Hypercapnic acidosis attenuates ventilation-induced lung injury by a nuclear factor-κB dependent mechanism

Objectives: Hypercapnic acidosis protects against ventilation-induced lung injury. We wished to determine whether the beneficial effects of hypercapnic acidosis in reducing stretch-induced injury were mediated via inhibition of nuclear factor-kappa B, a key transcriptional regulator in inflammation, injury, and repair. Design: Prospective randomized animal study. Setting: University research laboratory. Subjects: Adult male Sprague-Dawley rats. Interventions: In separate experimental series, the potential for hypercapnic acidosis to attenuate moderate and severe ventilation-induced lung injury was determined. In each series, following induction of anesthesia and tracheostomy, Sprague-Dawley rats were randomized to (normocapnia; Fico(2) 0.00) or (hypercapnic acidosis; Fico(2) 0.05), subjected to high stretch ventilation, and the severity of lung injury and indices of activation of the nuclear factor-kappa B pathway were assessed. Subsequent in vitro experiments examined the potential for hypercapnic acidosis to reduce pulmonary epithelial inflammation and injury induced by cyclic mechanical stretch. The role of the nuclear factor-kappa B pathway in hypercapnic acidosis mediated protection from stretch injury was then determined. Measurements and Main Results: Hypercapnic acidosis attenuated moderate and severe ventilation-induced lung injury, as evidenced by improved oxygenation, compliance, and reduced histologic injury compared to normocapnic conditions. Hypercapnic acidosis reduced indices of inflammation such as interleukin-6 and bronchoalveolar lavage neutrophil infiltration. Hypercapnic acidosis reduced the decrement of the nuclear factor-kappa B inhibitor I kappa B alpha and reduced the generation of cytokine-induced neutrophil chemoattractant-1. Hypercapnic acidosis reduced cyclic mechanical stretch-induced nuclear factor-kappa B activation, reduced interleukin-8 production, and decreased epithelial injury and cell death compared to normocapnia. Conclusions: Hypercapnic acidosis attenuated ventilation-induced lung injury independent of injury severity and decreased mechanical stretch-induced epithelial injury and death, via a nuclear factor-kappa B dependent mechanism. (Crit Care Med 2012; 40:2622-2630)