Liu Danya, Zienkiewicz Jozef, DiGiandomenico Antonio, Hawiger Jacek
Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2363, USA.
Mol Ther. 2009 May;17(5):796-802. doi: 10.1038/mt.2009.18. Epub 2009 Mar 3.
Acute lung inflammation is a potentially life-threatening complication of infections due to community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), a worldwide emerging pathogen, which causes necrotizing pneumonia and acute respiratory distress syndrome (ARDS). MRSA virulence factors encompass immunotoxins termed superantigens that contribute to lung inflammation. In this study, we demonstrate that staphylococcal enterotoxin B (SEB)-induced lung inflammation is attenuated by a cell-penetrating peptide nuclear import inhibitor of nuclear factor (NF)-kappaB and other stress-responsive transcription factors (SRTFs). This inhibitor suppressed production of a wide spectrum of cytokines and chemokines induced by direct SEB airway exposure. Consequently, trafficking of neutrophils, monocytes/macrophages, and lymphocytes to the bronchoalveolar space was significantly reduced while vascular injury, manifested by increased permeability and protein leakage, was attenuated. Moreover, induction of systemic proinflammatory cytokines and chemokines in response to direct SEB airway exposure was reduced. Thus, intracellular delivery of a nuclear import inhibitory peptide suppresses respiratory and systemic expression of key mediators of lung inflammation evoked by SEB.
急性肺部炎症是由社区获得性耐甲氧西林金黄色葡萄球菌（CA-MRSA）感染引起的一种潜在危及生命的并发症，CA-MRSA是一种在全球范围内出现的病原体，可导致坏死性肺炎和急性呼吸窘迫综合征（ARDS）。MRSA毒力因子包括称为超抗原的免疫毒素，它们会导致肺部炎症。在本研究中，我们证明，核因子（NF）-κB和其他应激反应转录因子（SRTF）的细胞穿透肽核输入抑制剂可减轻葡萄球菌肠毒素B（SEB）诱导的肺部炎症。该抑制剂抑制了直接气道暴露于SEB所诱导的多种细胞因子和趋化因子的产生。因此，中性粒细胞、单核细胞/巨噬细胞和淋巴细胞向支气管肺泡腔的迁移显著减少，而以通透性增加和蛋白质渗漏为表现的血管损伤也有所减轻。此外，直接气道暴露于SEB后，全身促炎细胞因子和趋化因子的诱导也减少。因此，核输入抑制肽的细胞内递送可抑制SEB诱发的肺部炎症关键介质的呼吸道和全身表达。
