A PPARγ AGONIST ENHANCES BACTERIAL CLEARANCE THROUGH NEUTROPHIL EXTRACELLULAR TRAP FORMATION AND IMPROVES SURVIVAL IN SEPSIS.
A PPARγ AGONIST ENHANCES BACTERIAL CLEARANCE THROUGH NEUTROPHIL EXTRACELLULAR TRAP FORMATION AND IMPROVES SURVIVAL IN SEPSIS.
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DOI：
10.1097/shk.0000000000000520
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发表时间：
2016-04
期刊：
影响因子：
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通讯作者：
Silva AR
中科院分区：
文献类型：
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作者：
Araújo CV;Campbell C;Gonçalves-de-Albuquerque CF;Molinaro R;Cody MJ;Yost CC;Bozza PT;Zimmerman GA;Weyrich AS;Castro-Faria-Neto HC;Silva AR
针对感染的炎症反应的失调有助于脓毒症的死亡率。炎症提供了关键的宿主防御，但它可以导致组织损伤，多器官衰竭和死亡。由于核转录因子过氧化物酶体增殖物激活受体γ（过氧化物酶体增殖物激活受体γ）具有治疗潜力，我们确定了过氧化物酶体增殖物激活受体γ在脓毒症中的作用。我们分析了瑞士小鼠盲肠结扎穿孔（CLP）脓毒症模型中临床体征的严重程度、存活率、细胞因子产生、白细胞内流和细菌清除。CLP后24 h，PPARγ激动剂罗格列酮治疗改善了临床状态和死亡率，同时增加了IL-10的产生，降低了TNF-α和IL-6水平以及腹膜中性粒细胞蓄积。我们注意到罗格列酮治疗小鼠的细菌杀伤增加，与活性氧产生增加相关。用LPS或E.大肠杆菌和罗格列酮增加腹膜中性粒细胞胞外陷阱（NET）介导的细菌杀伤，这种作用可被PPARγ拮抗剂（GW 9662）逆转。罗格列酮还能促进PMN释放组蛋白，这是一种NET形成的替代标记物，GW 9662可消除这种作用。罗格列酮通过激活PPARγ和形成NET调节炎症反应并增加细菌清除，结合免疫调节和宿主依赖性抗菌作用，因此，值得进一步研究作为脓毒症的潜在治疗药物。
Dysregulation of the inflammatory response against infection contributes to mortality in sepsis. Inflammation provides critical host defense, but it can cause tissue damage, multiple organ failure and death. Because the nuclear transcription factor peroxisome proliferator-activated receptor γ (PPARγ) exhibits therapeutic potential, we characterized the role of PPARγ in sepsis. We analyzed severity of clinical signs, survival rates, cytokine production, leukocyte influx, and bacterial clearance in a cecal ligation and puncture (CLP) model of sepsis in Swiss mice. The PPARγ agonist rosiglitazone treatment improved clinical status and mortality, while increasing IL-10 production and decreasing TNF-α and IL-6 levels, and peritoneal neutrophil accumulation 24 h after CLP. We noted increased bacterial killing in rosiglitazone treated mice, correlated with increased generation of reactive oxygen species. Polymorphonuclear leukocytes (PMN) incubated with LPS or E. coli and rosiglitazone increased peritoneal neutrophil extracellular trap (NET)-mediated bacterial killing, an effect reversed by the PPARγ antagonist (GW 9662) treatment. Rosiglitazone also enhanced the release of histones by PMN, a surrogate marker of NET formation, effect abolished by GW 9662. Rosiglitazone modulated the inflammatory response and increased bacterial clearance through PPARγ activation and NET formation, combining immunomodulatory and host-dependent anti-bacterial effects and, therefore, warrants further study as a potential therapeutic agent in sepsis.