| Cognitive impairment is one of the common complications of acute respiratory distress syndrome(ARDS),which seriously affects the patients’ quality of life.In order to avoid lung injury,the small tidal volume ventilation strategy has often been applied to treat ARDS patients,which almost leads to hypercapnia.The benefits gained from the strategy have always been focused on,while the effects of hypercapnia on cognitive fnction are ignored.Whether hypercapnia can have negative effects on ARDS patients with persistent hypoxemia is not certain.It has been reported in various studies that hypercapnia contributes to cognitive impairment.Increasing evidence suggests that IL-1β plays a pivotal role in inducing cognitive impairment in many neurodegenerative diseases.To exert its functions,pro-IL-1βrequires cleavage to an active form by caspase-1,which is regulated by NLRP3 inflammasome.It has remained to be explored whether hypercapnia aggravates the cognitive impairment in adult male Sprague-Dawley(SD)rats with hypoxemia.It was surmised that hypercapnia may exert its effect through increasing IL-1β secretion,and via activating the NLRP3 inflammasome,it can cause excessive apoptosis of hippocampal neurons.In this study,SD rats were treated with hypoxemia and/or hypercapnia.To elucidate the effect of hypercapnia on cognitive function in hypoxemic rats,we conducted MWM tests;To explore the effects of hypercapnia on the expression of IL-1β and activation of NLRP3 inflammasome,the protein expression of IL-1β and members of NLRP3 inflammasome including NLRP3,pro-caspase-1 and caspase-1 in the hippocampus was detected;To determine if hypercapnia played any role in apoptosis of hippocampal neurons in hypoxemic rats,the expression levels of Bcl-2,Bax and caspase-3 were examined.In addition,to explore the effects of high concentration of CO2 on activation of NLRP3 inflammasome and the expression of IL-1β,the protein expression of IL-1β,NLRP3,pro-caspase-1 and caspase-1 in BV-2 microglia was detected;To determine if high concentration of CO2 played any role in apoptosis of cultured neurons via hypoxia-activated microglia,cultured microglia cells were stimulated with 0.2%O2 or(and)15%CO2,and conditioned medium derived from those cultures was used to maintain neuronal cultures.Hypercapnia can significantly aggravate the cognitive function of hypoxic rats.Hypercapnia can increase the secretion of IL-1β through activating the NLRP3 inflammasome in the hypoxic hippocampal microglia.The protein expression levels of NLRP3,pro-caspase-1,and caspase-1 were significantly increased.Hypercapnia can aggravate the apoptosis of hypoxic hippocampus neurons.The protein expression levels of Bax,caspase-3 were significantly increased.The protein expression levels of Bcl-2 were significantly decreased.High concentrations of CO2 can exert an effect in increasing IL-1β production through activating the NLRP3 inflammasome in hypoxia-activated BV-2 microglia.The protein expression levels of NLRP3,pro-caspase-1 and caspase-1 were significantly increased.The protein expression of IL-1β was markedly enhanced by high concentration of CO2 in hypoxic BV-2 microglia;it was significantly suppressed with the treatment of Z-YVAD-FMK.Cultured BV-2 microglia cells were stimulated with 0.2%O2 or(and)15%CO2,and conditioned medium derived from those cultures was used to maintain neuronal cultures.The levels of Bax and caspase-3 expression in CM + Hypoxia + HC group were the highest as compared to CM + HC group and CM + Hypoxia group.When BV-2 conditioned medium was pretreated with Z-YVAD-FMK,the protein expression of caspase-3 of neurons was significantly suppressed.In a word,hypercapnia aggravates the cognitive impairment in adult male SD rats with hypoxemia.Hypercapnia may exert its effect through increasing IL-1β secretion,and via activating the NLRP3 inflammasome,it can cause excessive apoptosis of hippocampal neurons. |
