Epithelial cell α3β1 integrin links β-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis
Kevin K. Kim, … , Jordan A. Kreidberg, Harold A. Chapman
Kevin K. Kim, … , Jordan A. Kreidberg, Harold A. Chapman
Published December 22, 2008
Citation Information: J Clin Invest. 2009;119(1):213-224. https://doi.org/10.1172/JCI36940.
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Research Article

Epithelial cell α3β1 integrin links β-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis

Abstract

Pulmonary fibrosis, in particular idiopathic pulmonary fibrosis (IPF), results from aberrant wound healing and scarification. One population of fibroblasts involved in the fibrotic process is thought to originate from lung epithelial cells via epithelial-mesenchymal transition (EMT). Indeed, alveolar epithelial cells (AECs) undergo EMT in vivo during experimental fibrosis and ex vivo in response to TGF-β1. As the ECM critically regulates AEC responses to TGF-β1, we explored the role of the prominent epithelial integrin α3β1 in experimental fibrosis by generating mice with lung epithelial cell–specific loss of α3 integrin expression. These mice had a normal acute response to bleomycin injury, but they exhibited markedly decreased accumulation of lung myofibroblasts and type I collagen and did not progress to fibrosis. Signaling through β-catenin has been implicated in EMT; we found that in primary AECs, α3 integrin was required for β-catenin phosphorylation at tyrosine residue 654 (Y654), formation of the pY654–β-catenin/pSmad2 complex, and initiation of EMT, both in vitro and in vivo during the fibrotic phase following bleomycin injury. Finally, analysis of lung tissue from IPF patients revealed the presence of pY654–β-catenin/pSmad2 complexes and showed accumulation of pY654–β-catenin in myofibroblasts. These findings demonstrate epithelial integrin–dependent profibrotic crosstalk between β-catenin and Smad signaling and support the hypothesis that EMT is an important contributor to pathologic fibrosis.

Authors

Kevin K. Kim, Ying Wei, Charles Szekeres, Matthias C. Kugler, Paul J. Wolters, Marla L. Hill, James A. Frank, Alexis N. Brumwell, Sarah E. Wheeler, Jordan A. Kreidberg, Harold A. Chapman

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Figure 3

Preserved acute lung injury response in FASC mice.

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Preserved acute lung injury response in FASC mice. (A and B) Five days a...
(A and B) Five days after intratracheal bleomycin injury, littermate control (A) and FASC (B) lung sections (original magnification, ×20) were stained with H&E and demonstrated increased inflammation in FASC mice. (C) Cell counts from BAL of littermate control and FASC mice 5 days after intratracheal saline or bleomycin injury. FASC mice had an increased number of cells compared with littermate controls (n = 4–6 per group). (D) Lung permeability determined by extravasation of intravascular 125I-albumin into the lungs and expressed as EVP%. FASC and littermate control mice demonstrated similar permeability 5 days after bleomycin injury (n = 4 per group). (E) Lung compliance (μl/cm H2O) was determined from anesthetized and paralyzed ventilated mice. FASC and littermate control mice demonstrated a decrease in compliance 5 days after bleomycin injury. There was a trend toward less compliance in FASC mice after bleomycin injury compared with littermate control mice after bleomycin injury (P = 0.09; n = 4 per group). (F) Total protein concentration (mg/ml) from BAL 5 days after intratracheal saline or bleomycin injury. FASC and littermate control mice demonstrated a similar increase in BAL protein after bleomycin injury (n = 4–6 per group). (G) Excess lung water (determined as described in Methods) increased similarly in FASC and littermate control mice 5 days after bleomycin injury (n = 4 per group).