Hypercapnic acidosis confers antioxidant and anti-apoptosis effects against ventilator-induced lung injury

Abstract

Hypercapnic acidosis may attenuate ventilator-induced lung oxidative stress injury and alveolar cell apoptosis, but the underlying mechanisms are poorly understood. We examined the effects of hypercapnic acidosis on the role of apoptosis signal-regulating kinase 1 (ASK1), which activates the c-Jun N-terminal kinase (JNK) and p38 cascade in both apoptosis and oxidative reactions, in high-pressure ventilation stimulated rat lungs. Rats were ventilated with a peak inspiratory pressure (PIP) of 30 cmH 2 O for 4 h and randomly given FiCO 2 to achieve normocapnia (PaCO 2 at 35-45 mm Hg) or hypercapnia (PaCO 2 at 80-100 mm Hg); normally ventilated rats with PIP of 15 cmH 2 O were used as controls. Lung injury was quantified by gas exchange, microvascular leaks, histology, levels of inflammatory cytokines, and pulmonary oxidative reactions. Apoptosis through the ASK1-JNK/p38 mitogen-activated protein kinase (MAPK) cascade in type II alveolar epithelial cells (AECIIs) were evaluated by examination of caspase-3 activation. The results showed that injurious ventilation caused significant lung injury, including deteriorative oxygenation, changes of histology, and the release of inflammatory cytokines. In addition, the high-pressure mechanical stretch also induced apoptosis and caspase-3 activation in the AECIIs. Hypercapnia attenuated these responses, suppressing the ASK1 signal pathways with its downstream kinase phosphorylation of p38 MAPK and JNK, and caspase-3 activation. Thus, hypercapnia can attenuate cell apoptosis and oxidative stress damage in rat lungs during injurious ventilation, at least in part, due to the suppression of the ASK1-JNK/p38 MAPK pathways. © 2013 USCAP, Inc All rights reserved.