Hypercapnia promotes microglial pyroptosis via inhibiting mitophagy in hypoxemic adult rats.

BACKGROUND Hypoxemia is a typical symptom of acute respiratory distress syndrome. To avoid pulmonary morbidity, low tidal volume ventilation is often applied. The ventilation strategy will certainly cause hypercapnia. This study aimed to explore whether hypercapnia would promote microglial pyroptosis via inhibiting mitophagy in adult rats with hypoxemia. METHODS The cerebral oxygen extraction ratio (CERO2 ) and partial pressure of brain tissue oxygen (PbtO2 ) in a rat model of hypercapnia/hypoxemia were assessed. The reactive oxygen species (ROS) production and the expression of LC3-II/I, p62, caspase-1, gasdermin D-N domains (GSDMD-N), IL-1β, and IL-18 in microglial cells were detected. RESULTS Hypercapnia decreased the PbtO2 levels of the hypoxic rats, which was further evidenced by the increased levels of CERO2 . Expression levels of LC3-II were reduced, while p62 expression was increased by hypercapnia in hypoxic microglia. Hypercapnia increased the production of ROS and the expression of caspase-1, GSDMD-N, IL-1β, and IL-18 in hypoxia-activated microglia. Scavenging ROS inhibited microglial pyroptosis and expression of IL-1β and IL-18. CONCLUSIONS These results suggest that hypercapnia-induced mitophagy inhibition may promote pyroptosis and enhance IL-1β and IL-18 release in hypoxia-activated microglia.