Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients
Jun Araya, Stephanie Cambier, Jennifer A. Markovics, Paul Wolters, David Jablons, Arthur Hill, Walter Finkbeiner, Kirk Jones, V. Courtney Broaddus, Dean Sheppard, Andrea Barzcak, Yuanyuan Xiao, David J. Erle, Stephen L. Nishimura
Jun Araya, Stephanie Cambier, Jennifer A. Markovics, Paul Wolters, David Jablons, Arthur Hill, Walter Finkbeiner, Kirk Jones, V. Courtney Broaddus, Dean Sheppard, Andrea Barzcak, Yuanyuan Xiao, David J. Erle, Stephen L. Nishimura
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Research Article Pulmonology

Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients

Abstract

Squamous metaplasia (SM) is common in smokers and is associated with airway obstruction in chronic obstructive pulmonary disease (COPD). A major mechanism of airway obstruction in COPD is thickening of the small airway walls. We asked whether SM actively contributes to airway wall thickening through alteration of epithelial-mesenchymal interactions in COPD. Using immunohistochemical staining, airway morphometry, and fibroblast culture of lung samples from COPD patients; genome-wide analysis of an in vitro model of SM; and in vitro modeling of human airway epithelial-mesenchymal interactions, we provide evidence that SM, through the increased secretion of IL-1β, induces a fibrotic response in adjacent airway fibroblasts. We identify a pivotal role for integrin-mediated TGF-β activation in amplifying SM and driving IL-1β–dependent profibrotic mesenchymal responses. Finally, we show that SM correlates with increased severity of COPD and that fibroblast expression of the integrin αvβ8, which is the major mediator of airway fibroblast TGF-β activation, correlated with disease severity and small airway wall thickening in COPD. Our findings have identified TGF-β as a potential therapeutic target for COPD.

Authors

Jun Araya, Stephanie Cambier, Jennifer A. Markovics, Paul Wolters, David Jablons, Arthur Hill, Walter Finkbeiner, Kirk Jones, V. Courtney Broaddus, Dean Sheppard, Andrea Barzcak, Yuanyuan Xiao, David J. Erle, Stephen L. Nishimura

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Figure 9

Expression of the integrin β8 is increased in small airway fibroblasts in COPD; its expression correlates with GOLD stage, airway wall thickness, and TGF-β activation.

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Expression of the integrin β8 is increased in small airway fibroblasts i...
Human lung samples obtained from patients with COPD (n = 22) or from normal controls (n = 12) were evaluated for β8 expression by immunostaining (A–C), flow cytometry (D), and TGF-β bioassay (E). In A, a histologic section of a small airway with SM is depicted with strong β8 staining in the basal cells (arrowheads) and moderate staining in the adjacent subepithelial fibroblasts (arrows). Scale bar: 50 μm. (B) Average β8 staining intensity is shown for normal lung samples and samples from GOLD stage 1–3 patients based on the 0–3 grading scale (see Methods). *P < 0.05, **P < 0.01. (C) Wall thickness was approximated by measuring the area of the airway wall from the basement membrane (BM) to the adventitia/length of the BM, using the method of Hogg (5). Shown is the relationship between wall thickness and β8 staining intensity. (D and E) Fibroblasts were harvested from lung parenchyma from normal patients (n = 6) or patients with COPD (n = 5) and were (D) stained with anti-β8 and analyzed using flow cytometry or (E) cocultured with TGF-β reporter cells (TMLC) in the presence or absence of neutralizing anti-β8. In D, shown is mean fluorescence intensity ± SE. *P < 0.05. In E, TGF-β activation is expressed as relative to the total light units obtained with anti–TGF-β. *P < 0.05.