Wu Benedict, Capilato Joseph, Pham Michelle P, Walker Jean, Spur Bernd, Rodriguez Ana, Perez Lark J, Yin Kingsley
Department of Cell Biology, Rowan University School of Osteopathic Medicine, Stratford, New Jersey, USA; and.
Department of Chemistry and Biochemistry, Rowan University, Glassboro, New Jersey, USA.
FASEB J. 2016 Jun;30(6):2400-10. doi: 10.1096/fj.201500029R. Epub 2016 Mar 10.
Bacterial infections can quickly turn into sepsis, with its attendant clinical sequelae of inflammation, tissue injury, and organ failure. Paradoxically, sustained inflammation in sepsis may lead to immune suppression, because of which the host is unable to clear the existing infection. Use of agents that suppress the inflammatory response may accelerate host immune suppression, whereas use of traditional antibiotics does not significantly affect inflammation. In this study, we investigated whether lipoxin A4 (LXA4), a specialized, proresolution lipid mediator, could increase neutrophil phagocytic activity as well as reduce bacterial virulence. Using the mouse cecal ligation and puncture (CLP) model of sepsis, the administration of LXA4 (7 μg/kg i.v.) 1 h after surgery increased neutrophil phagocytic ability and Fcγ receptor I (CD64) expression. Ex vivo studies have confirmed that the direct addition of LXA4 to CLP neutrophils increased phagocytic ability but not CD64 expression. LXA4 did not affect neutrophils taken from control mice in which CD64 expression was minimal. Taken together with in vivo data, these results suggest that LXA4 directly augments CD64-mediated neutrophil phagocytic ability but does not directly increase neutrophil CD64 expression. Bacterial communication and virulence is regulated by quorum sensing inducers. In Pseudomonas aeruginosa, virulence is induced with release of various virulence factors, by N-3-oxododecanolyl homoserine lactone binding to the quorum sensing receptor, LasR. We show that LXA4 is an inhibitor of LasR in P. aeruginosa and that it decreases the release of pyocyanin exotoxin. These results suggest that LXA4 has the novel dual properties of increasing host defense and decreasing pathogen virulence by inhibiting quorum sensing.-Wu, B., Capilato, J., Pham, M. P., Walker, J., Spur, B., Rodriguez, A., Perez, L. J., Yin, K. Lipoxin A4 augments host defense in sepsis and reduces Pseudomonas aeruginosa virulence through quorum sensing inhibition.
细菌感染可迅速发展为脓毒症，并伴有炎症、组织损伤和器官衰竭等一系列临床后遗症。矛盾的是，脓毒症中持续的炎症反应可能导致免疫抑制，从而使宿主无法清除现有的感染。使用抑制炎症反应的药物可能会加速宿主免疫抑制，而使用传统抗生素对炎症没有显著影响。在本研究中，我们调查了一种特殊的促消退脂质介质脂氧素A4（LXA4）是否能增强中性粒细胞的吞噬活性并降低细菌毒力。使用脓毒症小鼠盲肠结扎穿孔（CLP）模型，术后1小时静脉注射LXA4（7μg/kg）可增强中性粒细胞的吞噬能力和Fcγ受体I（CD64）的表达。体外研究证实，直接向CLP中性粒细胞中添加LXA4可增强吞噬能力，但不影响CD64的表达。LXA4对来自CD64表达极低的对照小鼠的中性粒细胞没有影响。结合体内数据，这些结果表明LXA4直接增强CD64介导的中性粒细胞吞噬能力，但不直接增加中性粒细胞CD64的表达。细菌的交流和毒力受群体感应诱导剂调节。在铜绿假单胞菌中，N-3-氧代十二烷酰高丝氨酸内酯与群体感应受体LasR结合，释放各种毒力因子，从而诱导毒力。我们发现LXA4是铜绿假单胞菌中LasR的抑制剂，它可减少绿脓菌素外毒素的释放。这些结果表明，LXA4具有通过抑制群体感应来增强宿主防御和降低病原体毒力的新双重特性。-吴，B.，卡皮拉托，J.，范，M.P.，沃克，J.，斯珀，B.，罗德里格斯，A.，佩雷斯，L.J.，尹，K.脂氧素A4通过抑制群体感应增强脓毒症宿主防御并降低铜绿假单胞菌毒力。
