title: Stanniocalcin-1 inhibits thrombin-induced signaling and protects from bleomycin-induced lung injury.
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.
authors.affiliation: Division of Nephrology and Selzman Institute for Kidney Health/Department of Medicine, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Luping
authors.initials: L
authors.lastname: Huang
authors.affiliation: Center of General Surgery, Chengdu General Hospital of Chengdu Military Area Command, Chengdu, P.R. China.|Division of Nephrology and Selzman Institute for Kidney Health/Department of Medicine, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Nephrology and Selzman Institute for Kidney Health/Department of Medicine, Baylor College of Medicine, Houston, TX, United States.|College of Veterinary Medicine, Yangzhou University, Yangzhou 25009, Jiangsu, P.R.China.
authors.forename: Huiming
authors.initials: H
authors.lastname: Ju
authors.affiliation: Division of Nephrology and Selzman Institute for Kidney Health/Department of Medicine, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Qingtian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Division of Nephrology and Selzman Institute for Kidney Health/Department of Medicine, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Jenny Szu-Chin
authors.initials: JS
authors.lastname: Pan
authors.affiliation: Division of Nephrology and Selzman Institute for Kidney Health/Department of Medicine, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Zahraa
authors.initials: Z
authors.lastname: Al-Lawati
authors.affiliation: Division of Nephrology and Selzman Institute for Kidney Health/Department of Medicine, Baylor College of Medicine, Houston, TX, United States.
authors.forename: David
authors.initials: D
authors.lastname: Sheikh-Hamad
mesh_terms: D000818:Animals; D001761:Bleomycin; D002460:Cell Line; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006023:Glycoproteins / Q000097:blood / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D055370:Lung Injury / Q000097:blood / Q000139:chemically induced* / Q000150:complications / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053495:Osteopontin / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011014:Pneumonia / Q000097:blood / Q000139:chemically induced / Q000150:complications / Q000378:metabolism / Q000473:pathology; D020011:Protective Agents; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism*
chemical_list: D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6; D018925:Chemokines; C498926:Cxcl16 protein, mouse; D006023:Glycoproteins; D018836:Inflammation Mediators; D020011:Protective Agents; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D001761:Bleomycin; D013481:Superoxides; C051795:teleocalcin; D048049:Extracellular Signal-Regulated MAP Kinases; D013917:Thrombin