A phosphoinositide 3-kinase-gamma inhibitor, AS605240 prevents bleomycin-induced pulmonary fibrosis in rats.
Phosphoinositide 3-kinase-gamma (PI3Kgamma) has been identified to play the critical roles in inflammatory cells activation and recruitment in multiply inflammatory diseases and it promised to be a prospective target for relevant inflammatory diseases therapy. AS605240, a selective PI3Kgamma inhibitor, has been proved effective on several inflammatory diseases. In this study, we investigated the protective effect of AS605240 on bleomycin-induced pulmonary fibrosis in rats. Our results showed that orally administration of AS605240 significantly prevented lung inflammation and reduced collagen deposition. AS605240 also inhibited augmented expression of TNF-alpha and IL-1beta induced by bleomycin instillation. Moreover, the mRNA levels of TNF-alpha and IL-1beta in lung were remarkably suppressed. Histological assessment found that AS605240 reduced the expression of TGF-beta(1) and prevented T lymphocytes infiltration to lung. Phospho-Akt level in inflammatory cells by blocking PI3Kgamma was down-regulated and the inhibition of Akt phosphorylation was further confirmed by Western blot. Our findings illustrated that AS605240 was effective for preventing pulmonary fibrosis by suppressing inflammatory cells recruitment and production of inflammatory cytokines. These findings also suggest that PI3Kgamma may be a useful target in treating inflammation diseases and AS605240 may represent a promising novel agent for the future therapy of pulmonary fibrosis.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
Xin
X
Wei
Jing
J
Han
Zhi-zhi
ZZ
Chen
Bao-wen
BW
Qi
Guang-cheng
GC
Wang
Ying-hua
YH
Ma
Hao
H
Zheng
You-fu
YF
Luo
Yu-quan
YQ
Wei
Li-juan
LJ
Chen
D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D011810:Quinoxalines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000008:administration & dosage*
C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D045162:Thiazolidinediones; D001761:Bleomycin