Priming innate immune responses to infection by cyclooxygenase inhibition kills antibiotic-susceptible and -resistant bacteria
Priming innate immune responses to infection by cyclooxygenase inhibition kills antibiotic-susceptible and -resistant bacteria
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DOI：
10.1182/blood-2010-05-284844
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发表时间：
2010-10-21
期刊：
影响因子：
20.3
通讯作者：
Gilroy, Derek W.
中科院分区：
文献类型：
--
作者：
Stables, Melanie J.;Newson, Justine;Gilroy, Derek W.
非甾体抗炎药(NSAIDs)抑制环氧合酶(COX)衍生的前列腺素(PG)介导白细胞对细菌的杀伤作用。然而，COX1和COX2在这一过程中的相对贡献以及在老鼠和人类中控制它的机制尚不清楚。事实上，非甾体抗炎药促进白细胞杀死耐药细菌的潜力值得研究。因此，我们在小鼠和人身上进行了一系列实验，发现COX1是感染过程中PG合成的主要活性亚型，它的预防或治疗抑制启动了白细胞通过增加吞噬功能和活性氧中介介导的杀菌作用来杀灭细菌，这是一种环磷酸腺苷(CAMP)依赖的方式。此外，非甾体抗炎药可增强人类对细菌的杀灭作用，当与抗生素联合使用时，会产生相加的作用。最后，NSAIDs通过抑制COX启动先天免疫系统，介导青霉素耐药肺炎链球菌19A血清型的细菌清除，鉴于其日益增长的流行率和多重抗生素耐药性，19A是公认的疫苗逃逸血清型。因此，这些数据强调了脂质介质在宿主对感染的反应中的重要性，以及PG信号通路抑制剂作为辅助治疗的潜力，特别是在抗生素耐药性的背景下。(《血色》2010；116(16)：2950-2959)
Inhibition of cyclooxygenase (COX)-derived prostaglandins (PGs) by nonsteroidal anti-inflammatory drugs (NSAIDs) mediates leukocyte killing of bacteria. However, the relative contribution of COX1 versus COX2 to this process, as well as the mechanisms controlling it in mouse and humans, are unknown. Indeed, the potential of NSAIDs to facilitate leukocyte killing of drug-resistant bacteria warrants investigation. Therefore, we carried out a series of experiments in mice and humans, finding that COX1 is the predominant isoform active in PG synthesis during infection and that its prophylactic or therapeutic inhibition primes leukocytes to kill bacteria by increasing phagocytic uptake and reactive oxygen intermediate-mediated killing in a cyclic adenosine monophosphate (cAMP)-dependent manner. Moreover, NSAIDs enhance bacterial killing in humans, exerting an additive effect when used in combination with antibiotics. Finally, NSAIDs, through the inhibition of COX prime the innate immune system to mediate bacterial clearance of penicillin-resistant Streptococcus pneumoniae serotype 19A, a well-recognized vaccine escape serotype of particular concern given its increasing prevalence and multi-antibiotic resistance. Therefore, these data underline the importance of lipid mediators in host responses to infection and the potential of inhibitors of PG signaling pathways as adjunctive therapies, particularly in the context of antibiotic resistance. (Blood.2010;116(16):2950-2959)