Thromboxane–Prostanoid Receptor Signaling Drives Persistent Fibroblast Activation in Pulmonary Fibrosis
Toshio Suzuki, Jonathan A. Kropski, Jingyuan Chen, Erica J. Carrier, Xinping Chen, Taylor P. Sherrill, Nichelle I. Winters, Jane E. Camarata, Vasiliy V. Polosukhin, Wei Han, Anandharajan Rathinasabapathy, Sergey Gutor, Peter M. Gulleman, Carleen Mae P. Sabusap, Nicholas E. Banovich, Harikrishna Tanjore, Michael L. Freeman, Yuji Tada, Lisa R. Young, Jason J. Gokey, Timothy S. Blackwell, James West
Abstract
Abstract 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 vivo treatment 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.