Abstract
Thrombin-induced and proteinase-activated receptor 1 (PAR1)-mediated signaling increases ROS production, activates ERK, and promotes inflammation and fibroblast proliferation in bleomycin-induced lung injury. Stanniocalcin-1 (STC1) activates anti-oxidant pathways, inhibits inflammation and provides cytoprotection; hence, we hypothesized that STC1 will inhibit thrombin/PAR1 signaling and protect from bleomycin-induced pneumonitis. We determined thrombin level and activity, thrombin-induced PAR-1-mediated signaling, superoxide generation and lung pathology after intra-tracheal administration of bleomycin to WT and STC1 Tg mice. Lungs of bleomycin-treated WT mice display: severe pneumonitis; increased generation of superoxide; vascular leak; increased thrombin protein abundance and activity; activation of ERK; greater cytokine/chemokine release and infiltration with T-cells and macrophages. Lungs of STC1 Tg mice displayed none of the above changes. Mechanistic analysis in cultured pulmonary epithelial cells (A549) suggests that STC1 inhibits thrombin-induced and PAR1-mediated ERK activation through suppression of superoxide. In conclusion, STC1 blunts bleomycin-induced rise in thrombin protein and activity, diminishes thrombin-induced signaling through PAR1 to ERK, and inhibits bleomycin-induced pneumonitis. Moreover, our study identifies a new set of cytokines/chemokines, which play a role in the pathogenesis of bleomycin-induced lung injury. These findings broaden the array of potential therapeutic targets for the treatment of lung diseases characterized by thrombin activation, oxidant stress and inflammation.
Highlights
Thrombin-induced and proteinase-activated receptor 1 (PAR1)-mediated signaling increases reactive oxygen species (ROS) production, activates extracellular regulated kinase (ERK), and promotes inflammation and fibroblast proliferation in bleomycininduced lung injury
The data suggest that transgenic overexpression of STC1 protects from acute bleomycin-induced lung injury and pneumonitis
Cumulative evidence suggests that thrombin promotes inflammation and fibroblast proliferation following bleomycin- and radiation-induced lung injuries[19,20]
Summary
Thrombin-induced and proteinase-activated receptor 1 (PAR1)-mediated signaling increases ROS production, activates ERK, and promotes inflammation and fibroblast proliferation in bleomycininduced lung injury. Studies from our lab suggest that mammalian STC1 upregulates uncoupling proteins and suppresses mitochondrial superoxide generation[8]; and in doing so, it inhibits macrophage function[8], attenuates cytokine-induced rise in endothelial permeability[9] and migration of lymphocytes and macrophages across endothelial cells[10]. Combined, these effects predict potent anti-inflammatory action. We hypothesized that transgenic overexpression of STC1 in mice will inhibit thrombin actions, diminish ROS production and inflammation, and protect from bleomycin-induced lung injury and inflammation
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