstein-Barr virus (EBV) is well recognized. It has been postulated that preemptive reduction of immunosuppression guided by EBV-DNA load may lead to a significantly lower incidence of PTLD, because of the reconstitution of T-cell control. In this report, we describe the feasibility of this approach in terms of safety with regard to the risk of acute as well as chronic allograft rejection in 75 lung transplant recipients transplanted between 1990 and 2001 and followed for this study from June 1, 2001 until January 1, 2006., Methods: From all patients visiting our outpatient clinic, EBV-DNA load was measured at least twice a year during the study period. In patients with positive results, measurements were repeated every two to four weeks. EBV reactivation was defined as two consecutive EBV-DNA load measurements with a rising trend; with the last measurement exceeding 10.000 copies/mL under stable immunosuppression. In such case, immunosuppression was reduced., Results: EBV reactivation was observed in 26/75 patients (35%). One (1.5%) of these patients developed PTLD during the study period. Acute rejection, acceleration of chronic allograft rejection, or worse survival were not observed after reduction of immunosuppression., Conclusions: Preemptive reduction of immunosuppression after lung transplantation guided by EBV-DNA load appears to be a safe approach for the prevention of PTLD in lung transplant recipients late after transplantation.

A 55-year-old man complained of cough and dyspnea. His chest radiograph and CT scan revealed a solitary nodule with a diameter of 2 cm, which showed an air bronchogram and had a hazy contour. After 3 weeks, the radiologic findings changed to diffuse infiltration with small centrilobular nodules, alveolar consolidation, and bronchial wall thickening. The alveoli contained numerous fibrin balls and organizing tissue, which are typical pathologic features of acute fibrinous and organizing pneumonia (AFOP), on histologic examination. We report the initial radiologic features of AFOP and suggest that there are some radiologic similarities between this condition and cryptogenic organizing pneumonia.

Background: T lymphocytes are crucial in lung allorejection. The contribution of lymphocyte subtypes to the pathogenesis of chronic rejection (bronchiolitis obliterans syndrome [BOS]) remains unclear., Methods: Twenty-nine initially healthy lung transplant recipients underwent 136 bronchoscopic assessments, including bronchoalveolar lavage (BAL) (with flow cytometry) and endobronchial biopsies (EBB) (with immunohistochemistry) over 3 years of follow-up., Results: Of the 29 patients studied over 3 years, 23 developed BOS category 0 p and 17 went on to BOS 1. Compared with controls, the BAL percentage of CD4 cells was lower and the percentage of CD8 cells was increased significantly early posttransplant. Subsequent BAL lymphocyte subtype changes with time, or with the development of BOS, were minimal. By contrast, the early posttransplant EBB lymphocyte numbers were normal (P>0.05 vs. controls); subsequently, CD3 and CD8 (but not CD4) cells were increased with time in patients who did not develop BOS (P<0.05) and, more strikingly, in patients who eventually developed BOS (P<0.01). Multivariate analyses suggested an association between BAL lymphocytes (percentage) and azathioprine dose, female gender, rejection grade A on transbronchial biopsies, and pre-BOS status, whereas EBB CD8 cell counts were associated with time posttransplant, pretransplant diagnosis, and rejection grade B on TBB., Conclusions: There is an early, persistent low percentage of BAL CD4 T cells, high BAL CD8 T cells, and progressively increasing airway wall CD3 and CD8 T cells with time posttransplant in healthy patients (but more predominantly in BOS patients) after transplantation. These immunopathologic changes may suggest that CD8 T cells could escape current immunosuppression and participate in chronic lung rejection.

Purpose of Review: Bronchiolitis obliterans (BO) occurs in both post-lung transplant and nontransplant-related individuals, and is characterized by mainly irreversible airflow obstruction that is often ultimately progressive., Recent Findings: While post-lung transplant BO is a major cause of lung allograft dysfunction, and hence is better characterized than nontransplant-related BO, it is likely that many similarities in pathogenesis and treatment apply to both categories., Summary: Optimal management for BO remains to be established, and the role of retransplantation in this disease requires further consensus. Minimization of risk factors for BO and earlier detection in the form of methacholine challenge testing and HRCT scans of the chest amongst other forms of detection, may help in the stabilization and possible resolution of early BO.

Background: Recent studies have shown the possible role of growth factors and the involvement of macrophages as a source of them in the pathogenesis of bronchiolitis obliterans (BO) after lung transplantation., Objective: The authors intended to determine whether depletion of recipient macrophages by gadolinium chloride (GdCl3) resulted in decreased obliterative airway disease (OAD) in a rat model of heterotopic tracheal transplantation., Methods: A tracheal segment of donor rats (Brown Norway) was transplanted into a subcutaneous pouch of fully major histocompatibility complex-incompatible recipient rats (Lewis). Recipients were injected intravenously with 80 mg/kg of GdCl3.6H2O or saline on days 0, 7, and 14 posttransplant. Allografts were harvested on days 7, 14, 17, and 21 and the degree of OAD resulting from fibroproliferative tissue was pathologically scored on a scale of 0 to 4. A portion of allografts was submitted to reverse-transcriptase polymerase chain reaction analysis to examine mRNA expression for platelet-derived growth factor (PDGF), basic fibroblast growth factor, and transforming growth factor-beta1., Results: Immunohistochemical studies confirmed reduction in the number of ED2+ macrophages in tracheal allografts by GdCl3 injection. GdCl3 treatment significantly decreased OAD of allografts, with the histologic score of 1.4+/-0.3 in the treated animals compared with 3.0+/-0.5 in the controls (mean+/-SE, P=0.02) at day 21 posttransplant, and this was accompanied by decreased PDGF-A and PDGF-B gene expression in the GdCl3 group at day 17 posttransplant., Conclusions: Macrophage reduction by GdCl3 resulted in significantly decreased OAD development and reduced PDGF mRNA expression in allografts. This suggests a potential effectiveness of therapies targeting recipient macrophages in preventing BO after lung transplantation.

Background: Immune injury to airway epithelium is suggested to play a central role in the pathogenesis of obliterative bronchiolitis (OB) after clinical lung transplantation. In several studies, a rejection model of murine trachea transplants is used, resulting in obliterative airway disease (OAD) with similarities to human OB. To focus on the role of an immune response specifically against airway epithelium, we transplanted tracheas from transgenic mice expressing human epithelial glycoprotein (hEGP) on epithelial cells. We hypothesized that the immune response against the hEGP-2 antigen would result in OAD in the trachea transplants., Methods: Tracheas from hEGP-2 transgenic and control nontransgenic FVB/N mice were heterotopically transplanted into FVB/N mice and harvested at week 1, 3, 6, and 9. Anti-hEGP-2 antibodies were determined in the recipient blood. The trachea grafts were analyzed for cellular infiltration, epithelial cell injury, and luminal obliteration., Results: Recipients of transgenic tracheal grafts gradually developed anti-hEGP-2 antibodies. In the transgenic grafts, the submucosa was infiltrated predominantly by CD4+ T cells. Epithelial cells remained present but showed progressive abnormality. The tracheal lumen showed a mild degree of obliteration. All these changes were absent in nontransgenic FVB/N trachea transplants., Conclusion: The hEGP-2 antigen on the epithelial cells of transgenic trachea transplants induces specific humoral and cellular immune responses, leading to a mild form of OAD. It provides a suitable model for further investigation of the role of epithelial cells in the development of OAD in animals and OB in human-lung transplantation.

Background: In posttransplant obliterative bronchiolitis (OB), the major pathologic features are inflammation, epithelial cell injury, fibrosis, and obliteration of the small airways. Tumor necrosis factor (TNF)-alpha is a cytokine known to mediate and augment the inflammatory reaction and to enhance fibroblast proliferation. We assessed the role of TNF-alpha in the development of OB in our heterotopic porcine bronchial transplantation model., Methods: Three groups were formed: autografts, nontreated allografts, and allografts treated with preoperative anti-TNF-alpha monoclonal antibody (infliximab) infusion. The implants were harvested on days 2, 4, 7, 11, 14, 21, and 28 for histologic and immunohistochemical analysis., Results: TNF-alpha inhibition reduced inflammation, rate of epithelial loss, fibrosis, and obliteration early in the development of OB. In the epithelium, the numbers of TNF-alpha-positive epithelial and inflammatory cells and macrophages were significantly lower in treated than in nontreated allografts on day 4; furthermore, in the epithelium and in the bronchial wall, invasion of CD8+ lymphocytes was significantly decreased during the first week., Conclusions: These results indicate that TNF-alpha promotes the development of OB, and inhibition of TNF-alpha may prove beneficial in a clinical setting.

The purpose of this study was to correlate the extent of computed tomographic (CT) findings with the severity of respiratory dysfunction in lung transplant recipients with bronchiolitis obliterans syndrome (BOS). Eighty-nine conventional and 61 thin-section CT scans performed in 44 transplant recipients (17 bilateral, 27 single) with BOS were reviewed for mosaic attenuation, degree of bronchial dilation, bronchial thickening, central and peripheral bronchiectasis, mucus plugging, and air trapping. Findings on conventional and thin-section CT scans were correlated with BOS stage for bilateral and single-lung transplant recipients. In bilateral-lung recipients, a significant correlation existed, although weak, between BOS stage and findings of degree of bronchial dilation (P < 0.01), bronchial wall thickening (P = 0.01), peripheral bronchiectasis (P = 0.01), and mosaic attenuation (P = 0.01) on conventional CT; and bronchial wall thickening (P = 0.01) and mosaic attenuation (P = 0.03) on thin-section CT. In single-lung recipients, BOS stage correlated only with the finding of central bronchiectasis (P = 0.02) on conventional CT scans. No correlation was found between the extent of air trapping and BOS stage in either single- or bilateral-lung transplant recipients. CT findings are relatively poor indices of airflow obstruction in lung transplant recipients with BOS, particularly in those with single-lung transplants for emphysema.

Background: Inflammation, epithelial cell injury, and development of fibrosis and airway obliteration are the major histological features of posttransplant obliterative bronchiolitis (OB). The expression of inducible nitric oxide synthase (iNOS) in the damaged epithelium, accompanied by peroxynitrite, suggests that endogenous nitric oxide (NO) mediates the epithelial destruction preceding obliteration. To elucidate the role of NO in this cascade, heterotopic bronchial allografts were studied in pigs., Methods: Allografts or autografts were harvested serially 3-90 days after transplantation and processed for histology and immunocytochemistry for iNOS, nitrotyrosine, a marker of peroxynitrite formation, and superoxide dismutase (SOD)., Results: During initial ischemic damage to the epithelium, iNOS, nitrotyrosine, and SOD were found to be strongly expressed in the epithelium of all implants as well as later, after partial recovery, parallel to onset of epithelial destruction and subsequent airway obliteration in allografts. The levels of expression of iNOS in fibroblasts during the early phase of obliteration paralleled the onset of fibrosis. Constant expression of iNOS and SOD, but not nitrotyrosine, occurred in autografts and allografts with blocked alloimmune response., Conclusions: These findings suggest that an excessive amount of NO promotes posttransplant obliterative bronchiolitis by destroying airway epithelium and stimulating fibroblast activity. SOD may provide protection by binding reactive molecules and preventing peroxynitrite formation.

Background: In rodent models, investigators have transplanted donor tracheas into a recipient rat's abdomen or s.c. tissue to study airway rejection. We describe a modification of this model, which provides improved histology to study the airway injury related to obliterative bronchiolitis., Methods: The standard technique of implanting the donor trachea was compared to a model in which a tracheal Y graft was created by anastomosis of the donor trachea to the recipient airway. Syngeneic and allogeneic tracheal grafts (Lewis and Brown Norway rats) were harvested at 2 and 4 weeks using each model (eight groups)., Results: Gross patency at the tracheal anastomosis grafts was 100%. All donor tracheas, which were implanted without an anastomosis, were occluded with mucus (syngeneic) or granulation tissue (allogeneic). Syngeneic implant grafts demonstrated significantly less lumenal granulation tissue 35.3%+/-32 than the allograft implant group (95.3%+/-9.2, P=0.0005 at 4 weeks). The anastomotic allograft group demonstrated significantly less lumenal granulation tissue 48.3%+/-23.7 when compared with the implanted allograft group (P=0.003). The implanted allograft demonstrated a severe loss of epithelial integrity by 2 weeks (16.7%+/-38), which progressed to complete loss by 4 weeks (P=0.0001 and P=0.0001 vs. native). This loss was significantly more than that of the anastomotic group at 2 weeks (89.5%+/-13, P=0.004) and 4 weeks (88.3+/-29, P=0.005)., Conclusions: The rat tracheal allograft anastomosed to the recipient airway demonstrated less lumenal granulation tissue obstruction and better preservation of epithelial integrity than an implant allograft, suggesting that an open airway improves assessment of transplant-related changes associated with rejection.

Background: Decreased in vitro T cell alloreactivity, demonstrated by decreased frequencies of peripheral blood donor-specific T cell precursors, may reflect a tolerant state after transplantation and lower the risk for development of chronic graft dysfunction. It is unknown whether a decrease in donor-specific T cell frequencies also occurs after clinical lung transplantation and if such a decrease lowers the risk for bronchiolitis obliterans syndrome (BOS), a hallmark of chronic graft dysfunction. Therefore, we compared changes in posttransplant donor-specific cytotoxic T lymphocyte (CTLp) and helper T lymphocyte precursor (HTLp) frequencies in lung allograft recipients with good graft function and in recipients with BOS., Methods: Donor and third party specific CTLp and HTLp frequencies were determined by limiting dilution assay in pre- and posttransplant (1 year) peripheral blood samples of lung allograft recipients with good graft function (n = 13) and BOS (n = 10)., Results: In recipients with good graft function, mean donor-specific CTLp frequencies decreased after transplantation (183 vs. 16 precursors before and after transplantation, respectively). Additionally, HTLp frequencies decreased but this was not specific for donor alloantigens because third party-specific HTLp frequencies decreased also. Surprisingly, recipients with BOS also showed a decrease in mean donor-specific CTLp frequencies after transplantation (332 vs. 49 precursors before and after transplantation, respectively). Again, HTLp frequencies decreased nonspecifically., Conclusions: We conclude that donor-specific CTLp frequencies decrease after lung transplantation, but that this does not result in transplantation tolerance protecting the lung against the development of chronic graft dysfunction.

Background: CTLA4IgG that binds to B7 effectively inhibits the signaling of CD28/B7 pathway and induces antigen-specific T-cell unresponsiveness in vitro and in vivo. We examined whether the development of obliterative bronchiolitis in a murine heterotopic airway transplantation model is T cell dependent and whether CTLA4IgG abrogates the development of obliterative bronchiolitis., Methods: Tracheae with main bronchi from C3H/He (H2k), BALB/C (H2d), or C57BL/6 (H2b) mice were transplanted heterotopically into subcutaneous pockets on the backs of BALB/C or BALB/C nu/nu mice on day 0. Recipient mice were untreated or intraperitoneally treated with either CTLA4IgG or human IgG with different time and dose schedules., Results: The development of obliterative bronchiolitis, which leads to luminal obliteration by fibrous tissue in a murine heterotopic airway transplantation model, was T cell dependent and the development of obliterative bronchiolitis was significantly abrogated by the CTLA4IgG treatment. However, the normal ciliated columnar respiratory epithelial cells in allografts were lost and replaced by flattened attenuated epithelial cells even after the CTLA4IgG treatment. We further demonstrated that CTLA4IgG treatment did not result in the induction of donor-specific unresponsiveness., Conclusions: We demonstrated that the development of obliterative bronchiolitis in a murine heterotopic airway model involves both CD28/B7-dependent and -independent processes. The luminal obliteration by fibrous tissue is clearly CD28/B7 dependent and can be inhibited by CTLA4IgG. The luminal obliteration of allografted trachea by fibrous tissues and the loss of ciliated columnar respiratory epithelial cells represent distinct disease processes.

Purpose: The purpose of our study was to evaluate CT findings during respiratory syncytial virus (RSV) infection in lung transplant recipients and to identify sequelae., Method: Thirty-nine CT scans prior to, during, and following acute infection in 10 lung transplant recipients were reviewed. Abnormalities that were new from baseline observations and occurred within 4 weeks of diagnosis were defined as acute. Chronic findings were defined as those present >4 weeks after diagnosis., Results: Findings in nine patients were ground-glass (seven), air-space (five), and tree-in-bud (four) opacities and acute bronchial dilatation (four) and wall thickening (four). Patients lacked pleural effusions or lymph node enlargement. Five of seven patients with follow-up exams had new air trapping (three), persistent bronchial dilatation (three), and thickening (two). Three and 2 of the 10 patients developed bronchiolitis obliterans syndrome and obliterative bronchiolitis, respectively., Conclusion: During acute infection, patients commonly had ground-glass opacities but lacked pleural effusions and lymph node enlargement. There can be chronic sequelae after infection.

Background: Obliterative bronchiolitis (OB), the major long-term complication of lung transplantation, has thus far lacked a good large-animal model. Our goal was to develop such a model on the basis of previous rodent models with tracheal implants., Methods: Fragments of pulmonary tissue with structures of terminal bronchi were subcutaneously transplanted to four random-bred domestic piglets. Each animal received 10 autograft and 10 allograft implants. The histologic findings were graded from 0 to 3 for implants harvested repeatedly over 2 months., Results: In autografts, partial destruction of the respiratory epithelium and gradual luminal obliteration as well as mild damage to the cartilage and the bronchial wall underwent rapid reversal after initial ischemic injury. In the allografts, epithelial destruction and gradual obliteration were total within 14 days, the difference being statistically significant (P<0.05) in both. The histologic features of the obliterative plug were similar to those of human OB. In the allografts, cartilaginous destruction and pericartilaginous inflammation increased gradually to severe levels, significantly worse than in the autografts (P<0.05). Necrosis and inflammation of the bronchial wall were also more severe in the allografts (P<0.05)., Conclusions: At the end of follow-up, all autografts were vital, whereas the allografts were almost totally rejected and were without native structures. All bronchi in the allografts exhibited accelerated obliteration with histologic features characteristic of human OB, thus providing a model for research into OB and its prevention.

Purpose: The purpose of this work was to investigate thin section CT image enhancement of subtle areas of decreased attenuation of the lung parenchyma in suspected airways disease., Method: Forty-seven consecutive patients with chronic sputum production underwent pulmonary function tests and high resolution CT (HRCT). Single section inspiratory (INSP), expiratory (EXP), and minimum intensity projection (MINIP) images through the lower lobes were acquired. A histogram stretch was applied to the INSP and MINIP images, generating two further image formats. The five image types were compared for the extent of decreased attenuation, observer confidence, and correlations with pulmonary function tests., Results: Interobserver variation was lowest with MINIP images (mean weighted K: MINIP 0.70, INSP sections 0.65, other image formats < or =0.48). Observers were most confident with EXP and MINIP images. EXP sections identified more disease than MINIP images (p<0.001). Correlations with pulmonary function tests were similar for each image format., Conclusion: The HRCT changes of small airways disease are enhanced with image postprocessing. MINIP images are associated with increased observer confidence and agreement as compared with HRCT alone.

Background: This study was designed to assess which cells in transplanted lungs express endothelin-1 (ET-1) and if expression of the peptide can be used to discriminate between rejection and infection in transplanted lungs., Methods: Transbronchial biopsies (n=104) from 29 human lung transplant recipients were stained immunohistochemically for ET-1. Cells expressing ET-1 (pneumocytes, endothelial cells, airway epithelial cells, lymphocytes, and macrophages) were quantified and correlated with clinical histopathology findings., Results: ET-1 was expressed in airway epithelial cells (93% of the biopsies), infiltrating macrophages (86%), and lymphocytes (19%) but not in endothelial cells or pneumocytes. ET-1 expression did not vary with rejection, obliterative bronchiolitis, or infection. ET-1 expression did not correlate with age, grade of rejection, pulmonary function, or time after transplantation., Conclusion: In transplanted human lungs, ET-1 is expressed in airway epithelial cells and infiltrating macrophages, and expression does not vary with pathological processes. Therefore, immunostaining for ET-1 probably cannot be used to discriminate between rejection and infection in transplanted lungs.

The bronchiolitides can be categorized broadly as constrictive or proliferative, each with characteristic CT features. The cardinal CT signs of constrictive bronchiolitis are mosaic perfusion, enhanced on expiratory CT scan and variably associated with bronchiectasis and, less frequently, centrilobular branching structures. These features are common to postinfective bronchiolitis, bronchiolitis associated with collagen vascular disease, obliterative bronchiolitis following lung transplantation, and bronchiolitis following inhalation of toxic fumes and consumption of Sauropus androgynus. Proliferative bronchiolitis manifests on CT scan as patchy bilateral consolidation, variably associated with nodular abnormalities. The CT appearances of other rare bronchiolitides are discussed here including diffuse panbronchiolitis, follicular bronchiolitis, and respiratory bronchiolitis-associated interstitial lung disease.

Background: Bronchiolitis obliterans is the most significant complication adversely affecting prolonged survival of lung allograft recipients. The evolution from the initial insult to the final pathologic entity is largely unknown. The aim of this study was to characterize the evolution of transplant-induced fibrous airway obliteration in a rat tracheal transplant model of bronchiolitis obliterans., Methods: Tracheal segments were transplanted from Brown Norway rats to Brown Norway rats (isografts) or to Lewis rats (allografts). Grafts were implanted into a subcutaneous pouch and an abdominal omental wrap. They were harvested at 14 different time points (from 1 day to 1 year after transplantation) and assessed histologically., Results: The fibrous airway obliteration developed only in allografts showing a triphasic time course: an initial ischemic phase (observed in both isografts and allografts) was followed by a marked lymphocytic infiltrative phase with complete epithelial loss (observed only in allografts, P<0.01), and finally by an obliterative phase with fibrous obliteration of the allograft airway lumen (P<0.01)., Conclusions: This animal model shows a distinct and reproducible triphasic time course in the development of obliterative airway lesions in allografts. It confirms that the mechanism leading to airway obliteration is immune mediated as only allografts showed this lesion and that lymphocytic infiltration is a precursor of the lesion in this model. The insights into the different phases demonstrated may lead to novel approaches regarding the type and timing of therapeutic interventions.

Bronchiolar lesions are becoming increasingly recognized as an important cause of airflow obstruction. For this reason, it is helpful to have an update of the current clinical, radiographic, and immunologic perspective. Among the bronchiolar airflow disorders, diffuse panbronchiolitis is related to HLA antigen Bw54, and low-dose, long-term erythromycin appears to be effective therapy. Bronchiolitis obliterans can be classified histologically as constrictive bronchiolitis and as proliferative bronchiolitis obliterans. Idiopathic, postfume, postinfectious, and connective tissue disease bronchiolitis obliterans continue to be rare and often have a poor prognosis. Bronchiolitis obliterans associated with lung transplantation is undergoing intensive investigation with regard to pathogenesis, immunologic study, early detection, and treatment. The lesion appears to be a form of chronic organ rejection. The recognition of the distinctive differences among the bronchiolar airflow disorders by clinicians and clinical investigators is essential for improved patient care, for a greater understanding of the pathogenesis of the disorder, and for development of new therapeutic advances.

The expression of MHC class II antigens and ICAM-1 and the composition of lymphocyte infiltrates have been studied in frozen sections of transbronchial biopsies from lung transplant recipients. First, biopsies obtained from patients who showed acute rejection, OB, and normal features were compared. Second, we compared first-year biopsies from patients developing OB and patients with a good clinical outcome. HLA-DR was widely expressed on epithelia and vascular endothelium. Increased vascular HLA-DP expression was found in OB biopsies. In OB patients there was a significantly increased frequency of bronchial HLA-DP and vascular HLA-DQ expression. Expression of ICAM-1 by bronchial and bronchiolar basal cells, a phenomenon not reported previously in humans, was seen in a small number of biopsies. CD8 predominant lymphocytic infiltrates were present in all groups and were increased in OB biopsies and OB patients. Increased numbers of CD4-positive cells were found in rejection and OB when compared with normal biopsies. These findings support an immunological basis for the development of OB.

Twelve patients receiving lung transplants between 1988 and 1992 who developed clinical and histological features of obliterative bronchiolitis (OB) were compared with a group of 13 patients with good stable lung function (FEV1 more than 80% of predicted). Histological features of 180 biopsies were studied from the first postoperative year in order to assess whether any were associated with the development of OB. Clinically and histologically defined pulmonary rejection occurring after the first month was more frequent in OB patients (P = 0.03). Organizing pneumonia that was associated with acute rejection but not with nonviral infection was also seen more frequently in OB patients (P = 0.003). When all available lung transplant recipients surviving beyond 18 months were included in analyses, organizing pneumonia in the first year was associated with an increased relative risk of developing OB of 2.26 (95% CL 1.19-4.29), and the occurrence of coexistent organizing pneumonia and pulmonary rejection gave a relative risk for OB of 6.33 (95% CL 1.61-24.94). An increased incidence of histologically defined organizing pneumonia in OB patients has not been described previously. Furthermore the coexistence of organizing pneumonia with pulmonary rejection in the first year posttransplantation is a strong predictive factor for the development of OB.

The CT features of 12 patients with bronchiolitis obliterans organizing pneumonia (BOOP) were reviewed and correlated with clinical history, histologic specimens, and chest radiography. From our series, a spectrum of CT findings of parenchymal lung involvement in BOOP emerged. Focal nodular or mass-like opacities were found in 42% (5 of 12). Areas of consolidation resembling pneumonia were seen in 33% (4 of 12). Peripheral subpleural reticular opacities were identified in 25% (3 of 12). Patchy ground glass infiltrates were seen in 8% (1 of 12). One patient demonstrated a mixed pattern consisting of nodular opacities and areas of pneumonic consolidation. In 4 of the 5 cases demonstrating the nodular form of BOOP either a feeding vessel or bronchus sign could be identified. This feature consisted of a pulmonary vessel leading to a nodular opacity or an air bronchogram entering into a nodular opacity. Correlation of the CT findings of BOOP with histologic specimens showed nodular opacities and areas of consolidation to be associated with classic pathologic features of BOOP including bronchiolar plugs of granulation tissue and surrounding organizing pneumonia. Cases demonstrating peripheral subpleural reticular opacities showed, in addition to pathologic evidence of BOOP, other features such as interstitial disease and fibrosis.

Airway disease after lung or heart-lung transplantation is one of late major complications, affecting the prognosis of the transplants. Little is known about the causes of airway changes. We performed rat lung transplantation and investigated the late airway changes of the long-term surviving lung grafts: allografts, BN to Lewis; isografts, BN to BN rat. All recipients were treated with CsA. We found airway changes, i.e., mucosal ulceration, granulation, submucosal fibrosis, which was located in the large airways, in four of five allografted lungs. The lung isografts showed no pathological abnormalities. Immunopathological studies disclosed the localized expression of MHC class II antigens on the bronchial epithelium of the large airways where recipient type dendritic cells accumulated in the submucosa and CD4 positive predominant lymphocytes infiltrated. These findings support the idea that the late airway changes in lung transplants are caused by immunologically mediated chronic rejection.

Clinical acute lung rejection (AR) occurs in lung allografts usually within 50 days after transplantation. While perivascular infiltrates characterize AR, with moderate-to-severe acute rejection small airway injury occurs. We investigated the significance of small airway injury in AR and its relationship to the development of bronchiolitis obliterans (OB) in 11 recipients of combined heart-lung or double-lung allografts. In general, the intensity and persistence of early acute rejection episodes associated with injury to bronchioles correlated with the development of histologic bronchiolitis obliterans. Early AR may "prime" lymphocytes for subsequent respiratory epithelial injury and airway fibrosis late in the postoperative period.

The pathology of drug-induced lung disease is approached on the basis of patterns of tissue reaction in this review. The entities described include various pathologic lesions, from diffuse alveolar damage to interstitial pneumonias and angiopathies. Because the histopathologic manifestations of drug injury are variable and nonspecific, pathogenetic mechanisms are emphasized. Drugs may cause injury by direct toxicity or by triggering immunologic responses, but often this neat distinction is blurred by the combined effects of preexisting lung injury and the concurrent administration of several drugs. Thus the identification of drug-induced lung disease requires thorough knowledge of the clinical history and rigorous analysis of histopathologic features.

Long-term survival in heart-lung transplantation has ben hindered by the development of bronchiolitis obliterans (OB), which is believed to be a manifestation of chronic rejection of the lung. Since HLA-class II antigens are involved in the rejection response, the distribution of the class II products HLA-DR, HLA-DQ, and HLA-DP were studied in normal lung, and in transplanted lung with and without OB, utilizing frozen-section immunohistochemical techniques. All three allelic products are usually expressed on the epithelial, endothelial, and mesenchymal components of the lung. Sequential transbronchial biopsies from 4 recipients before and concurrent with the diagnosis of OB were stained with serial dilutions of monoclonal antibodies to assess the level of expression of the above class II products. Increased levels of HLA-DR and HLA-DP antigens may be seen on the bronchial and bronchiolar epithelium during OB, but the changes are subtle and complicated by many other variables. Additional studies are needed to confirm these preliminary results.

Pulmonary infections and lung rejection are the two major complications of lung transplantation. Although the therapies for these two processes differ greatly, they often cannot be differentiated using standard radiography. We applied high resolution CT (HRCT) to seven lung specimens that were obtained from patients who had received a heart-lung transplant. The lungs were fixed by a method that allows for direct one-to-one pathologic-radiologic correlation. We found: (a) that in contrast to the extensive changes present microscopically, acute lung allograft rejection was characterized by only minor changes on HRCT; (b) that bronchiolitis obliterans, the hallmark of chronic lung allograft rejection, was not reliably identifiable on HRCT; (c) that bronchiectasis with associated peribronchial inflammation and fibrosis, a common finding in lung allograft rejection, was identifiable on HRCT, but that the HRCT appearance of this lesion was not specific for rejection; and (d) that pulmonary infections were often identifiable as a mixed airway-interstitial process on HRCT.