CHEMOKINE INTERACTIONS & PMN?CA2+ PRIMING IN TRAUMA

在美国，创伤每年导致超过14万人死亡。大多数患者 可存活的伤者死亡，死于多系统器官衰竭和 成人呼吸窘迫综合征ARDS。ARDS在很大程度上是一种 中性粒细胞侵袭肺作为全身性肺炎的表现 炎症反应综合征(SIRS)尽管许多调解人参与了 启动PMN对肺的攻击，C-X-C趋化因子(CXC)IL-8启动PMN和 与ARDS有明显的统计学关联。已有研究表明，IL-8 从损伤部位进入循环，通过以下途径调节PMN的活动 胞浆钙([Ca2+]i)通量。钙离子通量是中心细胞 PMN可以整合许多细胞外刺激的信号机制，以及 此外，高[Ca~(2+)]i流量使PMN参与呼吸爆发等活动 和脱颗粒。初步研究表明人多形核细胞对[Ca2+]i的反应 生理性IL-8剂量增加到02-Burst活性可能 在患者的血浆中孵育后预计(251 v 218 NM，p=0.03) 阿兹。此外，PMN[Ca~(2+)]i对CXCs的反应具有复杂的交叉调节 已经描述了由两个CXC受体(RI和 R2)使得CXCR2处的Gro-α启动IL-8反应(242 v 201 nM，p=0.003) 但IL-8完全抑制对Gro-α的反应。这项正常的规定是 创伤患者的中性粒细胞受到干扰。因此，调查人员提议 探讨临床上有意义的中性粒细胞过度活动的假设 严重创伤可能是由PMN[Ca~(2+)]i对CXCs的异常反应所致。是这样的 研究可能会让创伤患者受益，因为他们建议了具体的 临床治疗的方法以及治疗癌症的新分子方法 创伤中PMN-肺相互作用的研究进展。此应用程序建议 为了确定PMN特异性CXC，如IL-8和Gro-α在 创伤诱导的中性粒细胞过度活动的调节，以及在随后的 急性呼吸窘迫综合征的发展。此外，它还建议通过以下方式描述这些机制 体内循环环境调节人PMN对CXCs的反应，AS 以及CXCs启动PMN活性和增强PMN活性的细胞机制 中性粒细胞损伤后对人肺的攻击。 目的1：确定损伤后中性粒细胞对CXCs的[Ca~(2+)]i反应的变化 建立高反应状态和易患创伤后不良反应，然后 将这些变化与人口统计学、损伤严重程度的临床测量以及 与ARDS相关的患者结局。 目的2：确定PMN的体液、细胞和分子机制 创伤和易感性创伤背景下CXCs对[Ca~(2+)]i反应紊乱 患者转到ARDS。

Trauma causes over 140,000 deaths per year in the USA. Most patients with survivable injuries who die, die from multi-system organ failure and the adult respiratory distress syndrome ARDS. ARDS is in great measure a function of PMN attack on the lung as a manifestation of the Systemic Inflammatory Response Syndrome (SIRS). Although many mediators participate in priming PMN attack on the lung, the C-X-C chemokine (CXC) IL-8 primes PMN and has a clear statistical association with ARDS. It has been shown that IL-8 enters the circulation from injury sites, and modulates PMN activity via cytoplasmic calcium ([Ca 2+]i ) fluxes. Calcium fluxes are central cell signaling mechanisms by which PMN can integrate many extracellular stimuli, and moreover high [Ca2+]i fluxes commit PMN to activities such as respiratory burst and degranulation. Preliminary studies showed [Ca2+]i responses of human PMN to physiologic IL-8 doses were increased into a range where 02-burst activity may be expected (251 v 218 nM, p=.03) after incubation in plasma from patients with ARDS. Also, a complex cross-regulation of PMN [Ca 2+]i responses to CXCs have been described which result from interactions of the two CXC receptors (RI and R2) such that GRO-alpha at CXCR2 primes IL-8 responses (242 v 201 nM, p=.003) but IL-8 totally inhibits response to GRO-alpha. This normal regulation is disturbed in PMN from trauma patients. The investigators therefore propose to investigate the hypothesis that clinically significant PMN hyperactivity after major trauma may be mediated by abnormal PMN [Ca2+]i responses to CXCs. Such investigations are likely to benefit trauma patients by suggesting specific approaches to clinical management as well as novel molecular approaches to the modification of PMN-pulmonary interactions in trauma. This application proposes to determine the role of PMN specific CXCs such as IL-8 and GRO-alpha in the mediation of trauma-induced PMN hyperactivity, and in the subsequent development of ARDS. Additionally, it proposes to describe the mechanisms by which the in-vivo circulatory milieu modulates human PMN responses to CXCs, as well as the cellular mechanisms by which CXCs prime PMN activity and potentiate PMN attack on the human lung after injury. AIM 1: To identify changes in [Ca2+]i responses of PMNs to CXCs after injury which contribute to the creation of a hyper responsive state and predispose to post-traumatic ARDs, and then to correlate those changes with demographics, clinical measures of injury severity, and patient outcome with respect to ARDS. AIM 2: To identify the specific humoral, cellular and molecular mechanisms whereby PMN [Ca2+]i responses to CXCs are disturbed in the setting of trauma and predispose trauma patients to ARDS.