Simvastatin regulates CXC chemokine formation in streptococcal M1 protein-induced neutrophil infiltration in the lung

Abstract

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.

Simvastatin suppresses RANTES-mediated neutrophilia in polyinosinic–polycytidylic acid-induced pneumonia

“…In addition to the anti-viral effects of simvastatin demonstrated in this study, there are other reports indicating that simvastatin has antimicrobial activity. For example, simvastatin is protective during Staphylococcus aureus pneumonia [21] and ameliorates acute lung injury in streptococcal infections [22]. A recent study indicates that oral simvastatin at physiologically relevant doses only modestly protects against pneumococcal pneumonia [23].…”

Dopamine inhibits pulmonary edema through the VEGF-VEGFR2 axis in a murine model of acute lung injury

“…Tissue myeloperoxidase (MPO) activity is a quantitative marker for the presence of neutrophils in the lungs (55). MPO activity was measured in tissue homogenates at 24 h after LPS injection in placebo and dopamine treated animals (n ϭ 6).…”

Targeting CD162 protects against streptococcal M1 protein-evoked neutrophil recruitment and lung injury

“…A functional role of CXC chemokines has been proposed in streptococcal infections (44), and we have demonstrated that M1 protein is a potent stimulator of CXCL1 and CXCL2 production in the lung (41). Herein, we found that inhibition of CD162 reduced M1 protein-induced formation of CXCL1 and CXCL2 in the lung.…”

“…A recent study demonstrated that M1 proteinprovoked pulmonary accumulation of neutrophils is critically dependent on the synthesis and action of CXC chemokines (44). Thus, the chemokine-mediated mechanisms behind accumulation of neutrophils in the lung are relatively well known, whereas the adhesive mechanisms regulating M1 protein-induced neutrophil recruitment and tissue damage in the lung remain elusive.…”