Thromboxane-Prostanoid Receptor Signaling Drives Persistent Fibroblast Activation in Pulmonary Fibrosis.
Thromboxane-Prostanoid Receptor Signaling Drives Persistent Fibroblast Activation in Pulmonary Fibrosis.
复制标题
血栓素-前列腺素受体信号传导驱动肺纤维化中成纤维细胞的持续激活。
DOI：
10.1164/rccm.202106-1503oc
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发表时间：
2022
影响因子：
24.7
通讯作者：
Sabusap,Carl
中科院分区：
文献类型：
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作者：
Suzuki,Toshio;Kropski,JonathanA;Chen,Jingyuan;Carrier,EricaJ;Chen,Xinping;Sherrill,TaylorP;Winters,NichelleI;Camarata,JaneE;Polosukhin,VasiliyV;Han,Wei;Rathinasabapathy,Anandharajan;Gutor,Sergey;Gulleman,Peter;Sabusap,Carl
理由：虽然持续性成纤维细胞激活是特发性肺纤维化（IPF）的一个标志，但调节肺部持续性成纤维细胞激活的机制尚未完全阐明。目的：根据我们观察到肺成纤维细胞在纤维化过程中表达 TBXA2R（血栓素-前列腺素受体），我们研究了 TBXA2R 信号在纤维化重塑中的作用。 TBXA2R 在 IPF 患者和小鼠肺部的表达，并研究了原代小鼠和人肺成纤维细胞，以确定 TBXA2R 信号传导对成纤维细胞活化的影响。我们使用 TBXA2R 缺陷小鼠和小分子抑制剂来研究临床前肺纤维化模型中的 TBXA2R 信号转导。测量和主要结果：IPF 患者肺部成纤维细胞和实验性肺纤维化期间小鼠肺部的 TBXA2R 表达上调。 TBXA2R 的基因缺失，但不抑制血栓素合酶，可以保护小鼠免受博莱霉素诱导的肺纤维化，从而表明替代配体激活促纤维化 TBXA2R 信号传导。与血栓素相反，F2-异前列烷是活性氧诱导的花生四烯酸的非酶产物，在纤维化过程中持续升高。 F2-异前列烷诱导成纤维细胞中的 TBXA2R 信号传导，并介导肌成纤维细胞激活谱，至少部分归因于 TGF-β（转化生长因子-β）信号传导的增强。使用 TBXA2R 拮抗剂伊非曲班进行体内治疗，可减少肺部促纤维化信号传导，在三种临床前模型（博来霉素小鼠、Hermansky-Pudlak 小鼠和放射诱导小鼠）中保护小鼠免受肺纤维化。纤维化），博莱霉素治疗后纤维化消退明显增强。结论：TBXA2R 将肺纤维化过程中的氧化应激与成纤维细胞活化联系起来。 TBXA2R 拮抗剂可用于治疗肺纤维化。
Rationale:Although persistent fibroblast activation is a hallmark of idiopathic pulmonary fibrosis (IPF), mechanisms regulating persistent fibroblast activation in the lungs have not been fully elucidated.Objectives:On the basis of our observation that lung fibroblasts express TBXA2R (thromboxane–prostanoid receptor) during fibrosis, we investigated the role of TBXA2R signaling in fibrotic remodeling.Methods:We identified TBXA2R expression in lungs of patients with IPF and mice and studied primary mouse and human lung fibroblasts to determine the impact of TBXA2R signaling on fibroblast activation. We used TBXA2R-deficient mice and small-molecule inhibitors to investigate TBXA2R signaling in preclinical lung fibrosis models.Measurements and Main Results:TBXA2R expression was upregulated in fibroblasts in the lungs of patients with IPF and in mouse lungs during experimental lung fibrosis. Genetic deletion of TBXA2R, but not inhibition of thromboxane synthase, protected mice from bleomycin-induced lung fibrosis, thereby suggesting that an alternative ligand activates profibrotic TBXA2R signaling. In contrast to thromboxane, F2-isoprostanes, which are nonenzymatic products of arachidonic acid induced by reactive oxygen species, were persistently elevated during fibrosis. F2-isoprostanes induced TBXA2R signaling in fibroblasts and mediated a myofibroblast activation profile due, at least in part, to potentiation of TGF-β (transforming growth factor-β) signaling.In vivotreatment with the TBXA2R antagonist ifetroban reduced profibrotic signaling in the lungs, protected mice from lung fibrosis in three preclinical models (bleomycin, Hermansky-Pudlak mice, and radiation-induced fibrosis), and markedly enhanced fibrotic resolution after bleomycin treatment.Conclusions:TBXA2R links oxidative stress to fibroblast activation during lung fibrosis. TBXA2R antagonists could have utility in treating pulmonary fibrosis.