Treatment of Chronic Obstructive Pulmonary Disease (COPD) is based on bronchodilation, with inhaled corticosteroids or azithromycin associated when frequent exacerbations occur. Despite the proven benefits of current treatment regimens, the need for new interventions in delineated subgroups remains. There is convincing evidence for oral vitamin D supplementation in reducing exacerbations in COPD patients severely deficient for circulating vitamin D. However, little is known about local vitamin D metabolism in the airways and studies examining expression of the vitamin D receptor (VDR), the activating enzyme (CYP27B1) and inactivating enzyme (CYP24A1) of vitamin D in lung tissue of COPD patients are lacking. Therefore, the expression and localization of key enzymes and the receptor of the vitamin D pathway were examined in tissue of 10 unused donor lungs and 10 COPD explant lungs. No differences in the expression of CYP27B1 and CYP24A1 were found. Although protein expression of VDR was significantly lower in COPD explant tissue, there was no difference in downstream expression of the antimicrobial peptide cathelicidin. Whereas CYP27B1 and CYP24A1 were present in all layers of the bronchial epithelium, VDR was only expressed at the apical layer of a fully differentiated bronchial epithelium with no expression in vascular endothelial cells. By contrast, CYP24A1 expression was highly present in lung endothelial cells suggesting that systemic vitamin D can be inactivated before reaching the epithelial compartment and the tissue immune cells. These data support the idea of exploring the role of vitamin D inhalation in patients with COPD.

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Scientific Knowledge on the Subject: The transcriptome landscape of pulmonary fibrosis has been studied almost univariably in the context of idiopathic pulmonary fibrosis (IPF). In fibrotic hypersensitivity pneumonitis (fHP), T cell activation has been shown, but it remains unclear what the most prevailing molecular traits are in fHP. What This Study Adds to the Field: In this explant lung study, we characterised the six most prevailing molecular traits including extracellular matrix, antigen presentation/sensitization, honeycombing, B-cell activation, endothelial dysfunction and progressive disruption in normal cellular homeostatic processes. The molecular traits differently associated with disease progression dynamics and correlated with in vivo disease behaviour in a separate clinical fHP cohort. Comparing IPF with fHP, the transcriptome landscape was determined considerably by local disease extent, rather than diagnosis alone.

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Purpose: Chronic allograft dysfunction (CLAD) limits survival after lung transplantation (LT), affecting 50% by 5-years and 75% by 10 years. Long-term survival (≥10 years) is seen in 35-40% after LT. While 10-15% of patients survive ≥10 years without CLAD, the reasons remain unclear. Our aim was to determine clinical factors that differ between long-term survivors with and without CLAD Methods: This was a single-center retrospective cohort study of all first LT performed between 1983 and 2010. Re-transplants and those without follow-up data were excluded. CLAD was adjudicated by ISHLT criteria in patients with ≥ 4 pulmonary function tests (PFTs). Associations of clinical variables with CLAD-free status were assessed using univariate logistic regression Results: 1110 patients underwent primary LT in the study period. 1-year survival was 79.5 (882/1110). 32.2% (357/1110) survived ≥10 years, and of those with sufficient PFTs, 10.6% (118/348) were long-term CLADfree survivors. 73.7% (87/357) of this cohort are still alive at a median follow-up of 12.49 (IQR 11.3-14.85) years. Among very long-term survivors (≥20 years; n=49) with sufficient PFTs, 83% were CLAD-free at a median of 23.3 (IQR 21.1-25.87) years. Shorter ischemic time, lower donor age, indication for transplant, higher baseline total lung capacity and baseline renal function, and absence of gastroparesis, major infections and treatment for acute rejection were all associated with ≥10-year CLAD-free survival. Compared to long-term survivors without CLAD, those with CLAD had higher mortality (<0.001) and skin cancers on follow-up Conclusion: We identified clinical variables associated with ≥10-year CLAD-free survival in our cohort. We will perform multiple regression and compare this cohort with those surviving 1 to 5 years post-LT using Cox proportional hazards model. We aim to optimize recipient-allograft matching leading to better long-term CLAD-free survival.