Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=26640170
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
Stanniocalcin-1 inhibits thrombin-induced signaling and protects from
bleomycin-induced lung injury
#MMPMID26640170
Huang L
; Zhang L
; Ju H
; Li Q
; Pan JS
; Al-Lawati Z
; Sheikh-Hamad D
Sci Rep
2015[Dec]; 5
(?): 18117
PMID26640170
show ga
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.
free
free
free
