A novel role for matrix metalloproteinase-8 in sepsis.
A novel role for matrix metalloproteinase-8 in sepsis.
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DOI：
10.1097/ccm.0b013e318232e404
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发表时间：
2012-02
影响因子：
8.8
通讯作者：
Wong HR
中科院分区：
文献类型：
--
作者：
Solan PD;Dunsmore KE;Denenberg AG;Odoms K;Zingarelli B;Wong HR
基质金属蛋白酶-8（MMP-8）mRNA的表达在感染性休克患儿的全血中增加。这一发现对脓毒症严重程度和炎症反应的影响尚不清楚。在此，我们研究了感染性休克患儿MMP-8与疾病严重程度的关系。我们进一步证实了MMP-8的作用，在败血症的小鼠模型。回顾性观察性临床研究和随机对照实验室实验。儿科重症监护室和一家学术儿童医院的动物研究机构。患者年龄≤ 10岁，诊断为感染性休克，入住重症监护室。对于实验室研究，我们利用MMP-8缺陷的雄性小鼠和雄性野生型C57/B16小鼠。分析感染性休克儿童血液中MMP-8 mRNA表达和MMP-8活性，并根据死亡率和器官衰竭程度与疾病严重程度相关。采用小鼠脓毒症模型，探讨MMP-8的遗传和药理学抑制对脓毒症炎症反应的影响。最后，在体外和体内评估核因子-κB（NF-κB）的活化。感染性休克中MMP-8 mRNA表达和活性增加与儿科患者生存率降低和器官衰竭增加相关。MMP-8的遗传和药理学抑制导致败血症小鼠模型中存活率提高和炎症特征减弱。我们还确定MMP-8作为促炎转录因子NF-κB的直接体外激活剂。MMP-8是脓毒症中的一种新型炎症调节因子，也是一种潜在的治疗靶点。
Matrix metalloproteinase-8 (MMP-8) mRNA expression was previously found to be increased in whole blood of children with septic shock. The impact of this finding on the severity and inflammatory response to sepsis is unknown. Here, we investigate the relationship between MMP-8 and disease severity in a children with septic shock. We further corroborate the role of MMP-8 in sepsis in a murine model. Retrospective observational clinical study and randomized controlled laboratory experiments. Pediatric intensive care units and an animal research facility at an academic children’s hospital. Patients age ≤ 10 years admitted to the intensive care unit with a diagnosis of septic shock. For laboratory studies, we utilized male mice deficient for MMP-8 and male wild type C57/Bl6 mice. Blood from children with septic shock was analyzed for MMP-8 mRNA expression and MMP-8 activity, and correlated with disease severity based on mortality and degree of organ failure. A murine model of sepsis was used to explore the effect of genetic and pharmacologic inhibition of MMP-8 on the inflammatory response to sepsis. Finally, activation of nuclear factor-κB (NF-κB) was assessed both in vitro and in vivo. Increased MMP-8 mRNA expression and activity in septic shock correlates with decreased survival and increased organ failure in pediatric patients. Genetic and pharmacologic inhibition of MMP-8 leads to improved survival and a blunted inflammatory profile in a murine model of sepsis. We also identify MMP-8 as a direct in vitro activator of the pro-inflammatory transcription factor, NF-κB. MMP-8 is a novel modulator of inflammation during sepsis and a potential therapeutic target.