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During T-cell receptor activation in a particular cytokine environment, naive CD41(+) T cells may differentiate into lineages defined by their pattern of cytokine production and transcription factors: T helper type 1 (Th1), Th2, Th17, and Th22 cells; follicular helper T cells; and inducible regulatory T cells. Th17 cells have been recognized as a distinct lineage of Th cells, and associations between IL-17 and human disease have been known somewhat longer. It would be an oversimplification to restrict IL-17 to Th17 cells. Indeed, IL-17 is also expressed by other cells including IL-17-producing gamma delta T (gamma delta T-17) cells, natural killer T-17 cells, and IL-17-producing lymphoid tissue-induced cells. IL-17 was cloned in 1995 as a cytokine expressed by T cells, exerting inflammatory effects on epithelial, endothelial, and fibroblast cells. IL-17 is a solid link between innate and adaptive immunity and can exert both beneficial and deleterious effects. The discovery of IL-17 T cells has provided exciting new insights into host defense, immunoregulation, and autoimmunity. Unquestionably, data from mouse models have contributed enormously to our insight into immunological mechanisms. However, because of numerous differences between murine and human immunology, data obtained in mice are not simply interchangeable. We review IL-17 T cells exclusively in the human situation and more specifically their potential role in respiratory diseases. The advances in our understanding of IL-17 regulation offer opportunities to dissect the human IL-17 system and to reflect on the clinical presentation of lung diseases. More importantly, the IL-17 system allows us to speculate on new therapeutic opportunities. Some results have been previously reported in an abstract.

Remodeling of airways and blood vessels is an important feature in chronic obstructive pulmonary disease (COPD). By using immunohistochemical analysis, we examined bronchial expression patterns of various extracellular matrix (ECM) components such as collagens (subtypes I, III, and IV), fibronectin, and laminin beta2 in patients with COPD (forced expiratory volume in 1 second [FEV1] or=85%; n = 16) and correlated expression data with lung function. Quantitative analysis revealed enhanced levels (P < .01) of total collagens I, III, and IV in surface epithelial basement membrane (SEBM) and collagens I and III in bronchial lamina propria (P < .02) and adventitia (P < .05) in COPD. Distinct and increased (P < .05) vascular expression of fibronectin accounts for intimal vascular fibrosis, whereas laminin beta2 (P < .05) was elevated in airway smooth muscle (ASM). FEV1 values inversely correlated with collagens in the SEBM, fibronectin in bronchial vessels, and laminin in the ASM. Our data suggest that COPD exhibits increased bronchial deposition of ECM proteins that contribute to deteriorated lung function and airway remodeling

An important feature of chronic obstructive pulmonary disease (COPD) is airway remodelling, the molecular mechanisms of which are poorly understood. In this study, the role of fibroblast growth factors (FGF-1 and FGF-2) and their receptor, FGFR-1, was assessed in bronchial airway wall remodelling in patients with COPD (FEV1 < 75%; n = 15) and without COPD (FEV1 > 85%; n = 16). FGF-1 and FGFR-1 were immunolocalized in bronchial epithelium, airway smooth muscle (ASM), submucosal glandular epithelium, and vascular smooth muscle. Quantitative digital image analysis revealed increased cytoplasmic expression of FGF-2 in bronchial epithelium (0.35 +/- 0.03 vs 0.20 +/- 0.04, p < 0.008) and nuclear localization in ASM (p < 0.0001) in COPD patients compared with controls. Elevated levels of FGFR-1 in ASM (p < 0.005) and of FGF-1 (p < 0.04) and FGFR-1 (p < 0.001) in bronchial epithelium were observed. In cultured human ASM cells, FGF-1 and/or FGF-2 (10 ng/ml) induced cellular proliferation, as shown by [3H]thymidine incorporation and by cell number counts. Steady-state mRNA levels of FGFR-1 were elevated in human ASM cells treated with either FGF-1 or FGF-2. The increased bronchial expression of fibroblast growth factors and their receptor in patients with COPD, and the mitogenic response of human ASM cells to FGFs in vitro suggest a potential role for the FGF/FGFR-1 system in the remodelling of bronchial airways in COPD

Almost all animal models for chronic rejection (CR) after lung transplantation (LTx) fail to resemble the human situation. It was our attempt to develop a representative model of CR in mice. Orthotopic LTx was performed in allografts receiving daily immunosuppression with steroids and cyclosporine. Controls included isografts and mice only undergoing thoracotomy (SHAM). Allografts were sacrificed 2, 4, 6, 8, 10 or 12 weeks after LTx. Pulmonary function was measured repeatedly in the 12w allografts, isografts and SHAM mice. Histologically, all allografts demonstrated acute rejection (AR) around the blood vessels and airways two weeks after LTx. This decreased to 50-75% up to 10 weeks and was absent after 12 weeks. Obliterative bronchiolitis (OB) lesions were observed in 25-50% of the mice from 4-12 weeks. Isografts and lungs of SHAM mice were normal after 12 weeks. Pulmonary function measurements showed a decline in FEV0.1, TLC and compliance in the allografts postoperatively (2 weeks) with a slow recovery over time. After this initial decline, lung function of allografts increased more than in isografts and SHAM mice indicating that pulmonary function measurement is not a good tool to diagnose CR in a mouse. We conclude that a true model for CR, with clear OB lesions in about one third of the animals, but without a decline in lung function, is possible. This model is an important step forward in the development of an ideal model for CR which will open new perspectives in unraveling CR pathogenesis and exploring new treatment options. GV is holder of the GSK (Belgium) chair in respiratory pharmacology at the Katholieke Universiteit Leuven (KUL), and is supported by grants from the KUL (OT/050/10) and the FWO (Fonds Wetenschappelijk Onderzoek)-Flanders: G.0643.08 and G.0723.10. DVR and BV are senior clinical investigators of the FWOFlanders. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Increase in size and number of bronchial blood vessels as well as hyperaemia are factors that contribute to airway wall remodelling in patients with chronic airway diseases, such as asthma and chronic obstructive pulmonary diseases (COPD). Expression of transforming growth factor beta 1 (TGF-beta 1), a multifunctional cytokine as well as vascular endothelial growth factor (VEGF), a key angiogenic molecule, has been shown in the inflammed airways in patients with chronic airway diseases. TGF-beta 1 has been implicated in the regulation of extracellular matrix, leading to airway remodelling in patients with chronic airway diseases. However, the role of TGF-beta 1 in regulating VEGF expression in patients with chronic airway diseases, as well as the underlying mechanisms are not yet well established. We investigated whether TGF-beta 1 stimulates VEGF expression in vitro and hence could influence vascular remodelling. Cultured human airway smooth muscle cells (HASMC) were serum deprived for 60 h before incubation with 5ng/ml of TGF-beta 1 for different time points. Control cells received serum-free culture medium. TGF-beta 1 treatment resulted in time dependent HASMC cell proliferation with maximal values for DNA biosynthesis at 24 h and cell number at 48 h. Northern blot analysis of VEGF mRNA expression showed increased levels in cells treated with TGF-beta 1 for 4 to 8 h. TGF-beta 1 also induced a time-dependent release of VEGF proteins in the conditioned medium after 48 h of treatment. Furthermore, the ability of HASMC-released VEGF proteins to induce human umbilical vein endothelial cells proliferation was inhibited by VEGF receptor antagonist, confirming that TGF-beta 1 induced VEGF was biologically active. We conclude that TGF-beta 1 in addition to an extracellular matrix regulator also could play a key role in bronchial angiogenesis and vascular remodelling via VEGF pathway in asthma.

BACKGROUND: Donation after cardiac death (DCD) to overcome the donor organ shortage is now moving into the clinical setting, but the medium-term outcome after DCD lung transplantation (LTx) remains largely unknown. METHODS: In this retrospective study, DCD LTx recipients (n = 21) were compared with a cohort of donation-after-brain-death (DBD) LTx recipients (n = 154) transplanted between February 2007 and July 2010. Immediate (post)operative outcome was evaluated by assessing need for pen-operative extracorporeal membrane oxygenation (ECMO), time to extubation, hospital discharge and primary graft dysfunction (PGD) within the first 48 hours. Survival, incidence of bronchiolitis obliterans syndrome (BOS), acute rejection (AR) and inflammatory markers in blood and in bronchoalveolar lavage (BAL) were assessed and compared over a median follow-up of 327 days for DCD and 531 days for DBD, showing no statistically significant difference (NS). RESULTS: There were no differences between groups with regard to patient characteristics except for a higher number of patients transplanted for obliterative bronchiolitis in the DCD group (4 of 21 vs 7 of 154; p < 0.05). In the DCD group, 2 of 21 patients died, vs 23 of 154 patients in the DBD group (NS). Actuarial survival rates at 6 months, 1 year and 3 years are 95%, 95% and 71% for the DCD group and 96%, 91% and 75% for the DBD group (NS). Three patients (14%) in the DCD group developed BOS vs 15 patients (10%) in the DBD group (NS). Survival and freedom from BOS were not different between the groups. AR, inflammatory markers and immediate (post)operative outcome also did not differ. CONCLUSIONS: In our experience, both early- and medium-term outcome in DCD lung recipients is comparable to that of DBD lung recipients. Use of lungs recovered from controlled donors after cardiac death is a safe option for expansion of the donor pool. J Heart Lung Transplant 2011;30:975-81 (C) 2011 International Society for Heart and Lung Transplantation. All rights reserved.

Background. Chronic lung allograft dysfunction (CLAD) remains the leading cause of mortality after lung transplantation. Methods. In this retrospective single-center study, we aimed to identify different phenotypes of and risk factors for mortality after CLAD diagnosis using univariate and multivariate Cox proportional hazard survival regression analysis. Results. CLAD was diagnosed in 71 of 294 patients (24.2%) at 30.9+/-22.8 months after transplantation. Pulmonary function was obstructive in 51 (71.8%) of the CLAD patients, restrictive in 20 (28.2%) patients, of whom 17 had persistent parenchymal infiltrates on pulmonary computer tomography (CAT) scan. In univariate analysis, previous development of neutrophilic reversible allograft dysfunction (NRAD, P=0.012) and a restrictive pulmonary function (P=0.0024) were associated with a worse survival, whereas there was a strong trend for early development of CLAD and persistent parenchymal infiltrates on CAT scan (P=0.067 and 0.056, respectively). In multivariate analysis, early development of CLAD (P=0.0067), previous development of NRAD (P=0.0016), and a restrictive pulmonary function pattern (P=0.0005) or persistent parenchymal infiltrates on CAT scan (P=0.0043) remained significant. Conclusion. Although most CLAD patients develop an obstructive pulmonary function, 28% develop a restrictive pulmonary function, compatible with the recently defined restrictive allograft syndrome phenotype. Early-onset CLAD, previous development of NRAD, and the development of restrictive allograft syndrome are associated with worse survival after CLAD has been diagnosed.

Background T helper 17 (Th17) cells can recruit neutrophils to inflammatory sites through production of IL-17, which induces chemokine release. IL-23 is an important inducer of IL-17 and IL-22 production. Our aim was to study the role of Th17 cells in cystic fibrosis (CF) lung disease by measuring IL-17 protein and mRNA levels and IL-22 and IL-23 mRNA in sputum of clinically stable CF patients and by comparing these levels with healthy controls. Methods Sputum induction was performed in adult CF patients outside of an exacerbation and healthy control subjects. IL-17A protein levels were measured in supernatants with cytometric bead array (CBA) and RNA was isolated and quantitative RT-PCR was performed for IL-17A, IL-22 and IL-23. Results We found significantly higher levels of IL-17A protein and mRNA levels (both: p < 0.0001) and IL-23 mRNA levels (p < 0.0001) in the sputum of CF group as compared to controls. We found very low levels of IL-22 mRNA in the CF group. The levels of IL-17 and IL-23 mRNA were higher in patients chronically infected with Pseudomonas aeruginosa (P. aeruginosa) as compared to those who were not chronically infected with P. aeruginosa. The presence of Staphylococcus aureus (S. aureus) on sputum did not affect the IL-17 or IL-23 levels. There was no correlation between IL-17 or IL-23 levels and FEV1 nor sputum neutrophilia. Conclusion The elevated levels of IL-17 and IL-23 might indicate that Th17 cells are implicated in the persistent neutrophil infiltration in CF lung disease and chronic infection with P. aeruginosa.

BACKGROUND: Acute cellular rejection and lymphocytic bronchiolitis can impair allograft function after lung transplant (LTx). Both may be refractory to corticosteroid treatment. We hypothesized that bronchoalveolar lavage (BAL) neutrophilia may be increased in either acute rejection or lymphocytic bronchiolitis or may increase with increasing histologic severity. METHODS: All consecutive BAL with subsequent transbronchial biopsy (TBB) specimens, performed in 339 LTx recipients from 2001 to 2008, were retrospectively analyzed. TBB specimens were classified according to histologic grade with analysis of BAL total cell count and cell differentials. RESULTS: The analysis included 768 TBB specimens. After adjustment for possible confounders, BAL total cell count significantly increased both with grade A or B severity (p < 0.0001). A higher A grade was characterized by a significant increase in BAL lymphocytosis and neutrophilia (p < 0.0001), whereas for higher B grades, only a more prominent BAL neutrophilia was seen (p < 0.0001). CONCLUSIONS: Higher grade A, but, particularly, higher grade B severity scores are characterized by increased BAL neutrophilia. J Heart Lung Transplant 2010;29:1259-69 (C) 2010 International Society for Heart and Lung Transplantation. All rights reserved.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) remains a major risk factor for death after lung transplantation. Previous data suggested that within CLAD at least 2 phenotypes are present: a neutrophilic type (nCLAD or neutrophilic reversible allograft dysfunction [NRAD]), reversible with azithromycin therapy, vs a low neutrophilic type, non-responsive to azithromycin (fibrotic bronchiolitis obliterans syndrome [fBOS]). We aimed to further characterize this dichotomy by measuring multiple proteins in the bronchoalveolar lavage (BAL) fluid of 28 lung recipients. METHODS: Patients were retrospectively subdivided by the absence or presence of CLAD and subsequently by their response to azithromycin, resulting in 3 groups: 10 stable, 9 responsive (nCLAD/NRAD), and 9 non-responsive (fBOS). Enzyme-linked immunosorbent assay was used to measure 32 different proteins. RESULTS: Protein variations were predominantly present in the nCLAD/NRAD group, whereas no differences were observed in the fBOS group compared with control. MCP-1 (p < 0.01), RANTES (p < 0.05), IL-beta (p < 0.01), IL-8 (p < 0.01), TIMP-1 (p < 0.01), MMP-8 (p < 0.01), MMP-9 (p < 0.01), HGF (p < 0.001), MPO (p < 0.01), and bile acid (p < 0.05) concentrations were upregulated in nCLAD/NRAD compared with fBOS, whereas PDGF-AA (p < 0.05) was downregulated. CONCLUSIONS: These data provide further evidence that within CLAD there is a heterogeneity of phenotypes with different mechanisms involved. Further investigation is warranted to unravel the pathophysiology of both phenotypes. J Heart Lung Transplant 2011;30:667-73 (C) 2011 International Society for Heart and Lung Transplantation. All rights reserved.

BACKGROUND Azithromycin may reverse or halt the decline of pulmonary function (FEV(1)) in bronchiolitis obliterans syndrome (BOS) In this study we investigated the effects of long-term azithromycin treatment in lung transplant recipients with BOS METHODS A retrospective, observational cohort study was performed on 107 patients with BOS (Stages 0p/1/2/3, n = 23/62/20/2), who were treated with azithromycin for 3 1 +/- 1 9 years Patients were evaluated 6 3 +/- 3 8 years after transplantation and assessed for evolution of FEV(1), bronchoalveolar lavage neutrophilia and overall survival after initiation of azithromycin Survival curves were analyzed using the log rank test Cox proportional hazard survival regression analysis was performed to estimate hazard ratios of clinical variables predicting outcome RESULTS FEV(1), Increased >= 10% after 3 to 6 months of treatment in 40% of patients, of whom 33% later redeveloped BOS FEV(1) further declined in 78% and stabilized in 22% of the remaining non-responders Pre-treatment neutrophilia was higher in responders 293% (93% to 697%) vs 11 5% (29% to 438%) (p = 0 025) in whom it significantly decreased to 42% (1 8% to 17 6%) (p = 0 041) after 3 to 6 months of azithromycin Responders demonstrated better survival compared with non-responders (p = 0050), with 6 and 21 patients, respectively, dying during follow-up (p = 0 027) Multivariate analysis identified initial azithromycin response and earlier post transplant initiation of azithromycin to be protective for both BOS progression/relapse (hazard ratio [HR] = 0 12 [95% confidence interval 005 to 028], p < 0 0001 and HR = 098 [95% confidence interval 097 to 098], p < 0 0001, respectively) and retransplantation/death during follow-up (HR 0 10 [95% confidence interval 0 02 to 0 48] p = 0004, and BR 0 96 [95% confidence interval 095 to 098] p < 0 0001, respectively) CONCLUSIONS Long term azithromycin benefits pulmonary function and survival in BOS particularly in patients with Increased lavage neutrophilia J Heart Lung Transplant 2010 29 1358-68 (C) 2010 International Society for Heart and Lung Transplantation All rights reserved

Background Elevated C-reactive protein (CRP) levels have been associated with allograft failure and recipient death in renal and cardiac transplantation. Data in lung transplantation (LTx) are lacking. We hypothesized that baseline plasma or bronchoalveolar lavage (BAL) CRP might be prognostic for the long-term outcome after LTx. Methods This retrospective cohort study included 121 LTx recipients. Plasma CRP and BAL CRP, together with cell differentials, and interleukin-6 (IL-6) and IL-8 protein levels, were evaluated at 90 days after LTx and associated with bronchiolitis obliterans syndrome (BOS)-free and overall survival. Results Plasma CRP, BAL CRP, and BAL neutrophilia, but not IL-6 or IL-8, were significantly increased in patients with BOS ≥ 1 or not surviving at 3 years after LTx. In univariate analysis, plasma CRP > 5 mg/liter, elevated BAL CRP levels, and BAL neutrophilia > 15% were predictive for graft failure. In multivariate analysis, only BAL CRP was an independent predictor for graft failure ( p = 0.004). A trend was seen for plasma CRP as a predictor ( p = 0.077), but BAL neutrophilia was no longer an independent predictor. Conclusions Baseline CRP may be predictive for the long-term outcome after LTx. To confirm the present findings, prospective and longitudinal studies on a larger patient population are required.

Summary Lung transplantation has come of age and is now considered a valid treatment for selected patients with end-stage lung disease. In recent years, survival rates have much improved, although the development of chronic rejection, characterized by a progressive and irreversible decline in FEV1, which is clinically defined as bronchiolitis obliterans syndrome (BOS) remains the major obstacle to long-term survival. Extensive research efforts with special emphasis on innate immunity have recently led to new insights with the identification of at least two different phenotypes: on the one hand there is an azithromycin-responsive phenotype (the so-called neutrophilic reversible allograft/airways dysfunction (NRAD), on the other hand there is an azithromycin-unresponsive phenotype (the fibroproliferative form of BOS or classical obliterative bronchiolitis). The present review intends to give the scientific evidence for these two subtypes, and to clarify the role of azithromycin in the treatment of BOS.

Altered extracellular matrix (ECM) deposition contributing to airway wall remodeling is an important feature of asthma and chronic obstructive pulmonary disease (COPD). The molecular mechanisms of this process are poorly understood. One of the key pathological features of these diseases is thickening of airway walls. This thickening is largely to the result of airway smooth muscle (ASM) cell hyperplasia and hypertrophy as well as increased deposition of ECM proteins such as collagens, elastin, laminin, and proteoglycans around the smooth muscle. Many growth factors and cytokines, including fibroblast growth factor (FGF)-1, FGF-2, and transforming growth factor (TGF)-beta1, that are released from the airway wall have the potential to contribute to airway remodeling, revealed by enhanced ASM proliferation and increased ECM protein deposition. TGF-beta1 and FGF-1 stimulate mRNA expression of collagen I and III in ASM cells, suggesting their role in the deposition of extracellular matrix proteins by ASM cells in the airways of patients with chronic lung diseases. Focus is now on the bidirectional relationship between ASM cells and the ECM. In addition to increased synthesis of ECM proteins, ASM cells can be involved in downregulation of matrix metalloproteinases (MMPs) and upregulation of tissue inhibitors of metalloproteinases (TIMPs), thus eventually contributing to the alteration in ECM. In turn, ECM proteins promote the survival, proliferation, cytokine synthesis, migration, and contraction of human airway smooth muscle cells. Thus, the intertwined relationship of ASM and ECM and their response to stimuli such as chronic inflammation in diseases such as asthma and COPD contribute to the remodeling seen in airways of patients with these diseases.