Thromboxane-Prostanoid Receptor Signaling Drives Persistent Fibroblast Activation in Pulmonary Fibrosis

Area of Science:

• Pulmonary Medicine
• Fibrosis Research
• Molecular Biology

Background:

• Persistent fibroblast activation is a key feature of idiopathic pulmonary fibrosis (IPF).
• Mechanisms driving sustained fibroblast activation in lung fibrosis remain incompletely understood.
• Lung fibroblasts express thromboxane-prostanoid receptor (TBXA2R) during fibrotic processes.

Purpose of the Study:

• To investigate the role of TBXA2R signaling in fibrotic remodeling of the lungs.
• To determine if TBXA2R mediates fibroblast activation in the context of lung fibrosis.
• To explore TBXA2R as a potential therapeutic target for pulmonary fibrosis.

Main Methods:

• Quantified TBXA2R expression in human IPF lungs and mouse models.
• Studied primary mouse and human lung fibroblasts to assess TBXA2R signaling.
• Utilized TBXA2R-deficient mice and small-molecule inhibitors in preclinical fibrosis models.
• Investigated the effects of F2-isoprostanes and TGF-β signaling.

Main Results:

• TBXA2R expression is elevated in fibrotic lung fibroblasts.
• Genetic TBXA2R deletion protected mice from bleomycin-induced lung fibrosis.
• F2-isoprostanes, not thromboxane, activated profibrotic TBXA2R signaling.
• TBXA2R antagonism with ifetroban reduced fibrosis and enhanced resolution in multiple models.
• TBXA2R signaling potentiated TGF-β-mediated myofibroblast activation.

Conclusions:

• TBXA2R serves as a crucial link between oxidative stress and fibroblast activation in lung fibrosis.
• Targeting TBXA2R with antagonists represents a potential therapeutic strategy for pulmonary fibrosis.