Hypercapnia intensifies cerebral hypoxia via increasing cerebral oxygen extraction ratio: implication in neuroinflammation in hypoxemic adult rats

Abstract

Background: Hypoxemia is a typical symptom of acute respiratory distress syndrome (ARDS). Ventilations are always needed for correcting hypoxemia. To avoid pulmonary morbidity, the low tidal volume ventilation is often applied. The ventilation strategy will certainly result in hypercapnia. Our previous study found that hypercapnia increase neuronal death and aggravate the cognitive function of hypoxic adult rats. However, the underlying mechanism has remained unclear. This study aimed to explore whether hypercapnia would induce neuroinflammation through increasing cerebral oxygen extraction ratio in adult rats with hypoxemia. Methods: Cerebral oxygen extraction ratio (CERO2), partial pressure of brain tissue oxygen (PbtO2), and reactive oxygen species (ROS) production in brain tissue in a rat model of hypercapnia/hypoxemia were evaluated. Along with this, the oxygen consumption rate (OCR) and ROS production of BV-2 microglial cells were evaluated after 15% CO2/0.2% O2 treatment. The protein expression level of caspase-1 and IL-1β in microglia cells were detected before and after application of a ROS scavenger in vivo and in vitro. Results: PbtO2 level was elevated by hypercapnia in the hypoxemic rats in the first 1.5 h, but it was significantly decreased 2 h after ventilation. This was further evident by the increased levels of CERO2 at 3 h after ventilation. Besides, a high concentration of CO2 treatment could increase the levels of OCR in hypoxic BV-2 microglial cells in vitro. Hypercapnia markedly increased the production of ROS and the expression of caspase-1 and IL-1β in hypoxia-activated microglia both in vivo and in vitro. Pharmacological scavenging ROS inhibited the NLRP3 inflammasome activation and expression of IL-1β. Conclusion: Hypercapnia-intensified cerebral hypoxia via increasing cerebral oxygen extraction ratio may induce ROS overproduction, activate the NLRP3 inflammasome and enhance IL-1β release in hypoxia-activated microglia.