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，从而诱导急性肺损伤（ALI）。我们以前证明，当CO在低浓度吸入之前和之后的失血性休克和复苏（HSR），它改善HSR诱导的ALI大鼠由于其抗炎作用。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治疗动物并不能防止肺损伤。通过使动物出血以达到30 mmHg的平均动脉压持续1 h，然后用取出的血液复苏来诱导HSR。HSR导致炎症基因表达上调，并增加肺中凋亡细胞死亡率。这是根据观察到的转移酶介导的dUTP-异硫氰酸荧光素（FITC）、缺口末端标记染色和活化半胱天冬酶-3阳性细胞数量增加确定的。HSR还导致显著的组织病理学损害，包括充血、水肿、细胞浸润和出血。相比之下，CO吸入3小时后复苏显着改善这些炎症事件，表现为减少组织损伤，炎症介质和凋亡细胞死亡。CO对肺损伤的保护作用与肺组织中抗炎转录调节因子过氧化物酶体增殖物激活受体（过氧化物酶体增殖物激活受体）-γ蛋白表达水平的增加显著相关。此外，CO吸入不影响HSR期间的血流动力学状态或组织氧合。这些结果表明，吸入低浓度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.