Endothelial MKK3 is a critical mediator of lethal murine endotoxemia and acute lung injury.
Endothelial MKK3 is a critical mediator of lethal murine endotoxemia and acute lung injury.
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DOI：
10.4049/jimmunol.1202012
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发表时间：
2013-02-01
期刊：
影响因子：
--
通讯作者：
Lee PJ
中科院分区：
文献类型：
--
作者：
Mannam P;Zhang X;Shan P;Zhang Y;Shinn AS;Zhang Y;Lee PJ
脓毒症是重症监护病房入院的主要原因，具有高死亡率和高发病率。虽然随着更好的支持性治疗，结果有所改善，但具体的治疗方法有限。内皮细胞活化和氧化损伤是脓毒症肺损伤发病机制中的关键事件。导致这些事件的信号通路仍然不清楚，需要进行研究。我们试图确定MAP激酶激酶3（MKK 3），p38组激酶在脓毒症发病机制中的作用。我们使用小鼠腹腔内脂多糖（LPS）模型的全身炎症模拟败血症。在肺组织和支气管肺泡灌洗中评估肺损伤参数。培养原代肺内皮细胞并评估炎症和损伤介质，如ICAM-1、AP-1、NF-κB和线粒体ROS。我们的研究表明，MKK 3缺陷赋予几乎完全的保护，防止器官损伤后腹腔内脂多糖。具体而言，MKK 3 −/−小鼠受到保护，免受急性肺损伤，通过减少炎症，线粒体活性氧（ROS）生成，内皮损伤和LPS后ICAM-1表达进行评估。我们的研究结果表明，内皮MKK 3是必需的炎症细胞募集到肺，线粒体氧化剂介导的AP-1，NF-κB激活和ICAM-1表达在LPS的挑战。总的来说，这些研究确定了MKK 3在致死性LPS应答中的新作用，并提供了针对脓毒症和急性肺损伤的新治疗靶点。
Sepsis is a leading cause of intensive care unit admissions with high mortality and morbidity. Although outcomes have improved with better supportive care, specific therapies are limited. Endothelial activation and oxidant injury are key events in the pathogenesis of sepsis-induced lung injury. The signaling pathways leading to these events remain poorly defined and need to be studied. We sought to determine the role of MAP kinase kinase 3 (MKK3), a kinase of the p38 group in the pathogenesis of sepsis. We used a murine intraperitoneal lipopolysaccharide (LPS) model of systemic inflammation to mimic sepsis. Lung injury parameters were assessed in lung tissue and bronchoalveolar lavage. Primary lung endothelial cells were cultured and assessed for mediators of inflammation and injury such as ICAM-1, AP-1, NF-κB and mitochondrial ROS. Our studies demonstrate that MKK3 deficiency confers virtually complete protection against organ injury after intraperitoneal LPS. Specifically, MKK3 −/− mice were protected against acute lung injury, as assessed by reduced inflammation, mitochondrial reactive oxygen species (ROS) generation, endothelial injury and ICAM-1 expression after LPS. Our results show that endothelial MKK3 is required for inflammatory cell recruitment to the lungs, mitochondrial oxidant-mediated AP-1, NF-κB activation and ICAM-1 expression during LPS challenge. Collectively, these studies identify a novel role for MKK3 in lethal LPS responses and provide new therapeutic targets against sepsis and acute lung injury.
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