Department of Surgery, Skåne University Hospital, Lund University, Malmö, Sweden.
J Leukoc Biol. 2011 May;89(5):735-42. doi: 10.1189/jlb.0510279. Epub 2011 Feb 17.
Statins have been reported to exert anti-inflammatory actions and protect against septic organ dysfunction. Herein, we hypothesized that simvastatin may attenuate neutrophil activation and lung damage in abdominal sepsis. Male C57BL/6 mice were pretreated with simvastatin (0.5 or 10 mg/kg) before CLP. In separate groups, mice received an anti-CD40L antibody or a CXCR2 antagonist (SB225002) prior to CLP. BALF and lung tissue were harvested for analysis of neutrophil infiltration, as well as edema and CXC chemokine formation. Blood was collected for analysis of Mac-1 and CD40L expression on neutrophils and platelets, as well as soluble CD40L in plasma. Simvastatin decreased CLP-induced neutrophil infiltration and edema formation in the lung. Moreover, Mac-1 expression increased on septic neutrophils, which was significantly attenuated by simvastatin. Inhibition of CD40L reduced CLP-induced up-regulation of Mac-1 on neutrophils. Simvastatin prevented CD40L shedding from the surface of platelets and reduced circulating levels of CD40L in septic mice. CXC chemokine-induced migration of neutrophils in vitro was decreased greatly by simvastatin. Moreover, simvastatin abolished CLP-evoked formation of CXC chemokines in the lung, and a CXCR2 antagonist attenuated pulmonary accumulation of neutrophils. Our data suggest that the inhibitory effect of simvastatin on pulmonary accumulation of neutrophils may be related to a reduction of CD40L secretion into the circulation, as well as a decrease in CXC chemokine formation in the lung. Thus, these protective mechanisms help to explain the beneficial actions exerted by statins, such as simvastatin, in sepsis.
他汀类药物已被报道具有抗炎作用，并可预防脓毒症器官功能障碍。在此，我们假设辛伐他汀可能会减轻腹部分离脓毒症中的中性粒细胞激活和肺损伤。雄性 C57BL/6 小鼠在 CLP 前用辛伐他汀（0.5 或 10mg/kg）预处理。在单独的组中，在 CLP 前，小鼠接受抗 CD40L 抗体或 CXCR2 拮抗剂（SB225002）。采集 BALF 和肺组织分析中性粒细胞浸润以及水肿和 CXC 趋化因子形成。收集血液分析中性粒细胞和血小板上的 Mac-1 和 CD40L 表达以及血浆中的可溶性 CD40L。辛伐他汀降低 CLP 诱导的中性粒细胞浸润和肺水肿形成。此外，在脓毒症中性粒细胞上 Mac-1 的表达增加，而辛伐他汀则明显减弱。CD40L 抑制减少了 CLP 诱导的中性粒细胞上 Mac-1 的上调。辛伐他汀可防止 CD40L 从血小板表面脱落，并降低脓毒症小鼠循环中的 CD40L 水平。辛伐他汀大大降低了 CXC 趋化因子诱导的中性粒细胞体外迁移。此外，辛伐他汀消除了 CLP 诱导的肺中 CXC 趋化因子的形成，而 CXCR2 拮抗剂减弱了中性粒细胞在肺中的积聚。我们的数据表明，辛伐他汀对中性粒细胞在肺中积聚的抑制作用可能与减少 CD40L 分泌到循环中以及减少肺中 CXC 趋化因子形成有关。因此，这些保护机制有助于解释他汀类药物（如辛伐他汀）在脓毒症中的有益作用。
