Amphiregulin contributes to airway remodeling in chronic allograft dysfunction after lung transplantation

Abstract

Chronic lung allograft dysfunction (CLAD), a condition of excess matrix deposition and airways fibrosis, limits survival after lung transplantation. Amphiregulin (Areg) is an epidermal growth factor receptor (EGFR) ligand suggested to regulate airway injury and repair. We sought to determine whether Areg expression increases in CLAD, localize the cellular source of Areg induction in CLAD, and assess its effects on airway matrix deposition. Lung fluid Areg protein was quantified in patients with or without CLAD. In situ hybridization was performed to localize Areg and EGFR transcript in CLAD and normal lung tissue. Expression of hyaluronan, a matrix constituent that accumulates in CLAD, was measured in Areg‐exposed bronchial epithelial cells in the presence or absence of an EGFR inhibitor. We demonstrated that lung fluid Areg protein was significantly increased in CLAD in a discovery and replication cohort. Areg and EGFR transcripts were abundantly expressed within CLAD tissue, localized to basally distributed airway epithelial cells overlying fibrotic regions. Areg‐exposed bronchial epithelial cells increased hyaluronan and hyaluronan synthase expression in an EGFR‐dependent manner. Collectively, these novel observations suggest that Areg contributes to airway remodeling and CLAD. Moreover these data implicate a role for EGFR signaling in CLAD pathogenesis, suggesting novel therapeutic targets.

Chronic lung allograft dysfunction small airways reveal a lymphocytic inflammation gene signature

“…We observed downregulation of EGFR in CLAD in contradistinction with recently published findings on the Amphiregulin pathway in CLAD. 26 However, this downregulation was limited to subjects with early CLAD, and this difference could reflect the enrichment of early CLAD cases in our cohort.…”

When tissue is the issue: A histological review of chronic lung allograft dysfunction

“…Evidence of aberrant angiogenesis is also seen in the form of an increase and enlargement of the microvasculature within and adjacent to BO lesions (Figure 1). 18,21 Here, the amphiregulin‐hyaluronan axis is considered a major driving force in the epithelial response to injury as it accumulates in the affected epithelium in fibrotic airways 22,23 . While amphiregulin, an epidermal growth factor receptor ligand, induces an increased proliferative capacity, an initial mucous hyperplasia, and altered ciliated cell differentiation in airway basal cells, hyaluronan regulates the subsequent innate inflammatory responses by releasing cytokines, chemokines, and growth factors attracting predominantly neutrophils and macrophages.…”

A prevalent and culturable microbiota links ecological balance to clinical stability of the human lung after transplantation

“…This is in contrast to taxa such as Streptococcus, whose abundance has been linked to low inflammation and tissue repair and remodeling (Bernasconi et al, 2016). Sustained inflammatory reactions and uncontrolled tissue remodeling can eventually lead to irreversible decline in lung function (Hardison et al, 2009;Todd et al, 2020). These previous data collectively suggest that the lung microbiota post-transplant can constitute different compositional states that may be linked to allograft function.…”