Sigma-1 receptor agonist mitigates bleomycin-induced pulmonary fibrosis in mice

Introduction and aims: Idiopathic pulmonary fibrosis is associated with a median survival of just 2-3 years after diagnosis. Current therapies ameliorate pulmonary functional decrement, but do not inhibit the progression of fibrosis or reduce mortality. Thus, effective anti-fibrotic therapies are desperately needed. Based on our previous results in other organs, we aimed to investigate whether Sigma-1 receptor (S1R) agonist fluvoxamine (FLU) can ameliorate pulmonary fibrosis. Methods: Fibrotic processes were induced with TGF-β or PDGF in A549 lung epithelial cells and primary fibroblasts isolated from the lungs of wt and S1R-/- mice. Cells were treated with FLU. Pulmonary fibrosis was induced in wild-type and S1R-/- mice by oropharyngeal bleomycin (BLM) administration. Mice were treated daily with FLU and sacrificed after 21 days. Results: FLU mitigated α-SMA production and F-actin formation in both A549 cells and primary lung fibroblasts after pro-fibrotic factor induction. The effect of FLU was not obeserved in fibroblasts isolated from S1R-/- mice. In mice, after 21 days pro-fibrotic factor Tgfb expression was unaltered, while Ctgf expression increased in the BLM group, but not in the wt BLM+FLU group. Elevated expressions of ECM components collagen I, collagen III and fibronectin were reduced to control levels in wt BLM+FLU mice. Evaluation of Masson9s trichrome-stained sections underlined the massive anti-fibrotic effect of FLU. In vivo MicroCT showed more preserved aerated tissue area in wt BLM+FLU vs. wt BLM and S1R-/- BLM+FLU. Conclusions: Based on our preclinical data S1R may be a novel, effective drug target in the treatment of pulmonary fibrosis.