Abstract
Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with a poor prognosis and increasing incidence. Pirfenidone and nintedanib are the only approved treatments for IPF but have limited efficacy and their mechanisms of action are poorly understood. Here we have examined the effects of pirfenidone and nintedanib in a human model of lung fibrogenesis, and compared these with the putative anti-fibrotic compounds Lipoxin A4 (LXA4), and senicapoc, a KCa3.1 ion channel blocker. Methods: Early fibrosis was induced in cultured human lung parenchyma using TGFβ1 for 7 days, ± pirfenidone, nintedanib, or LXA4. Pro-fibrotic responses were examined by RT-PCR, immunohistochemistry and soluble collagen secretion. Results: Thirty six out of eighty four IPF and fibrosis-associated genes tested were significantly upregulated by TGFβ1 in human lung parenchyma with a ≥0.5 log2FC (n = 32). Nintedanib (n = 13) reduced the mRNA expression of 14 fibrosis-associated genes including MMPs (MMP1,−4,−13,−14), integrin α2, CXCR4 and PDGFB, but upregulated α-smooth muscle actin (αSMA). Pirfenidone only reduced mRNA expression for MMP3 and −13. Senicapoc (n = 11) previously attenuated the expression of 28 fibrosis-associated genes, including αSMA, several growth factors, collagen type III, and αV/β6 integrins. Pirfenidone and nintedanib significantly inhibited TGFβ1-induced fibroblast proliferation within the tissue, but unlike senicapoc, neither pirfenidone nor nintedanib prevented increases in tissue αSMA expression. LXA4 was ineffective. Conclusions: Pirfenidone and nintedanib demonstrate modest anti-fibrotic effects and provide a benchmark for anti-fibrotic activity of new drugs in human lung tissue. Based on these data, we predict that the KCa3.1 blocker senicapoc will show greater benefit than either of these licensed drugs in IPF.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with a poor prognosis and increasing incidence
We have previously demonstrated that control and TGFβ1stimulated human lung tissue is viable over 7 days with no evidence of nuclear fragmentation, tissue necrosis or reduction in metabolic activity (MTS turnover), and that RNA integrity is maintained (Roach et al, 2018)
Fibrotic changes were present in the TGFβ1-stimulated tissue at both day 4 and day 7 identified using RT-PCR on a select panel of key fibrosis-associated genes, including the myofibroblast activation marker αSMA (ACT2A), and extracellular matrix deposition markers fibronectin (FN1), collagen type 1 (COL1A2) and collagen type 3 (COL3A1) (n 3) (Figure 1B)
Summary
Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with a poor prognosis and increasing incidence. Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a median survival of only 3–5 years, worse than many common cancers (Navaratnam et al, 2011; Raghu et al, 2011). It is characterised by parenchymal lung fibrosis leading to impairment of gas exchange and death (King et al, 2011). There are only two drugs approved for the treatment of IPF, nintedanib and pirfenidone Both drugs slow disease progression, but only modestly, and are often poorly tolerated (King et al, 2014). Understanding the mechanisms of action these drugs have in human lung tissue and their relative efficacy may uncover anti-fibrotic pathways that can be targeted more effectively, clarify where these drugs fail to influence the fibrotic process, as well as providing a benchmark for the assessment of novel putative anti-fibrotic compounds
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