October 20, 2022

New target for lung fibrosis

Blocking thromboxane-prostanoid receptor signaling protected animals from lung fibrosis in preclinical models, suggesting a new treatment for IPF — a chronic, progressive lung disorder that often kills within 3-5 years of diagnosis.

Idiopathic pulmonary fibrosis (IPF) — a chronic, progressive syndrome — is marked by persistent activation and proliferation of fibroblast cells and the pathologic accumulation of extracellular matrix (scar tissue). Most patients die within 3-5 years of diagnosis. 

Timothy Blackwell, MD, James West, PhD, and colleagues have now discovered that TBXA2R (thromboxane-prostanoid receptor) signaling links oxidative stress to fibroblast activation during lung fibrosis. 

They found that TBXA2R expression was increased in fibroblasts in the lungs of patients with IPF and in mouse models of lung fibrosis, and they implicated F2-isoprostanes (products of arachidonic acid induced by reactive oxygen species) and TGF-beta signaling in fibroblast activation. In vivo treatment with the TBXA2R antagonist ifetroban reduced profibrotic signaling in the lungs and protected mice from lung fibrosis in three different preclinical models. 

The findings, reported in the American Journal of Respiratory and Critical Care Medicine, suggest that ifetroban and other TBXA2R antagonists may be useful for treating pulmonary fibrosis.

Toshio Suzuki, MD, a former fellow in the Division of Allergy, Pulmonary and Critical Care Medicine at VUMC, is the first author of the paper. Other co-authors include Jonathan Kropski, MD, Jingyuan Chen, Erica Carrier, PhD, Xinping Chen, Taylor Sherrill, Nichelle Winters, MD, PhD, Jane Camarata, Vasiliy Polosukhin, MD, PhD, Wei Han, Anandharajan Rathinasabapathy, PhD, Sergey Gutor, PhD, Peter Gulleman, Carleen Sabusap, PhD, Nicholas Banovich, PhD, Harikrishna Tanjore, PhD, Michael Freeman, PhD, Yuji Tada, MD, PhD, Lisa Young, MD, and Jason Gokey, PhD. 

The research was supported by grants from the National Institutes of Health (HL151016, HL135011, HL095797, HL108800, HL092870, HL145372, HL143281, HL119503, HL094296, HL130595) and the Doris Duke Charitable Foundation. Ifetroban was provided by Cumberland Pharmaceuticals.