Cyclooxygenase-2 deficient mice are resistant to endotoxin-induced inflammation and death
Cyclooxygenase-2 deficient mice are resistant to endotoxin-induced inflammation and death
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DOI：
10.1096/fj.02-1078fje
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发表时间：
2003-05-01
期刊：
影响因子：
4.8
通讯作者：
Perrella, MA
中科院分区：
文献类型：
--
作者：
Ejima, K;Layne, MD;Perrella, MA
脓毒症是对血液传播感染的全身性炎症反应，其与极高的发病率和死亡率相关。本研究探讨了环氧合酶（考克斯）-2在细菌性内毒素血症中的作用。给予大肠杆菌脂多糖后，50%的野生型小鼠在96小时内死亡。考克斯-2缺陷小鼠表现出存活率的显著改善，减少了关键器官（肾和肺）的白细胞浸润，细胞因子诱导基因一氧化氮合酶2和血红素加氧酶-1的诱导减弱和延迟。在炎症反应过程中，对信号传导事件重要的转录因子（如核因子（NF）-κ B）的易位和激活也显著减少。虽然考克斯-2的缺乏没有改变组织巨噬细胞中几种促炎细胞因子的诱导，但抗炎细胞因子IL-10的诱导被夸大。向野生型小鼠施用IL-10减少NF-κ B活化。综上所述，我们的数据表明，考克斯-2缺陷小鼠对内毒素血症的许多有害后果具有抵抗力。这些有益作用部分地通过IL-10的代偿性增加而发生，所述IL-10的代偿性增加抵消了促炎宿主对内毒素血症的反应。
Sepsis is a systemic inflammatory response to a blood-borne infection that is associated with an extremely high rate of morbidity and mortality. The present study investigates the role of cyclooxygenase (COX)-2 in host responses to bacterial endotoxemia. After administration of Escherichia coli lipopolysaccharide, 50% of wild-type mice die within 96 h. COX-2 deficient mice displayed a dramatic improvement in survival with reduced leukocyte infiltration into critical organs (kidneys and lungs) and a blunted and delayed induction of the cytokine inducible genes nitric oxide synthase 2 and heme oxygenase-1. Translocation and activation of transcription factors important for signaling events during an inflammatory response, such as nuclear factor (NF)-kappaB, were also markedly reduced. While the absence of COX-2 did not alter the induction of several pro-inflammatory cytokines in tissue macrophages, induction of the anti-inflammatory cytokine IL-10 was exaggerated. Administration of IL-10 to wild-type mice reduced NF-kappaB activation. Taken together, our data suggest that COX-2 deficient mice are resistant to many of the detrimental consequences of endotoxemia. These beneficial effects occur, in part, by a compensatory increase in IL-10 that counterbalances the pro-inflammatory host response to endotoxemia.