WIN55212-2 inhibits glycolysis and attenuates acute lung injury in septic mice by regulating mTOR/HIF-1α/PFKFB3 signaling pathway / 中国病理生理杂志
Chinese Journal of Pathophysiology
; (12): 521-526, 2024.
Article
in Zh
| WPRIM
| ID: wpr-1023902
Responsible library:
WPRO
ABSTRACT
AIM:
To investigate the effects of cannabinoid receptor agonist WIN55212-2(WIN)on acute lung injury(ALI)in septic mice,and to explore its potential mechanisms through glycolysis.METHODS:
A mouse model of septic ALI was established by intraperitoneal injections of lipopolysaccharide(LPS).Male C57BL/6J mice were randomly divided into 4 groups(n=6)(1)control group;(2)LPS group,receiving intraperitoneal injections of LPS at 10 mg/kg;(3)LPS+WIN group,receiving 1 mg/kg WIN intraperitoneally 30 min prior to LPS injection;(4)LPS+WIN+MHY1485[mammalian target of rapamycin(mTOR)activator]group,receiving 10 mg/kg MHY1485 intraperitoneally 1 d before LPS injection and 1 mg/kg WIN plus 10 mg/kg MHY1485 30 min before LPS injection.Tissues were collected 24 h after modeling for analysis.Lung indexes were calculated,and histopathological changes of lung tissues were observed via he-matoxylin-eosin(HE)staining.Inflammatory cytokines interleukin-1β(IL-1β)and IL-10 in lung tissues,and lactic acid and lactate dehydrogenase A(LDHA)in serum were quantified using ELISA.The levels of mTOR/hypoxia-inducible fac-tor-1α(HIF-1α)/6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3(PFKFB3)signaling pathway-related proteins were assessed by Western blot.RESULTS:
Compared with control group,the LPS group exhibited an increased lung in-dex,significant lung tissue damage,an increase in IL-1β levels(P<0.05),a decrease in IL-10 levels(P<0.05),and el-evated expressions of lactate and LDHA(P<0.05),along with increased levels of phosphorylated mTOR(p-mTOR),HIF-1α and PFKFB3 proteins(P<0.05).The LPS+WIN group showed improvements with a reduced lung index(P<0.05),lessened lung injury,decreased IL-1β levels(P<0.05),increased IL-10 levels(P<0.05),and lower levels of lactic acid,LDHA,p-mTOR,HIF-1α,and PFKFB3(P<0.05).Conversely,the LPS+WIN+MHY1485 group displayed increased lung indexes and lung tissue damage,elevated IL-1β levels(P<0.05),reduced IL-10 levels(P<0.05),and higher expressions of lactic acid,LDHA,p-mTOR,HIF-1α and PFKFB3(P<0.05)compared to the LPS+WIN group.CONCLUSION:
WIN55212-2 mitigates sepsis-induced ALI,potentially by modulating the mTOR/HIF-1α/PFKFB3 sig-naling pathway,thereby inhibiting glycolysis and alleviating inflammatory responses.
Full text:
1
Database:
WPRIM
Language:
Zh
Journal:
Chinese Journal of Pathophysiology
Year:
2024
Document type:
Article