title: 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 cmH2O for 4 h and randomly given FiCO2 to achieve normocapnia (PaCO2 at 35-45 mm Hg) or hypercapnia (PaCO2 at 80-100 mm Hg); normally ventilated rats with PIP of 15 cmH2O 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.
authors.affiliation: Department of Anesthesiology, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Wan-Chao
authors.initials: WC
authors.lastname: Yang
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Song
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Zhang
authors.forename: Zi-Yong
authors.initials: ZY
authors.lastname: Yue
authors.forename: Xiao-Guang
authors.initials: XG
authors.lastname: Cui
authors.forename: Hua-Cheng
authors.initials: HC
authors.lastname: Zhou
mesh_terms: D000138:Acidosis / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D006439:Hemodynamics; D006935:Hypercapnia / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012121:Respiration, Artificial / Q000009:adverse effects*; D013314:Stress, Mechanical; D055397:Ventilator-Induced Lung Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D017382:Reactive Oxygen Species