Immunosuppression by leukocyte ADAM17 during sepsis

总结。 脓毒症是对细菌感染的一种严重的全身炎症反应，目前是最常见的十分之一。 美国的死因和医院感染的主要死因。尽管 支持性护理和疾病特异性治疗的进展、脓毒症的发生率和相关成本 随着其治疗的增加，预计将随着人口老龄化而进一步增加。目标是 炎症期脓毒症不能提高存活率，需要新的治疗策略。 越来越多的证据支持免疫抑制在脓毒症中的核心作用，这增加了机会 用于长期和继发性感染。例如，中性粒细胞募集功能受损，第一白细胞 在细菌感染期间人群的反应，是败血症的重要标志，并与 疾病的严重程度。此时，对潜在的分子机制有了更深的理解 败血症期间中性粒细胞功能障碍是必要的。我们的长期目标是增强中性粒细胞的反应 在脓毒症期间，特别是在细菌对抗生素的耐药性增加的情况下。我们的研究小组，它 提供了广泛的白细胞效应活性的专业知识，已经确定了与膜相关的 白细胞中的金属蛋白酶ADAM17是中性粒细胞向外周血中渗透的重要门卫 感染。例如，小鼠白细胞中的基因靶向ADAM17被发现可以加速中性粒细胞 招募和细菌清除，并显著提高脓毒症期间的存活率。中心假说 我们的建议之一是，在脓毒症期间ADAM17的过度激活促进了中性粒细胞功能障碍。这个 本研究的目的是确定ADAM17调节中性粒细胞募集和 目的：评价该酶作为治疗脓毒症的药物靶点。我们的初步调查结果首次显示， 中性粒细胞上的趋化因子受体CXCR2，它引导中性粒细胞迁移到感染部位，被 ADAM17对细胞激活的影响，循环中性粒细胞表面CXCR2的表达水平 在脓毒症中被ADAM17下调。R21的具体目标(探索性/开发性) 建议确定ADAM17脱落的CXCR2在以下调节中性粒细胞募集中的作用 盲肠结扎穿刺术，一种急性多菌败血症模型(目标1)。此外，我们还将评估 ADAM17作为治疗脓毒症的药物靶点(目标2)。我们研究的独特资源包括有条件的ADAM17 基因敲除小鼠和高度选择性和有效的ADAM17抑制剂。我们研究的影响是它追求一种 开发治疗靶点以提高脓毒症患者存活率的新角度。如果成功，我们的研究 将提供新的信息，以促进我们对反兴奋剂机构17在 脓毒症，并建立其治疗潜力。

SUMMARY. Sepsis - a severe systemic inflammatory response to bacterial infection - is currently the tenth most common cause of death in the United States and the primary cause of death from infection in hospitals. Despite advances in supportive care and disease-specific treatments, the incidence of sepsis and the costs associated with its treatment are rising, and are predicted to increase further as the population ages. Targeting the inflammatory phase of sepsis has failed to improve survival and there is a need for new therapeutic strategies. Increasing evidence supports a central role for immunosuppression in sepsis, which enhances the opportunity for prolonged and secondary infections. For instance, impairment of neutrophil recruitment, the first leukocyte population to respond during bacterial infection, is a critical hallmark of sepsis and is directly related to the severity of the disease. At this time, a deeper understanding of the molecular mechanisms underlying neutrophil dysfunction during sepsis is needed. Our long-term goal is to bolster the neutrophil response during sepsis, especially in light of increasing bacterial resistance to antibiotics. Our research group, which provides broad expertise in leukocyte effector activities, has determined that the membrane-associated metalloprotease ADAM17 in leukocytes is an important gatekeeper of neutrophil infiltration into sites of infection. For instance, gene-targeting ADAM17 in mouse leukocytes was found to accelerate neutrophil recruitment and bacterial clearance, and significantly improve survival during sepsis. The central hypothesis of our proposal is that over-activation of ADAM17 during sepsis promotes neutrophil dysfunction. The objective of our study is to determine the mechanism by which ADAM17 regulates neutrophil recruitment and to assess the protease as a drug target for sepsis. Our preliminary findings reveal for the first time that the chemokine receptor CXCR2 in neutrophils, which directs their migration into sites of infection, is cleaved by ADAM17 upon cell activation and that the surface expression levels of CXCR2 on circulating neutrophils are down-regulated by ADAM17 during sepsis. The specific aims of this R21 (exploratory/developmental) proposal are to establish the role of CXCR2 shedding by ADAM17 in regulating neutrophil recruitment following cecal ligation and puncture, a model of acute polymicrobial sepsis (Aim 1). In addition, we will evaluate ADAM17 as a drug target for sepsis (Aim 2). Resources unique to our study include conditional ADAM17 knockout mice and highly selective and potent ADAM17 inhibitors. The impact of our study is that it pursues a novel angle for developing therapeutic targets to improve survival by septic patients. If successful, our study will provide new information to advance our understanding of the mechanisms of action of ADAM17 during sepsis and establish its therapeutic potential.