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

即使在成功复苏后，失血性休克也经常引起肺部炎症，从而导致急性肺损伤(ALI)。我们先前已经证明，在失血性休克和复苏(HSR)前后吸入低浓度的CO可减轻失血性休克和复苏(HSR)所致的大鼠ALI，这是由于其抗炎作用。在本研究中，我们仅在复苏后才对相同的ALI模型给予CO，并检测其是否对HSR诱导的ALI起到治疗作用而没有不良反应，因为在HSR之前给予CO治疗并不能预防肺损伤。用失血动物诱导HSR，使平均动脉压达到30 mm Hg，持续1h，然后用取出的血进行复苏。HSR导致肺组织炎症基因表达上调，细胞凋亡率增加。这是通过观察到转移酶介导的dUTP-异硫氰酸荧光素(FITC)、缺口末端标记染色和激活的caspase-3阳性细胞数量的增加而确定的。高铁还导致明显的组织病理损害，包括充血、水肿、细胞渗出和出血。相比之下，复苏后吸入CO 3h可显著改善这些炎症事件，表现为组织学损伤、炎症介质和细胞凋亡减少。CO对肺损伤的保护作用与上调肺内抗炎转录调节因子--过氧化体增殖物激活受体γ的蛋白表达水平显著相关。此外，吸入CO不影响HSR期间的血流动力学状态或组织氧合。这些结果表明，吸入低浓度的CO对高铁诱导的ALI有明显的治疗作用，并通过增加PPAR-γ蛋白的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.