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Disruption of Prostaglandin F2α Receptor Signaling Attenuates Fibrotic Remodeling and Alters Fibroblast Population Dynamics in A Preclinical Murine Model of Idiopathic Pulmonary Fibrosis

ABSTRACT: Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, and diffuse parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition resulting in progressive loss of lung function. Despite approved treatment options, unmet need persists for effective IPF therapeutics. The bioactive eicosanoid, prostaglandin F2a, and its cognate receptor FPr (Ptfgr) are implicated as a TGFb1 independent signaling hub for IPF. To further assess this signaling in IPF, we leveraged our published murine PF model (IER-SftpcI73T) expressing an inducible disease associated missense mutation in the SFTPC gene (I73T). Tamoxifen induction of IER-SftpcI73T mice resulted in an early multiphasic alveolitis and transition to spontaneous fibrotic remodeling by 28 days. IER-SftpcI73T mice were crossed to a Ptgfr null (FPr-/-) line and resulted in attenuated weight loss and reductions in fibrotic endpoints. Through single cell RNA sequencing, pseudotime analysis, and in-vitro assays we demonstrated expression of Ptgfr predominantly within adventitial fibroblasts whichwere reprogrammed to an “inflammatory/transitional” cell state population in a PGF2a / FPr dependent manner.. Collectively, the findings provide added evidence a role for PGF2a signaling in IPF, mechanistically identify a susceptible fibroblast subpopulation, and establish a benchmark effect size for disruption of this pathway in mitigating fibrotic lung disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE234604 | GEO | 2023/12/04

REPOSITORIES: GEO

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Project description:As a group, fibroproliferative disorders of the lung, liver, kidney, heart, vasculature and integument are common, progressive and refractory to therapy. They can emerge following toxic insults, but are frequently idiopathic. Their enigmatic propensity to resist therapy and progress to organ failure has focused attention on the myofibroblast – the primary effector of the fibroproliferative response. A central unanswered question is whether these myofibroblasts have acquired a distinct pathological phenotype - or whether they are normal myofibroblasts with a pathological phenotype that depends upon residing in a sea of pro-fibrotic cytokines and an abnormal extracellular matrix. Using a systems approach to study this question in a prototype fibrotic disease, Idiopathic Pulmonary Fibrosis (IPF); here we show organized changes in the gene expression pathway of primary lung myofibroblasts that persist for up to 9 sub-cultivations in vitro. When comparing IPF and control myofibroblasts in a 3-dimensional type I collagen matrix, more genes differed at the level of ribosome recruitment than at the level of transcript abundance, indicating pathological translational control as a major characteristic of IPF myofibroblasts. To determine the effect of matrix state on translational control, myofibroblasts were permitted to contract the matrix. Ribosome recruitment in control myofibroblasts was relatively stable. In contrast, IPF cells manifested large alterations in the ribosome recruitment pattern. Pathological studies suggest an epithelial origin for IPF myofibroblasts through the epithelial to mesenchymal transition (EMT). In accord with this, we found systems-level indications for TGF?b -driven EMT as one source of IPF myofibroblasts. Keywords: cell type comparison Comparison of lung myofibroblasts from patients with Idiopatic Pulmonary Fibrosis (IPF, 6 donors) to control (6 donors) in contractile and non-contractile matrices using both total and polyribosomal RNA

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Disruption of Prostaglandin F2α Receptor Signaling Attenuates Fibrotic Remodeling and Alters Fibroblast Population Dynamics in A Preclinical Murine Model of Idiopathic Pulmonary Fibrosis

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