Autophagy and the Unfolded Protein Response Promote Pro-fibrotic Effects of TGF{beta}1 in Human Lung Fibroblasts

Background: Idiopathic pulmonary fibrosis (IPF) is a lethal fibrotic lung disease in adults with limited treatment options. Autophagy and the unfolded protein response (UPR), fundamental processes induced by cell stress, are dysregulated in lung fibroblasts and epithelial cells from humans with IPF. Methods: Human primary cultured lung parenchymal and airway fibroblasts from non-IPF and IPF donors were stimulated with TGFβ1 with or without the inhibitors of autophagy or UPR (IRE1α inhibitor). We monitored temporal changes in abundance of protein markers of autophagy (LC3βII, Atg5-12), UPR (BIP, IRE1α, cleaved XBP1), and fibrosis (collagen 1α2, fibronectin) using immunoblotting. Using fluorescent immunohistochemistry we profiled autophagy (LC3βII) and UPR (BIP, XBP1) markers in human non-IPF and IPF lung tissue. Results: TGFβ1-induced collagen1α2 and fibronectin protein production was significantly higher in IPF lung fibroblasts compared to lung and airway fibroblasts from non-IPF donors. TGFβ1 induced the accumulation of LC3βII in parallel with collagen 1α2 and fibronectin, but, autophagy marker content was significantly lower in lung fibroblasts from IPF subjects. Inhibition of autophagy flux significantly reduced TGFβ1-induced collagen and fibronectin in fibroblasts from the lungs of non-IPF and IPF donors. Conversely, only in lung fibroblasts from IPF donors did TGFβ1 induce UPR markers. IRE1α inhibitor decreased TGFβ1-induced collagen 1α2 biosynthesis and fibronectin in IPF lung fibroblasts, but not those from non-IPF donors. Conclusions: The IRE1 pathway of the UPR is uniquely induced by TGFβ1 in lung fibroblasts from human IPF donors, and is required for excessive biosynthesis of collagen and fibronectin in these cells.

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