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PGF2α 信号通路驱动小鼠的纤维化重塑和成纤维细胞群体动力学。

PGF2α signaling drives fibrotic remodeling and fibroblast population dynamics in mice.

机构信息

Pulmonary, Allergy, and Critical Care Division, Department of Medicine.

PENN-CHOP Lung Biology Institute, and.

出版信息

JCI Insight. 2023 Dec 22;8(24):e172977. doi: 10.1172/jci.insight.172977.

DOI:10.1172/jci.insight.172977
PMID:37934604
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10807712/
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 F2α, 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 (IER-SftpcI73T) expressing a disease-associated missense mutation in the surfactant protein C (Sftpc) gene. Tamoxifen-treated IER-SftpcI73T mice developed 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 with FPr+/+ cohorts. IER-SftpcI73T/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 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.

摘要

特发性肺纤维化（IPF）是一种慢性实质肺疾病，其特征为反复的肺泡细胞损伤、肌成纤维细胞增殖和细胞外基质过度沉积，目前仍需要有效的治疗方法。生物活性类二十烷酸前列腺素 F2α 及其同源受体 FPr（Ptgfr）被认为是 IPF 的 TGF-β1 非依赖性信号枢纽。为了评估这一点，我们利用我们发表的表达 SURFACTANT PROTEIN C（Sftpc）基因中疾病相关错义突变的小鼠 PF 模型（IER-SftpcI73T）。用他莫昔芬处理的 IER-SftpcI73T 小鼠发生早期多相性肺泡炎，并在 28 天内过渡到自发性纤维化重塑。与 FPr+/+ 队列相比，IER-SftpcI73T 小鼠与 Ptgfr 缺失（FPr-/-）系杂交显示出体重减轻减轻和死亡率的基因剂量依赖性挽救。IER-SftpcI73T/FPr-/-小鼠还显示出多种纤维化终点的减少，而 nintedanib 的给药没有叠加作用。单细胞 RNA-Seq、拟时序分析和体外测定表明 Ptgfr 表达主要在 adventitial 成纤维细胞内，这些细胞以 PGF2α/FPr 依赖的方式被重新编程为“炎症/过渡”细胞状态。总之，这些发现为 PGF2α 信号在 IPF 中的作用提供了证据，从机制上确定了易感性成纤维细胞亚群，并为破坏该途径减轻纤维化肺重塑建立了基准效应大小。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de9a/10807712/a67d0e95a209/jciinsight-8-172977-g113.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de9a/10807712/770e9eb99f65/jciinsight-8-172977-g106.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de9a/10807712/6556961206f5/jciinsight-8-172977-g107.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de9a/10807712/7b01dbc0727e/jciinsight-8-172977-g108.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de9a/10807712/d35be3deefad/jciinsight-8-172977-g109.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de9a/10807712/2d84dc188b34/jciinsight-8-172977-g110.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de9a/10807712/6b51160d8ff6/jciinsight-8-172977-g111.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de9a/10807712/234d2b113d97/jciinsight-8-172977-g112.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de9a/10807712/a67d0e95a209/jciinsight-8-172977-g113.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de9a/10807712/770e9eb99f65/jciinsight-8-172977-g106.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de9a/10807712/6556961206f5/jciinsight-8-172977-g107.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de9a/10807712/7b01dbc0727e/jciinsight-8-172977-g108.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de9a/10807712/d35be3deefad/jciinsight-8-172977-g109.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de9a/10807712/2d84dc188b34/jciinsight-8-172977-g110.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de9a/10807712/6b51160d8ff6/jciinsight-8-172977-g111.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de9a/10807712/234d2b113d97/jciinsight-8-172977-g112.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de9a/10807712/a67d0e95a209/jciinsight-8-172977-g113.jpg

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