PGF2α signaling drives fibrotic remodeling and fibroblast population dynamics in mice

Abstract

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 F 2α , and its cognate receptor FPr ( Ptgfr ) are implicated as a TGF-β1–independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (I ER - Sftpc I73T ) expressing a disease-associated missense mutation in the surfactant protein C ( Sftpc ) gene. Tamoxifen-treated I ER - Sftpc I73T mice developed an early multiphasic alveolitis and transition to spontaneous fibrotic remodeling by 28 days. I ER - Sftpc I73T mice crossed to a Ptgfr- null (FPr –/– ) line showed attenuated weight loss and gene dosage–dependent rescue of mortality compared with FPr +/+ cohorts. I ER -Sftpc I73T /FPr –/– mice also showed reductions in multiple fibrotic endpoints for which administration of nintedanib was not additive. Single-cell RNA-Seq, pseudotime analysis, and in vitro assays demonstrated Ptgfr expression predominantly within adventitial fibroblasts, which were reprogrammed to an “inflammatory/transitional” cell state in a PGF 2α /FPr-dependent manner. Collectively, the findings provide evidence for a role for PGF 2α 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.

Impaired AMPK Control of Alveolar Epithelial Cell Metabolism Promotes Pulmonary Fibrosis

“…Quantitatively, these changes were reflected in improvements in lung physiology, measured as static lung compliance ( Figure 7D, E ), and reductions in total cell counts in bronchoalveolar lavage fluid (BALF) and total BALF protein ( Figure 7F, G ). The effect size of these metrics compares favorably with previously published data demonstrating the efficacy of nintedanib (BIBF1120) in the S ftpc I73T mouse model 56 .…”

“…In the intestinal epithelium, metabolic alterations have been associated with a defect in epithelial progenitor cell function 55 . To assess potential alterations in AT2 I73T progenitor cell function (self-renewal and differentiation to AT1 cells) due to the observed bioenergetic changes, we reanalyzed our recently published single cell RNA sequencing (scRNA-seq) time series profiles (GSE234604 56 ) of S ftpc I73T mouse lungs (14 and 28 days post tamoxifen induction; Supplemental Figure 4 ). Within this dataset composed of 35002 cells, 2500 alveolar epithelial cells were identified and reclustered for further analysis ( Figure 4A and Supplemental Figure 4) .…”