Airway colonisation with Pseudomonads, especially Pseudomonas aeruginosa, is common in lung transplant (LTx) recipients. The current authors investigated whether pseudomonal colonisation affects the prevalence of bronchiolitis obliterans syndrome (BOS) after lung transplantation.In the present retrospective study, 92 double (SS)LTx recipients (26 cystic fibrosis (CF) and 66 non-CF patients), with at least two consecutive post-operative bronchoalveolar lavage or sputum cultures evaluated for Pseudomonads, were included. Freedom of BOS was investigated in postoperatively colonised and noncolonised patients.The current study has shown post-operative airway colonisation to be an independent risk factor for BOS stage o1 and to be associated with a worse BOS stage o1-free survival in univariate analysis, especially in CF SSLTx recipients. Multivariate analysis demonstrated a trend for colonisation only as an independent risk factor for BOS; however, this pointed to a possible role in the development of BOS.In conclusion, pseudomonal airway colonisation after lung transplantation may be associated with an increased prevalence of bronchiolitis obliterans syndrome, especially in cystic fibrosis patients. Possible pathophysiological mechanisms in the development of bronchiolitis obliterans syndrome need further investigation, although the induction of neutrophilic airway inflammation seems to be its main characteristic.

Bronchiolitis obliterans syndrome (BOS) is the most important cause of late mortality following lung transplantation, resulting in major morbidity and a huge burden on healthcare resources. Treatment options are limited, resulting in a mere stabilisation of the lung function decline. Recent introduction of the macrolide antibiotic azithromycin raised new hope after demonstrating lung function improvement in subsets of patients.The present study aimed to provide an overview of the clinical effects on azithromycin in the setting of BOS after lung transplantation, with special emphasis on the anti-inflammatory actions. Moreover, the authors proposed a new frame of thinking centred on a dichotomy in the pathogenesis and clinical phenotype of BOS. Subsets of BOS patients were identified who do or do not respond to azithromycin (regarding forced expiratory volume in one second (FEV1), bronchoalveolar lavage (BAL) neutrophilia/interleukin-8). These observations have shed new light on the current belief that BOS represents a homogenous clinical entity in which the neutrophil is the main culprit.Recent clinical observations, supported by research findings, have revealed a dichotomy in the clinical spectrum of BOS with neutrophilic (partially) reversible allograft dysfunction (responding to azithromycin) and fibroproliferative BOS (not responding to azithromycin). This concept is reinforced by unique data obtained in BOS patients, consisting of histology specimens, physical and radiological examination, FEV1 and BAL examination.The acceptance of this dichotomy can improve understanding of the heterogeneous pathological condition that constitutes bronchiolitis obliterans syndrome, thus encouraging a more accurate diagnosis and, ultimately, better tailored treatment for each bronchiolitis obliterans syndrome patient.

Lung transplantation is hampered by bronchiolitis obliterans syndrome (BOS), although recently azithromycin treatment has a published response rate of about 42% in patients with established BOS. We linked this improvement to a reduction in airway neutrophilia and IL8. In the present study, we further investigated the intracellular mechanisms of azithromycin, looking at the possible involvement of mitogen-activated-protein kinases (MAPK) and oxidative stress. Simultaneously, currently used immunosuppressive agents were investigated. Human primary airway smooth muscle cells were stimulated with IL17 and incubated with increasing concentrations of steroids, immunosuppressive agents (tacrolimus, cyclosporine and rapamycin) or macrolides (erythromycin and azithromycin). We measured supernatant IL8 protein, 8-isoprostane and cell lysate MAPK. IL17-induced IL8 production was decreased by both erythromycin and azithromycin. In nonstimulated condition, IL8 production only increased at the highest dose of azithromycin. Dexamethasone failed to attenuate IL8 production, whereas immunosuppressive agents significantly increased IL8 production in both IL17-stimulated and nonstimulated conditions. 8-isoprostane production and MAPK activation proved to be decreased by the macrolides. We conclude that macrolides (but not steroids/immunosuppressive agents) inhibit IL17-induced IL8 production in human primary airway smooth muscle cells via a reduction in MAPK activation and 8-isoprostane production. In BOS patients, these phenomena may explain the antiinflammatory effects of azithromycin.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease without proper treatment. Despite intensive research, the exact underlying pathogenesis remains elusive. It is regarded as a continuous injury, resulting in inflammation, infiltration, and proliferation of fibroblasts and extracellular matrix deposition, leading to an irreversible restrictive lung function deterioration and death. In this study the effect of azithromycin, a macrolide antibiotic on bleomycin-induced pulmonary fibrosis was investigated. C57BL/6 mice were intratracheally instilled with bleomycin (0.5 mg/kg) or saline. In the bleomycin group, half of the animals received azithromycin every other day from day 1 on. Bronchoalveolar lavage and histology were performed at days 7 and 35, and pulmonary function tests on day 35. At day 35, fibrotic lesions (spindle cell proliferation/collagen I deposition) were paralleled by a restrictive lung function pattern. Alterations were found in neutrophils and macrophages (innate immunity) and in T(H)2, T(H)17, and Treg cytokines (adaptive immunity). Azithromycin significantly reduced both fibrosis and the restrictive lung function pattern. This study demonstrated a beneficial effect of azithromycin on bleomycin-induced pulmonary fibrosis. A possible mechanism could be a modulation of both innate immunity and adaptive immunity. These findings might suggest a potential role for azithromycin in the treatment of IPF.

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