Department of Clinical Sciences, Section for Surgery, Malmö University Hospital, Lund University, Sweden.
Am J Physiol Lung Cell Mol Physiol. 2011 Jun;300(6):L930-9. doi: 10.1152/ajplung.00422.2010. Epub 2011 Mar 25.
Streptococcus pyogenes of the M1 serotype can cause streptococcal toxic shock syndrome and acute lung injury. Statins exert beneficial effects in septic patients although the mechanisms remain elusive. This study examined effects of simvastatin on M1 protein-provoked pulmonary inflammation and tissue injury. Male C57BL/6 mice were pretreated with simvastatin or a CXCR2 antagonist before M1 protein challenge. Bronchoalveolar fluid and lung tissue were harvested for determination of neutrophil infiltration, formation of edema, and CXC chemokines. Flow cytometry was used to determine Mac-1 expression on neutrophils. Gene expression of CXC chemokines was determined in alveolar macrophages by using quantitative RT-PCR. M1 protein challenge caused massive infiltration of neutrophils, edema formation, and production of CXC chemokines in the lung as well as upregulation of Mac-1 on circulating neutrophils. Simvastatin reduced M1 protein-induced infiltration of neutrophils and edema in the lung. In addition, M1 protein-induced Mac-1 expression on neutrophils was abolished by simvastatin. Furthermore, simvastatin markedly decreased pulmonary formation of CXC chemokines and gene expression of CXC chemokines in alveolar macrophages. Moreover, the CXCR2 antagonist reduced M1 protein-induced neutrophil expression of Mac-1 and accumulation of neutrophils as well as edema formation in the lung. These novel findings indicate that simvastatin is a powerful inhibitor of neutrophil infiltration in acute lung damage triggered by streptococcal M1 protein. The inhibitory effect of simvastatin on M1 protein-induced neutrophil recruitment appears related to reduced pulmonary generation of CXC chemokines. Thus, simvastatin may be a useful tool to ameliorate acute lung injury in streptococcal infections.
M1 型化脓性链球菌可引起链球菌中毒性休克综合征和急性肺损伤。他汀类药物对脓毒症患者具有有益作用，但其机制尚不清楚。本研究探讨了辛伐他汀对 M1 蛋白引起的肺部炎症和组织损伤的影响。雄性 C57BL/6 小鼠在 M1 蛋白攻击前用辛伐他汀或 CXCR2 拮抗剂预处理。收集支气管肺泡灌洗液和肺组织，以确定中性粒细胞浸润、水肿形成和 CXC 趋化因子的形成。采用流式细胞术测定中性粒细胞上 Mac-1 的表达。采用定量 RT-PCR 测定肺泡巨噬细胞中 CXC 趋化因子的基因表达。M1 蛋白攻击导致大量中性粒细胞浸润、肺水肿形成和 CXC 趋化因子在肺中产生，以及循环中性粒细胞上 Mac-1 的上调。辛伐他汀减少 M1 蛋白诱导的中性粒细胞浸润和肺水肿。此外，辛伐他汀消除了 M1 蛋白诱导的中性粒细胞上 Mac-1 的表达。此外，辛伐他汀还显著降低了 M1 蛋白诱导的 CXC 趋化因子在肺中的形成和肺泡巨噬细胞中 CXC 趋化因子的基因表达。此外，CXCR2 拮抗剂减少了 M1 蛋白诱导的中性粒细胞表达 Mac-1 和中性粒细胞在肺中的积聚以及水肿的形成。这些新发现表明，辛伐他汀是一种强大的抑制剂，可抑制 M1 型链球菌蛋白引起的急性肺损伤中的中性粒细胞浸润。辛伐他汀对 M1 蛋白诱导的中性粒细胞募集的抑制作用与肺内 CXC 趋化因子生成减少有关。因此，辛伐他汀可能是改善链球菌感染引起的急性肺损伤的有用工具。
