EGF-Amphiregulin Interplay in Airway Stem/Progenitor Cells Links the Pathogenesis of Smoking-Induced Lesions in the Human Airway Epithelium

Abstract

The airway epithelium of cigarette smokers undergoes dramatic remodeling with hyperplasia of basal cells (BC) and mucus-producing cells, squamous metaplasia, altered ciliated cell differentiation and decreased junctional barrier integrity, relevant to chronic obstructive pulmonary disease and lung cancer. In this study, we show that epidermal growth factor receptor (EGFR) ligand amphiregulin (AREG) is induced by smoking in human airway epithelium as a result of epidermal growth factor (EGF)-driven squamous differentiation of airway BC stem/progenitor cells. In turn, AREG induced a unique EGFR activation pattern in human airway BC, distinct from that evoked by EGF, leading to BC- and mucous hyperplasia, altered ciliated cell differentiation and impaired barrier integrity. Further, AREG promoted its own expression and suppressed expression of EGF, establishing an autonomous self-amplifying signaling loop in airway BC relevant for promotion of EGF-independent hyperplastic phenotypes. Thus, EGF-AREG interplay in airway BC stem/progenitor cells is one of the mechanisms that mediates the interconnected pathogenesis of all major smoking-induced lesions in the human airway epithelium.

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

“…Similar to prior work, we found Areg to be barely detectable in normal human airway epithelium. 17 Although there are no previous studies examining Areg expression in the context of CLAD or OB in human lung recipients, our observation demonstrating that Areg expression localizes to the bronchial epithelium of OB-affected airways is consistent with those recently shown in a rodent toxin-induced OB model. 11 In addition, this finding is consistent with clinical studies of nontransplant-related airways diseases.…”

“…In particular, Areg‐exposed airway basal cells demonstrated increased proliferative capacity, mucous hyperplasia, and altered ciliated cell differentiation . Thus, endogenously produced Areg may be important in expanding the basal cell population to promote airway repair in the setting of injury . Consistent with this idea, Snyder and colleagues, observed a transient increase in whole‐lung Areg mRNA in an experimental model of airway injury that resolves with normal repair .…”

“…Of interest, recent work examining human airway basal cells demonstrated that these cells take on altered growth and morphologic characteristics upon exposure to Areg. In particular, Areg‐exposed airway basal cells demonstrated increased proliferative capacity, mucous hyperplasia, and altered ciliated cell differentiation . Thus, endogenously produced Areg may be important in expanding the basal cell population to promote airway repair in the setting of injury .…”

“…For example, sputum Areg protein has been shown to be increased in patients with asthma and is negatively correlated with pulmonary function in this context . Areg is also highly expressed in abnormal respiratory epithelium in smokers with chronic obstructive pulmonary disease …”

“…Specifically, prior work has demonstrated that Areg‐induced EGFR activation in cultured human airway epithelial cells is associated with EGFR stabilization on the cell surface, a finding not observed with EGF‐induced activation, which was associated with a reduction in total EGFR . This same group also demonstrated that Areg can promote its own expression, thus creating a positive feedback loop …”