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.
Highlights
Lung transplantation (LTx) is accepted as a well-established therapeutic option for patients with end-stage lung disease, yet long-term survival remains less than that achieved in transplantation of other solid organs, with a median survival of 5 years [1]
The cellular mechanisms driving chronic rejection remain poorly elucidated, but current consensus suggests that both alloantigen-dependent [3,4] and alloantigen-independent insults to airway epithelium lead to an influx of inflammatory cells, chronic neutrophilic inflammation, deregulated repair, and resultant fibrotic plugging of the small airways presenting in the typical obliterative bronchiolitis (OB) lesions [5,6]
Primary bronchial epithelial cells (PBEC) were obtained from a stable lung transplant recipient undergoing surveillance bronchoscopy at the Freeman Hospital, Newcastle. (The study was approved by the regional ethics committee, and the patient provided written informed consent to participate Ref. 2001/179.) IL-1a, IL-1b, IL-6, IL-8, and TNF-a proteins were measured in undiluted Bronchoalveolar lavage (BAL) using MSD electrochemiluminescence assay (MesoScale Discovery, Gaithersburg, US) according to the manufacturer’s instructions
Summary
Lung transplantation (LTx) is accepted as a well-established therapeutic option for patients with end-stage lung disease, yet long-term survival remains less than that achieved in transplantation of other solid organs, with a median survival of 5 years [1]. The cellular mechanisms driving chronic rejection remain poorly elucidated, but current consensus suggests that both alloantigen-dependent [3,4] and alloantigen-independent insults to airway epithelium lead to an influx of inflammatory cells, chronic neutrophilic inflammation, deregulated repair, and resultant fibrotic plugging of the small airways presenting in the typical obliterative bronchiolitis (OB) lesions [5,6]. Previous studies have demonstrated that damage to epithelium may result in the release of alarmins, including IL-1a, which in a paracrine manner may trigger expression of proinflammatory cytokines in lung fibroblasts and other epithelial cells [21]
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