Stanniocalcin-1 inhibits thrombin-induced signaling and protects from bleomycin-induced lung injury

Luping Huang, Lin Zhang, Huiming Ju, Qingtian Li, Jenny Szu Chin Pan, Zahraa Al-Lawati, David Sheikh-Hamad

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageEnglish (US)
Article number18117
JournalScientific Reports
Volume5
DOIs
StatePublished - Dec 7 2015

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Stanniocalcin-1 inhibits thrombin-induced signaling and protects from bleomycin-induced lung injury'. Together they form a unique fingerprint.

Cite this