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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.
Rodriguez, Luis R; Tang, Soon Yew; Barboza, Willy Roque; Murthy, Aditi; Tomer, Yaniv; Cai, Tian-Quan; Iyer, Swati; Chavez, Katrina; Das, Ujjalkumar Subhash; Ghosh, Soumita; Dimopoulos, Thalia; Babu, Apoorva; Connelly, Caitlin; FitzGerald, Garret A; Beers, Michael F.
Afiliación
  • Rodriguez LR; Pulmonary, Allergy, and Critical Care Division Department of Medicine; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104.
  • Tang SY; PENN-CHOP Lung Biology Institute; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104.
  • Barboza WR; 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.
  • Murthy A; Pulmonary, Allergy, and Critical Care Division Department of Medicine; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104.
  • Tomer Y; PENN-CHOP Lung Biology Institute; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104.
  • Cai TQ; Pulmonary, Allergy, and Critical Care Division Department of Medicine; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104.
  • Iyer S; 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.
  • Das US; PENN-CHOP Lung Biology Institute; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104.
  • Ghosh S; Calico Life Sciences LLC, South San Francisco, CA 94080.
  • Dimopoulos T; Pulmonary, Allergy, and Critical Care Division Department of Medicine; 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; Pulmonary, Allergy, and Critical Care Division Department of Medicine; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104.
  • FitzGerald GA; PENN-CHOP Lung Biology Institute; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104.
  • Beers MF; 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.
bioRxiv ; 2023 Jun 07.
Article en En | MEDLINE | ID: mdl-37333249
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 F2α, and its cognate receptor FPr (Ptfgr) are implicated as a TGFß1 independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (IER - SftpcI73T) expressing a disease-associated missense mutation in the surfactant protein C (Sftpc) gene. Tamoxifen treated IER-SftpcI73T mice develop an early multiphasic alveolitis and transition to spontaneous fibrotic remodeling by 28 days. IER-SftpcI73T mice crossed to a Ptgfr null (FPr-/-) line showed attenuated weight loss and gene dosage dependent rescue of mortality compared to FPr+/+ cohorts. IER-SftpcI73T/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 PGF2α/FPr dependent manner. Collectively, the findings provide evidence for a role for PGF2α 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: BioRxiv Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: BioRxiv Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos