Evaluation of Idiopathic Pulmonary Fibrosis therapies, Pirfenidone and Nintedanib, in a Human Experimental Model of Fibrosis

Introduction: Idiopathic pulmonary fibrosis (IPF) is an invariably fatal interstitial lung disease. The two currently approved drugs for the treatment of IPF (pirfenidone, nintedanib) have limited efficacy and their mechanisms of action are poorly understood. In this study we have compared the anti-fibrotic effects of these drugs using a human model of experimental lung fibrosis. Methods: 2 mm3 pieces of human lung parenchyma were cultured for 7 days in DMEM ± TGFβ1 (10 ng/ml) ± pirfenidone (500 mM) or nintedanib (1 mM). Pro-fibrotic pathways were examined by RT-PCR and soluble collagen secretion. Results: In 45 donor lung samples tested, 44 out of 84 IPF- and fibrosis-associated genes tested were significantly upregulated by TGFβ1, using a threshold of 0.5 log2 fold change. Nintedanib (n=13 donors) and pirfenidone (n=11 donors) dysregulated the mRNA expression of 14 and 2 fibrosis-associated genes respectively (≥ log2 fold change). Nintedanib attenuated the TGFβ1-dependent upregulation of mRNA for MMP1, 13 and 14, and PDGF, but upregulated α-smooth muscle actin and CTGF. Pirfenidone attenuated the TGFβ1-dependent expression of MMP3 and 13, but did not upregulate the expression of any genes. Both nintedanib and pirfenidone reduced the TGFβ1-dependent secretion of soluble collagen into the culture supernatants. Conclusions: This human experimental model of lung fibrosis recapitulates pro-fibrotic events evident in IPF and shows sensitivity to pirfenidone and nintedanib inhibition. Pirfenidone and nintedanib impact different molecular pathways.