Development of CO inhalation therapy for acute lung injury

失血性休克和复苏（HSR）引起肺部炎症，导致急性肺损伤。一氧化碳（CO），血红素催化的副产物，被证明具有有效的细胞保护和抗炎作用。本研究旨在探讨低浓度CO吸入对大鼠HSR所致肺损伤的影响。大鼠通过出血进行HSR，使平均动脉压达到30mmHg，持续60min，然后根据需要用放血和生理盐水复苏以恢复血压。高铁动物在高铁前1小时和高铁后3小时保持在室内空气中，或暴露于250ppm的一氧化碳中。高铁引起肺组织核因子(NF)-κB和激活蛋白1 (AP-1) DNA结合活性升高，肿瘤坏死因子-α、诱导型一氧化氮合酶和白细胞介素(IL)-10肺组织基因表达上调。HSR还导致肺内髓过氧化物酶活性和干重比升高，充血、水肿、细胞浸润和出血等组织病理改变更为突出。相比之下，通过减少组织学变化，减少炎症介质的上调以及减少NF-κB和AP-1的激活来判断，CO吸入显著改善了这些炎症事件。有趣的是，一氧化碳对肺损伤的保护作用与肺中IL-10 mRNA表达的进一步增加有关。这些发现表明，低浓度吸入CO可通过上调抗炎IL-10来改善hsr诱导的肺损伤和减轻炎症级联反应。

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.