Abstract
BackgroundPirfenidone is a novel anti-fibrotic and anti-inflammatory agent that inhibits the progression of fibrosis in animal models and in patients with idiopathic pulmonary fibrosis (IPF). We previously showed that pirfenidone inhibits the over-expression of collagen type I and of heat shock protein (HSP) 47, a collagen-specific molecular chaperone, in human lung fibroblasts stimulated with transforming growth factor (TGF)-β1 in vitro. The increased numbers of HSP47-positive type II pneumocytes as well as fibroblasts were also diminished by pirfenidone in an animal model of pulmonary fibrosis induced by bleomycin. The present study evaluates the effects of pirfenidone on collagen type I and HSP47 expression in the human alveolar epithelial cell line, A549 cells in vitro.MethodsThe expression of collagen type I, HSP47 and E-cadherin mRNAs in A549 cells stimulated with TGF-β1 was evaluated by Northern blotting or real-time PCR. The expression of collagen type I, HSP47 and fibronectin proteins was assessed by immunocytochemical staining.ResultsTGF-β1 stimulated collagen type I and HSP47 mRNA and protein expression in A549 cells, and pirfenidone significantly inhibited this process. Pirfenidone also inhibited over-expression of the fibroblast phenotypic marker fibronectin in A549 cells induced by TGF-β1.ConclusionWe concluded that the anti-fibrotic effects of pirfenidone might be mediated not only through the direct inhibition of collagen type I expression but also through the inhibition of HSP47 expression in alveolar epithelial cells, which results in reduced collagen synthesis in lung fibrosis. Furthermore, pirfenidone might partially inhibit the epithelial-mesenchymal transition.
Highlights
Pirfenidone is a novel anti-fibrotic and anti-inflammatory agent that inhibits the progression of fibrosis in animal models and in patients with idiopathic pulmonary fibrosis (IPF)
Using a mouse model of bleomycin-induced pulmonary fibrosis, we discovered that pirfenidone inhibits HSP47 overexpression in myofibroblasts and in type II pneumocytes, especially in fibrotic lesions, and that this activity is concomitant with an obvious reduction in fibrosis [12]
To clarify the association between alveolar epithelial cells and lung fibrosis and the action of pirfenidone in vitro, we examined the expression of collagen type I and HSP47 in the human alveolar epithelial cell line, A549, stimulated with transforming growth factor (TGF)-β1
Summary
Pirfenidone is a novel anti-fibrotic and anti-inflammatory agent that inhibits the progression of fibrosis in animal models and in patients with idiopathic pulmonary fibrosis (IPF). The exact mechanisms through which pirfenidone offers protection against lung fibrosis remain unclear In this context, we recently found that pirfenidone inhibits the expression of collagen type I and heat shock protein (HSP) 47, a collagenspecific molecular chaperone, in TGF-β-stimulated human lung fibroblasts in vitro [20]. HSP47-positive cells, especially myofibroblasts, might play a central role in the synthesis, deposition and remodeling of the ECM in pulmonary fibrosis in both patients and in animal models [12,26,27] In this context, collagen type I and HSP47 expression is recently considered to be one of the useful parameters for recognizing EMT [28]. The specific effects of pirfenidone upon collagen and HSP47 synthesis and EMT in alveolar epithelial cells in vitro remain obscure
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