Normal Human Lung Epithelial Cells Inhibit Transforming Growth Factor-β Induced Myofibroblast Differentiation via Prostaglandin E2

Abstract

IntroductionIdiopathic pulmonary fibrosis (IPF) is a chronic progressive disease with very few effective treatments. The key effector cells in fibrosis are believed to be fibroblasts, which differentiate to a contractile myofibroblast phenotype with enhanced capacity to proliferate and produce extracellular matrix. The role of the lung epithelium in fibrosis is unclear. While there is evidence that the epithelium is disrupted in IPF, it is not known whether this is a cause or a result of the fibroblast pathology. We hypothesized that healthy epithelial cells are required to maintain normal lung homeostasis and can inhibit the activation and differentiation of lung fibroblasts to the myofibroblast phenotype. To investigate this hypothesis, we employed a novel co-culture model with primary human lung epithelial cells and fibroblasts to investigate whether epithelial cells inhibit myofibroblast differentiation.Measurements and Main ResultsIn the presence of transforming growth factor (TGF)-β, fibroblasts co-cultured with epithelial cells expressed significantly less α-smooth muscle actin and collagen and showed marked reduction in cell migration, collagen gel contraction, and cell proliferation compared to fibroblasts grown without epithelial cells. Epithelial cells from non-matching tissue origins were capable of inhibiting TGF-β induced myofibroblast differentiation in lung, keloid and Graves’ orbital fibroblasts. TGF-β promoted production of prostaglandin (PG) E2 in lung epithelial cells, and a PGE2 neutralizing antibody blocked the protective effect of epithelial cell co-culture.ConclusionsWe provide the first direct experimental evidence that lung epithelial cells inhibit TGF-β induced myofibroblast differentiation and pro-fibrotic phenotypes in fibroblasts. This effect is not restricted by tissue origin, and is mediated, at least in part, by PGE2. Our data support the hypothesis that the epithelium plays a crucial role in maintaining lung homeostasis, and that damaged and/ or dysfunctional epithelium contributes to the development of fibrosis.

Human lung fibroblasts produce proresolving peroxisome proliferator-activated receptor-γ ligands in a cyclooxygenase-2-dependent manner

“…Moreover, we and others previously demonstrated that exogenously administered PPAR␥ ligands exert potent antifibrotic effects in the lung (14,26,31,43,51,55,57). Notably, PGE 2 is also well known to have antifibrotic effects in the lung (25,37,59,87) and might act additively or synergistically with these PPAR␥ ligands to inhibit pulmonary fibrosis. Nevertheless, our discovery of an endogenous source of PPAR␥ ligands discloses a novel proresolving pathway with potential therapeutic implications in chronic inflammatory or fibrotic lung disease.…”

Inhibiting eicosanoid degradation exerts antifibrotic effects in a pulmonary fibrosis mouse model and human tissue

“…8,9 Studies have shown that PGE 2 inhibits fibroblast proliferation, 10 decreases alveolar epithelial cell apoptosis, 11 is protective in bleomycin-induced pulmonary fibrosis in mice, 12,13 and inhibits myofibroblast differentiation in vitro. 14 The same holds true to some extent for PGD 2 . 15,16 Furthermore, there are publications showing strong beneficial effects of lipoxin A4 or its more stable analogs in preventing myofibroblast formation 17 and bleomycin-induced fibrosis 18 and in improving lung function of bleomycin-treated mice.…”

Phosphodiesterase 4 inhibition reduces lung fibrosis following targeted type II alveolar epithelial cell injury

“…In addition to promoting the integrity of the alveolar epithelium, PGE 2 as well as prostacyclin analogs have been found to hinder a myriad of fibroblast functions. Specifically, PGE 2 and treprostinil inhibit TGF-b-induced myofibroblast differentiation and promote the reversal of differentiated myofibroblasts to fibroblasts (Garrison et al 2013;Epa et al 2015;Corboz et al 2018). In addition, PGE 2 impedes the proliferation and migration of fibroblasts and also increases their susceptibility to apoptosis (Huang et al 2009;Maher et al 2010).…”