Development of CO inhalation therapy for acute lung injury

点击翻译按钮获取中文摘要

Hemorrhagic shock and resuscitation (HSR) induces pulmonary inflammation that leads to acute lung injury. Carbon monoxide (CO), a by-product of heme catalysis, was shown to have potent cytoprotective and anti-inflammatory effects. The aim of the present study was to examine the effects of CO inhalation at low concentration on lung injury induced by HSR in rats. Rats were subjected to HSR by bleeding to achieve mean arterial pressure of 30mmHg for 60min followed by resuscitation with shed blood and saline as needed to restore blood pressure. HSR animals were maintained either in room air, or exposed to CO at 250ppm for 1 hour before and 3 hours after HSR. HSR caused an increase in the DNA binding activity of nuclear factor (NF)-κB and activator protein 1 (AP-1) in the lung followed by the upregulation of pulmonary gene expression of tumor necrosis factor-α, inducible nitric oxide synthase and interleukin (IL)-10. HSR also resulted in an increase in myeloperoxidase activity and wet-weight to dry-weight ratio in the lung, and more prominent histopathological changes including congestion, edema, cellular infiltration and hemorrhage. In contrast, CO inhalation significantly ameliorated these inflammatory events as judged by fewer histological changes, less upregulation of inflammatory mediators and less activation of NF-κB and AP-1. Interestingly, the protective effects against lung injury afforded by CO were associated with further increases of mRNA expression of IL-10 in the lung. These findings suggest that inhaled CO at a low concentration ameliorated HSR-induced lung injury and attenuated inflammatory cascades by upregulation of anti-inflammatory IL-10.