Mechanistic differences between phenotypes of chronic lung allograft dysfunction after lung transplantation

Abstract

Distinct phenotypes of chronic lung allograft dysfunction (CLAD) after lung transplantation are emerging with lymphocytic bronchiolitis (LB)/azithromycin reversible allograft dysfunction (ARAD), classical or fibrotic bronchiolitis obliterans syndrome (BOS), and restrictive allograft syndrome (RAS) proposed as separate entities. We have additionally identified lung transplant recipients with prior LB, demonstrating persistent airway neutrophilia (PAN) despite azithromycin treatment. The aim of this study was to evaluate differences in the airway microenvironment in different phenotypes of CLAD. Bronchoalveolar lavage (BAL) from recipients identified as stable (control), LB/ARAD, PAN, BOS, and RAS were evaluated for differential cell counts and concentrations of IL-1α, IL-1β, IL-6, IL-8, and TNF-α. Primary human bronchial epithelial cells were exposed to BAL supernatants from different phenotypes and their viability measured. BOS and RAS showed increased BAL neutrophilia but no change in cytokine concentrations compared with prediagnosis. In both LB/ARAD and PAN, significant increases in IL-1α, IL-1β, and IL-8 were present. BAL IL-6 and TNF-α concentrations were increased in PAN and only this phenotype demonstrated decreased epithelial cell viability after exposure to BAL fluid. This study demonstrates clear differences in the airway microenvironment between different CLAD phenotypes. Systematic phenotyping of CLAD may help the development of more personalized approaches to treatment.

BAL neutrophilia in azithromycin-treated lung transplant recipients: Clinical significance

“…As previously described [14], the RAS phenotype (represented in 32% of CLAD development in the study group) is characterized by fibrotic areas that may be the result of the increased levels of IL-1Ra in the study group. In the recent study from Suwara et al, patients with persistent airway neutrophilia also demonstrated an increase in IL-1α and IL-1β [15], however no survival analysis was performed and limited cytokines were investigated compared to our study. Cytokine analysis and COX proportional hazards model demonstrated that the inflammatory mechanism in our study is possibly IL-1β mediated, which may open new perspectives for future therapies.…”

Report of the ISHLT Working Group on Primary Lung Graft Dysfunction Part III: Mechanisms: A 2016 Consensus Group Statement of the International Society for Heart and Lung Transplantation

“…That report suggested that an early chemotactic signal for monocytes and lymphocytes was present in lungs with PGD and that the activated endothelial or epithelial surfaces may have contributed to that signal. Notably, despite observations that cultured bronchial epithelial cells isolated from chronically rejected lung transplant recipients produced high amounts of inflammatory mediators, 18 it remains to be determined whether bronchial epithelium plays a direct role in IRI-mediated cytokine production in PGD patients.…”

Chronic lung allograft dysfunction phenotypes and treatment

“…These patients usually present with a colonized graft (mostly pseudomonas) and demonstrate inferior survival compared to patients without neutrophilia (38). Interestingly, IL-1α is increased in BAL of those patients indicating that these alarmins might play an important role in the pathophysiology of BOS (39). Macrolide treatment does not seem to affect these patients (40).…”