Disruption of Prostaglandin F 2 α Receptor Signaling Attenuates Fibrotic Remodeling and Alters Fibroblast Population Dynamics in A Preclinical Murine Model of Idiopathic Pulmonary Fibrosis.

Autor:	Rodriguez LR; Pulmonary, Allergy, and Critical Care Division Department of Medicine; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104.; PENN-CHOP Lung Biology Institute; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104., Tang SY; Institute for Translational Medicine and Therapeutics; Department of Systems Pharmacology and Translational Therapeutics; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104., Barboza WR; Pulmonary, Allergy, and Critical Care Division Department of Medicine; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104.; PENN-CHOP Lung Biology Institute; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104., Murthy A; Pulmonary, Allergy, and Critical Care Division Department of Medicine; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104.; PENN-CHOP Lung Biology Institute; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104., Tomer Y; Pulmonary, Allergy, and Critical Care Division Department of Medicine; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104.; PENN-CHOP Lung Biology Institute; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104., Cai TQ; Calico Life Sciences LLC, South San Francisco, CA 94080., Iyer S; Pulmonary, Allergy, and Critical Care Division Department of Medicine; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104.; PENN-CHOP Lung Biology Institute; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104., Chavez K; Pulmonary, Allergy, and Critical Care Division Department of Medicine; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104.; PENN-CHOP Lung Biology Institute; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104., Das US; Institute for Translational Medicine and Therapeutics; Department of Systems Pharmacology and Translational Therapeutics; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104., Ghosh S; Institute for Translational Medicine and Therapeutics; Department of Systems Pharmacology and Translational Therapeutics; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104., Dimopoulos T; Pulmonary, Allergy, and Critical Care Division Department of Medicine; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104.; PENN-CHOP Lung Biology Institute; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104., Babu A; PENN-CHOP Lung Biology Institute; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104., Connelly C; Calico Life Sciences LLC, South San Francisco, CA 94080., FitzGerald GA; Institute for Translational Medicine and Therapeutics; Department of Systems Pharmacology and Translational Therapeutics; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104., Beers MF; Pulmonary, Allergy, and Critical Care Division Department of Medicine; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104.; PENN-CHOP Lung Biology Institute; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Jun 07. Date of Electronic Publication: 2023 Jun 07.
DOI:	10.1101/2023.06.07.543956
Abstrakt:	Idiopathic Pulmonary Fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition for which unmet need persists for effective therapeutics. The bioactive eicosanoid, prostaglandin F2 α , and its cognate receptor FPr ( Ptfgr ) are implicated as a TGF β 1 independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (I ER - Sftpc I 73 T ) expressing a disease-associated missense mutation in the surfactant protein C ( Sftpc ) gene. Tamoxifen treated I ER - Sftpc I 73 T mice develop an early multiphasic alveolitis and transition to spontaneous fibrotic remodeling by 28 days. I ER - Sftpc I 73 T mice crossed to a Ptgfr null (FPr - / - ) line showed attenuated weight loss and gene dosage dependent rescue of mortality compared to FPr+/+ cohorts. I ER - Sftpc I 73 T /FPr - / - mice also showed reductions in multiple fibrotic endpoints for which administration of nintedanib was not additive. Single cell RNA sequencing, pseudotime analysis, and in vitro assays demonstrated Ptgfr expression predominantly within adventitial fibroblasts which were reprogrammed to an "inflammatory/transitional" cell state in a PGF2 α /FPr dependent manner. Collectively, the findings provide evidence for a role for PGF2 α signaling in IPF, mechanistically identify a susceptible fibroblast subpopulation, and establish a benchmark effect size for disruption of this pathway in mitigating fibrotic lung remodeling. Competing Interests: DISCLOSURES GAF is an advisor to Calico Life Sciences. Otherwise, no conflicts of interest, financial or otherwise, are declared by the authors.
Databáze:	MEDLINE
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