Immunosuppression by leukocyte ADAM17 during sepsis

摘要 脓毒症-细菌感染引起的严重全身炎症反应-目前是第十大最常见的 这是美国的死亡原因，也是医院感染死亡的主要原因。尽管 支持性护理和疾病特异性治疗的进展、脓毒症的发病率和相关费用 随着其治疗的增加，预计随着人口老龄化将进一步增加。针对 脓毒症的炎性阶段未能提高存活率，因此需要新的治疗策略。 越来越多的证据支持免疫抑制在脓毒症中的核心作用，这增加了脓毒症发生的机会。 长期和继发性感染。例如，中性粒细胞募集受损， 在细菌感染过程中，细菌感染是脓毒症的关键标志，与细菌感染的发生直接相关。 疾病的严重程度。在这个时候，更深入地了解分子机制， 脓毒症期间需要中性粒细胞功能障碍。我们的长期目标是加强中性粒细胞反应 在败血症期间，特别是鉴于细菌对抗生素的耐药性增加。我们的研究小组， 提供了广泛的专业知识，在白细胞效应活动，已确定，膜相关的 白细胞中的金属蛋白酶ADAM 17是中性粒细胞浸润到肿瘤部位的重要守门人。 感染例如，在小鼠白细胞中靶向ADAM 17的基因被发现可以加速中性粒细胞 募集和细菌清除，并显著提高脓毒症期间的存活率。核心假设 我们的建议是，在脓毒症过程中过度激活的ADAM 17促进中性粒细胞功能障碍。的 本研究的目的是确定ADAM 17调节中性粒细胞募集的机制， 以评估蛋白酶作为脓毒症的药物靶点。我们的初步研究结果首次揭示， 趋化因子受体CXCR 2在中性粒细胞中，指导其迁移到感染部位， CXCR 2在循环中性粒细胞上的表面表达水平与细胞活化后的ADAM 17水平有关。 在脓毒症期间被ADAM 17下调。R21的具体目标（探索性/开发性） 建议是建立CXCR 2脱落的作用，由ADAM 17在调节中性粒细胞募集以下 盲肠结扎和穿孔，急性多微生物脓毒症模型（目的1）。此外，我们将评估 ADAM 17作为脓毒症的药物靶点（目的2）。我们研究的独特资源包括条件性ADAM 17 敲除小鼠和高选择性和有效的ADAM 17抑制剂。我们研究的影响在于， 开发治疗靶点以提高脓毒症患者生存率的新角度。如果成功，我们的研究 将提供新的信息，以促进我们对ADAM 17作用机制的理解， 脓毒症并确定其治疗潜力。

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.