Department of Clinical Sciences, Section for Surgery, Lund University, Malmö, Sweden.
Infect Immun. 2012 Nov;80(11):3952-9. doi: 10.1128/IAI.00696-12. Epub 2012 Sep 4.
The M1 serotype of Streptococcus pyogenes plays an important role in streptococcal toxic shock syndrome. Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been shown to inhibit streptococcal M1 protein-induced acute lung damage, although downstream mechanisms remain elusive. Protein isoprenylation, such as farnesylation and geranylgeranylation, has been suggested to regulate anti-inflammatory effects exerted by statins. Here, we examined the effect of a farnesyltransferase inhibitor (FTI-277) on M1 protein-triggered lung inflammation. Male C57BL/6 mice were treated with FTI-277 prior to M1 protein challenge. Bronchoalveolar fluid and lung tissue were harvested for quantification of neutrophil recruitment, edema, and CXC chemokine formation. Flow cytometry was used to determine Mac-1 expression on neutrophils. The gene expression of CXC chemokines was determined in alveolar macrophages by using quantitative reverse transcription (RT)-PCR. We found that the administration of FTI-277 markedly decreased M1 protein-induced accumulation of neutrophils, edema formation, and tissue damage in the lung. Notably, inhibition of farnesyltransferase abolished M1 protein-evoked production of CXC chemokines in the lung and gene expression of CXC chemokines in alveolar macrophages. Moreover, FTI-277 completely inhibited chemokine-induced neutrophil migration in vitro. However, farnesyltransferase inhibition had no effect on M1 protein-induced expression of Mac-1 on neutrophils. Our findings suggest that farnesyltransferase is a potent regulator of CXC chemokine formation in alveolar macrophages and that inhibition of farnesyltransferase not only reduces neutrophil recruitment but also attenuates acute lung injury provoked by streptococcal M1 protein. We conclude that farnesyltransferase activity is a potential target in order to attenuate acute lung damage in streptococcal infections.
化脓性链球菌 M1 血清型在链球菌中毒性休克综合征中起重要作用。羟甲基戊二酰辅酶 A（HMG-CoA）还原酶抑制剂辛伐他汀已被证明可抑制链球菌 M1 蛋白诱导的急性肺损伤，尽管下游机制尚不清楚。蛋白异戊烯化，如法呢基化和香叶基香叶基化，被认为可调节他汀类药物发挥的抗炎作用。在这里，我们研究了法尼基转移酶抑制剂（FTI-277）对 M1 蛋白引发的肺炎症的影响。雄性 C57BL/6 小鼠在用 M1 蛋白进行攻击前用 FTI-277 进行治疗。收集支气管肺泡液和肺组织，以定量中性粒细胞募集、水肿和 CXC 趋化因子形成。使用流式细胞术确定中性粒细胞上 Mac-1 的表达。通过定量逆转录（RT）-PCR 确定肺泡巨噬细胞中 CXC 趋化因子的基因表达。我们发现，FTI-277 的给药显着减少了 M1 蛋白诱导的中性粒细胞积累、水肿形成和肺组织损伤。值得注意的是，法尼基转移酶抑制消除了 M1 蛋白引发的肺内 CXC 趋化因子的产生和肺泡巨噬细胞中 CXC 趋化因子的基因表达。此外，FTI-277 完全抑制趋化因子诱导的中性粒细胞在体外的迁移。然而，法尼基转移酶抑制对 M1 蛋白诱导的中性粒细胞上 Mac-1 的表达没有影响。我们的研究结果表明，法尼基转移酶是肺泡巨噬细胞中 CXC 趋化因子形成的有效调节剂，法尼基转移酶抑制不仅减少中性粒细胞募集，而且减轻链球菌 M1 蛋白引起的急性肺损伤。我们得出结论，法尼基转移酶活性是减轻链球菌感染引起的急性肺损伤的潜在靶标。
