Elucidation of therapeutic and anti-inflammatory effect of carbon monoxide inhalation against acute lung injury

即使在成功复苏后，失血性休克经常引起肺部炎症，诱发急性肺损伤（ALI）。我们之前证明，在失血性休克和复苏（HSR）之前和之后吸入低浓度的一氧化碳，由于其抗炎作用，可以改善大鼠HSR诱导的ALI。在本研究中，我们仅在复苏后对相同的ALI模型给予CO，并检查其是否对HSR诱导的ALI产生无不良事件的治疗效果，因为在HSR之前用CO治疗动物并不能预防肺损伤。用出血动物诱导HSR，使其平均动脉压达到30 mmHg，持续1小时，然后用取出的血液进行复苏。HSR导致炎症基因表达上调，增加肺细胞凋亡率。这是通过观察到的转移酶介导的dutp -异硫氰酸荧光素（FITC）、镍端标记染色和激活caspase-3阳性细胞数量的增加来确定的。HSR还导致明显的组织病理学损伤，包括充血、水肿、细胞浸润和出血。相比之下，复苏后吸入3小时CO可显著改善这些炎症事件，表现为组织学损伤、炎症介质和凋亡细胞死亡减少。CO对肺损伤的保护作用与过氧化物酶体增殖激活受体(PPAR)-γ蛋白表达水平的增加有关，PPAR -γ是肺中的一种抗炎转录调节因子。此外，CO吸入不影响HSR期间的血流动力学状态或组织氧合。这些发现表明，低浓度吸入CO对hsr诱导的ALI具有有效的治疗作用，并通过增加PPAR-γ蛋白表达来减轻炎症级联反应。

Even after successful resuscitation, hemorrhagic shock frequently causes pulmonary inflammation that induces acute lung injury (ALI). We previously demonstrated that when CO is inhaled at a low concentration both prior to and following hemorrhagic shock and resuscitation (HSR) it ameliorates HSR-induced ALI in rats due to its anti-inflammatory effects. In the present study, we administered CO to the same model of ALI only after resuscitation and examined whether it exerted a therapeutic effect without adverse events on HSR-induced ALI, since treatment of animals with CO prior to HSR did not prevent lung injury. HSR were induced by bleeding animals to achieve a mean arterial pressure of 30 mmHg for 1 h followed by resuscitation with the removed blood. HSR resulted in the upregulation of inflammatory gene expression and increased the rate of apoptotic cell death in the lungs. This was determined from an observed increase in the number of cells positive for transferase-mediated dUTP-fluorescein isothiocyanate (FITC), nick-end labeling staining and activated caspase-3. HSR also resulted in prominent histopathological damage, including congestion, edema, cellular infiltration and hemorrhage. By contrast, CO inhalation for 3 h following resuscitation significantly ameliorated these inflammatory events, demonstrated by reduced histological damage, inflammatory mediators and apoptotic cell death. The protective effects of CO against lung injury were notably associated with an increase in the protein expression level of peroxisome proliferator-activated receptor (PPAR)-γ, an anti-inflammatory transcriptional regulator in the lung. Moreover, CO inhalation did not affect the hemodynamic status or tissue oxygenation during HSR. These findings suggest that inhalation of CO at a low concentration exerts a potent therapeutic effect against HSR-induced ALI and attenuates the inflammatory cascade by increasing PPAR-γ protein expression.