Epithelial Origin of Myofibroblasts during Fibrosis in the Lung

Abstract

An understanding of the mechanisms underlying pulmonary fibrosis remains elusive. Once believed to result primarily from chronic inflammation, it is now clear that inflammation and chronic fibrosis, especially in diseases such as idiopathic pulmonary fibrosis/usual interstitial pneumonia, are often dissociated, and that inflammation is neither necessary nor sufficient to induce fibrosis. The origin of the primary effector cell of fibrosis in the lung, the myofibroblast, is not clearly established. Three potential sources have been hypothesized. Although conversion of resident fibroblasts and differentiation of circulating bone marrow-derived progenitors likely play a role, the possible contribution of alveolar epithelial cells (AECs), through a process termed "epithelial-mesenchymal transition" (EMT), has only recently received consideration. A process by which epithelial cells lose cell-cell attachment, polarity and epithelialspecific markers, undergo cytoskeletal remodeling, and gain a mesenchymal phenotype, EMT plays a prominent role in fibrogenesis in adult tissues such as the kidney. This review summarizes the evidence supporting a central role for EMT in the pathogenesis of lung fibrosis, the potential for EMT in AECs in vitro and in vivo and role of transforming growth factor-␤1 in this process, and the implications of epithelium-driven fibrosis on future research and treatment. Potential pathways involved in EMT are also discussed. It is hoped that a major shift in current paradigms regarding the genesis of pulmonary fibrosis and dissection of the relevant pathways may allow development of targeted interventions that could potentially reverse the process and ameliorate the debilitating effects of abnormal repair and progressive fibrosis.

TGF-β1 Induces Progressive Pleural Scarring and Subpleural Fibrosis

“…It is involved in a variety of normal physiological as well as pathological processes such as cancer progression and renal fibrosis (16,17). Recent evidence suggests a potential role for EMT in the pathogenesis of pulmonary fibrosis (14,15,(41)(42)(43). MFT is a similar process and has been described as a major factor in the development of peritoneal fibrosis (18).…”

“…TGF-␤ is a multifunctional cytokine critically involved in the pathogenesis of fibrosis through its potent effects on fibroblast differentiation, extracellular matrix formation (13,14), and epithelialto-mesenchymal transition (EMT) 3 (15). Peritoneal mesothelial cells may undergo mesenchymal conversion (16,17) and TGF-␤1 gene transfer to the peritoneal mesothelium induces peritoneal fibrosis with evidence of mesothelial-to-mesenchymal transition or "mesothelial-fibroblastoid transformation" (MFT) (18).…”

The murine lens: A model to investigate in vivo epithelial–mesenchymal transition

“…Myofibroblasts are involved in tissue fibrosis in lung (Willis et al, 2006), liver (Albanis and Friedman, 2001; Friedman, 2004), kidney (Sato et al, 2003; Zeisberg and Kalluri, 2004), skin (Darby et al, 2014), eye (retina [Bochaton‐Piallat et al, 2000; Saika et al, 2004a,2007a], lens [Saika et al, 2001; de Iongh et al, 2005; Shirai et al, 2006]) to name a few. Myofibroblasts that appear in the fibrotic lesion are considered to be a mixture of cells derived from either fibroblasts (Gabbiani, 2003; Hinz and Gabbiani, 2003; Micallef et al, 2012; Willis et al, 2006;), local epithelial cells (Kalluri and Neilson, 2003; Zeisberg and Kalluri, 2004), and bone‐marrow‐derived cells (Quan et al, 2006) (Fig.…”

“…Myofibroblasts that appear in the fibrotic lesion are considered to be a mixture of cells derived from either fibroblasts (Gabbiani, 2003; Hinz and Gabbiani, 2003; Micallef et al, 2012; Willis et al, 2006;), local epithelial cells (Kalluri and Neilson, 2003; Zeisberg and Kalluri, 2004), and bone‐marrow‐derived cells (Quan et al, 2006) (Fig. 1).…”

Plasticity, Nuclear Diapause, and a Requiem for the Terminal Differentiation of Epithelia

“…36 Secondary EMT is seen among differentiated epithelia that transition to interstitial fibroblasts during organogenesis 36 and is well described in tissue epithelia from the kidney, eye, liver, and lung undergoing fibrosis. [35][36][37][38][39][40] Fibroblasts are different from mesenchymal cells, because fibroblasts are not as multipotent and selectively express fibroblast-specific protein-1. 36 This protein is found in all fibroblasts or secondary epithelia in transition to fibroblasts.…”