INHIBITION OF NF-κB ACTIVITY PREVENTS DOWNREGULATION OF α1-ADRENERGIC RECEPTORS AND CIRCULATORY FAILURE DURING CLP-INDUCED SEPSIS
INHIBITION OF NF-κB ACTIVITY PREVENTS DOWNREGULATION OF α1-ADRENERGIC RECEPTORS AND CIRCULATORY FAILURE DURING CLP-INDUCED SEPSIS
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DOI：
10.1097/shk.0b013e3181994752
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发表时间：
2009-09-01
期刊：
影响因子：
3.1
通讯作者：
Bucher, Michael
中科院分区：
文献类型：
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作者：
Schmidt, Christoph;Kurt, Birguel;Bucher, Michael
脓毒症时对去甲肾上腺素的降压反应使我们对α(1)-肾上腺素能受体的调节产生了兴趣。由于核因子-kappa B在炎症级联反应中起着重要作用，我们推测核因子-kappaB通过释放促炎细胞因子下调α(1)受体，从而导致败血症循环衰竭。用盲肠结扎穿刺术(CLP)诱导野生型小鼠和致炎细胞因子缺乏的小鼠脓毒症，小鼠注射肿瘤坏死因子-α、白介素1-β、干扰素-γ或白介素6。用糖皮质激素或针对多种细胞因子和核因子-kappaB的小干扰RNA(SiRNA)处理动物，用细胞因子和钙动员孵育血管平滑肌细胞，分析mRNA的稳定性，并用α(1)-启动子-荧光素酶结构进行启动子研究。盲肠结扎和穿孔治疗导致高动力循环衰竭，对去甲肾上腺素的钙反应减弱，α(1)受体显著下调。促炎细胞因子还通过在基因转录水平上抑制启动子活性而下调α(1)受体。然而，抑制细胞因子基因敲除小鼠中的单一致炎细胞因子并不能减少CLP诱导的α(1)受体下调。相反，通过siRNA预处理或糖皮质激素给药阻断多种细胞因子可减轻CLP引起的心血管衰竭和α(1)受体下调。此外，通过siRNA抑制核因子-kappa B活性可以减少细胞因子的产生，防止循环衰竭和α(1)受体的下调，并改善脓毒症小鼠的存活率。我们的研究结果表明，在脓毒症中，核因子-kappa B在促进促炎细胞因子的产生中起着中心作用，而炎症细胞因子的产生反过来又下调了α(1)受体的表达。我们的数据进一步明确了核因子-kappa B在感染性休克发病机制中的关键作用，表明靶向核因子-kappa B是治疗感染性血管麻痹的理想治疗策略。
The reduced pressure response to norepinephrine during sepsis has directed our interest to the regulation of alpha(1)-adrenergic receptors. Because nuclear factor (NF)-kappa B occupies a prominent role in the inflammatory cascade, we hypothesized that NF-kappa B downregulates alpha(1)-receptors by liberation of proinflammatory cytokines and thereby contributes to septic circulatory failure. Sepsis was induced by cecal ligation and puncture (CLP) in wild-type mice and mice with deficiencies for proinflammatory cytokines, and mice were injected with TNF-alpha, IL-1 beta, IFN-gamma, or IL-6. Animals were treated with glucocorticoids or small interfering RNA (siRNA) targeting multiple cytokines and NF-kappa B. Vascular smooth muscle cells were incubated with cytokines and calcium mobilization, mRNA stability assays, and promoter studies with alpha(1)-promoter-luciferase constructs were performed. Cecal ligation and puncture treatment resulted in a hyperdynamic circulatory failure, diminished calcium response to norepinephrine, and a significant downregulation of alpha(1)-receptors. Proinflammatory cytokines also downregulated alpha(1)-receptors by suppressing promoter activity at the level of gene transcription. However, suppression of single proinflammatory cytokines in cytokine knockout mice did not diminish CLP-induced downregulation of alpha(1)-receptors. In contrast, blocking multiple cytokines via siRNA pretreatment or glucocorticoid administration attenuated CLP-induced cardiovascular failure and downregulation of alpha(1)-receptors. Furthermore, inhibiting NF-kappa B activity by siRNA reduced the production of cytokines, prevented circulatory failure and downregulation of alpha(1)-receptors, and improved survival of septic mice. Our findings indicate that NF-kappa B has a central role in augmenting proinflammatory cytokine production during sepsis, which in turn downregulates alpha(1)-receptor expression. Our data further define a critical role for NF-kappa B in the pathogenesis of septic shock, indicating that targeting NF-kappa B is a desired therapeutic strategy to treat septic vasoplegia.