Disruption of prostaglandin F2α receptor signaling attenuates fibrotic remodeling in a preclinical murine model of idiopathic pulmonary fibrosis

Abstract

Idiopathic Pulmonary Fibrosis (IPF) is characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition resulting in progressive loss of lung function culminating in death or need for transplantation. Despite approved treatment options (nintedanib; pirfenidone), unmet need persists for well-tolerated and effective IPF therapeutics. The bioactive eicosanoid, prostaglandin F2α, and its cognate receptor FPR are implicated as a TGFβ1 independent mediator of IPF. To assess the role of PGF2α/ FPR signaling in IPF, we leveraged our published murine PF model (I^ER-<i>Sftpc^I73T</i>) expressing an inducible disease associated missense mutation in the <i>SFTPC</i> gene (I73T). Tamoxifen treatment of I^ER-<i>Sftpc^I73T</i> mice results in an early multiphasic alveolitis and transition to spontaneous fibrotic remodeling. For this study, I^ER-<i>Sftpc</i>^<i>I73</i>T mice were crossed to a FPR null (FPR−/−) line and given 2 sequential doses of tamoxifen by intraperitoneal or oral routes. FPR deletion resulted in both attenuated weight loss and gene dosage dependent rescue of mortality compared to FPR+/+ cohorts. At day 28, lungs from surviving I^ER-<i>Sftpc^I73T</i>/FPR−/− mice showed 40-60% reductions in fibrotic endpoints including soluble collagen content (Sircol), fibrillar collagen deposition (picrosirius red), and collagen gene expression. Administration of nintedanib to I^ER-<i>Sftpc^I73T</i>/FPR−/− was not additive for any endpoint. Collectively, findings in&nbsp;I^ER-<i>Sftpc^I73T</i>/FPR−/− mice provide added equipoise for a role for PGF2α signaling in IPF and establish a benchmark effect size for this pathway in mitigating fibrotic lung disease.