Myofibroblast Differentiation and Enhanced Tgf-B Signaling in Cystic Fibrosis Lung Disease

William T Harris,David R Kelly,James S Hagood,Mark Macewen,Dezhi Wang,Eric J Sorscher,Namasivayam Ambalavanan,J P Clancy,Yong Zhou,Rory Edward Morty

doi:10.1371/journal.pone.0070196

Abstract

RationaleTGF-β, a mediator of pulmonary fibrosis, is a genetic modifier of CF respiratory deterioration. The mechanistic relationship between TGF-β signaling and CF lung disease has not been determined.ObjectiveTo investigate myofibroblast differentiation in CF lung tissue as a novel pathway by which TGF-β signaling may contribute to pulmonary decline, airway remodeling and tissue fibrosis.MethodsLung samples from CF and non-CF subjects were analyzed morphometrically for total TGF-β1, TGF-β signaling (Smad2 phosphorylation), myofibroblast differentiation (α-smooth muscle actin), and collagen deposition (Masson trichrome stain).ResultsTGF-β signaling and fibrosis are markedly increased in CF (p<0.01), and the presence of myofibroblasts is four-fold higher in CF vs. normal lung tissue (p<0.005). In lung tissue with prominent TGF-β signaling, both myofibroblast differentiation and tissue fibrosis are significantly augmented (p<0.005).ConclusionsThese studies establish for the first time that a pathogenic mechanism described previously in pulmonary fibrosis is also prominent in cystic fibrosis lung disease. The presence of TGF-β dependent signaling in areas of prominent myofibroblast proliferation and fibrosis in CF suggests that strategies under development for other pro-fibrotic lung conditions may also be evaluated for use in CF.

Highlights

Cystic fibrosis (CF) is a common inherited disease among Caucasians, affecting approximately 1 in 3000 births [1]
These studies establish for the first time that a pathogenic mechanism described previously in pulmonary fibrosis is prominent in cystic fibrosis lung disease
The presence of TGF-b dependent signaling in areas of prominent myofibroblast proliferation and fibrosis in CF suggests that strategies under development for other pro-fibrotic lung conditions may be evaluated for use in CF

Summary

Introduction

Cystic fibrosis (CF) is a common inherited disease among Caucasians, affecting approximately 1 in 3000 births [1]. The progression of CF lung disease is variable, even among individuals sharing the same mutation in the cystic fibrosis transmembrane regulator (CFTR) [3]. Recent progress in animal models such as the cystic fibrosis pig have expanded the understanding of CF pathogenesis beyond mucus obstruction and infection/inflammation to include defects in hormonemediated growth, development, and airway remodeling [4,5,6]. CF patients with specific polymorphisms in TGF-b1 (a potent pro-fibrotic cytokine) have a significantly increased odds ratio of severe lung disease [7]. TGF-b is a known mediator of fibroblast pathobiology in human lungs [9], and is a modifier of disease severity among CF individuals [7,10,11,12]. TGF-b signaling and the mechanisms underlying development of lung fibrosis in CF have not been characterized previously

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Conclusion