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

Sci Rep. 2015 Dec 7;5:18117. doi: 10.1038/srep18117.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Bleomycin
  • Cell Line
  • Chemokine CXCL16
  • Chemokine CXCL6 / metabolism
  • Chemokines / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Glycoproteins / blood
  • Glycoproteins / metabolism*
  • Humans
  • Inflammation Mediators / metabolism
  • Lung Injury / blood
  • Lung Injury / chemically induced*
  • Lung Injury / complications
  • Lung Injury / metabolism*
  • MAP Kinase Signaling System / drug effects
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Osteopontin / metabolism
  • Phosphorylation / drug effects
  • Pneumonia / blood
  • Pneumonia / chemically induced
  • Pneumonia / complications
  • Pneumonia / metabolism
  • Pneumonia / pathology
  • Protective Agents
  • Reactive Oxygen Species / metabolism
  • Recombinant Proteins / pharmacology
  • Signal Transduction* / drug effects
  • Superoxides / metabolism
  • Thrombin / metabolism*

Substances

  • Chemokine CXCL16
  • Chemokine CXCL6
  • Chemokines
  • Cxcl16 protein, mouse
  • Glycoproteins
  • Inflammation Mediators
  • Protective Agents
  • Reactive Oxygen Species
  • Recombinant Proteins
  • Spp1 protein, mouse
  • Osteopontin
  • Bleomycin
  • Superoxides
  • teleocalcin
  • Extracellular Signal-Regulated MAP Kinases
  • Thrombin