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 有幸存的受伤者，死于多系统器官衰竭， 成人呼吸窘迫综合征在很大程度上， PMN攻击肺的功能作为系统性 炎症反应综合征（SIRS）。虽然许多调解人参与 当启动PMN攻击肺时，C-X-C趋化因子（CXC）IL-8启动PMN， 与急性呼吸窘迫综合征有明显的统计学关联研究表明，IL-8 从损伤部位进入循环，并通过 胞浆钙（[Ca 2+]i）流。中央细胞钙流 PMN可以整合许多细胞外刺激的信号传导机制， 此外，高[Ca 2 +]i通量使PMN进行呼吸爆发等活动 和脱颗粒。初步研究表明，人PMN [Ca 2 +]i对 生理IL-8剂量增加到O2爆发活性可以 在来自以下患者的血浆中孵育后，预期（251 vs 218 nM，p=.03） ARDS。此外，PMN [Ca 2+]i对CXC反应的复杂交叉调节， 其由两种CXC受体（RI和RI）的相互作用产生。 R2），使得CXCR 2处的GRO-α引发IL-8应答（242 vs 201 nM，p=.003） 但IL-8完全抑制对GRO-α的应答。这一正常规定是 创伤患者中性粒细胞异常。因此，调查人员建议， 研究以下假设： 严重创伤可能由PMN [Ca 2 +]i对CXC的异常反应介导。等 研究可能会通过建议特定的 临床管理的方法以及新的分子方法， 创伤中中性粒细胞-肺相互作用的改变。本申请提出 为了确定PMN特异性CXC如IL-8和GRO-α在 介导创伤诱导的PMN过度活跃，并在随后的 ARDS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CXC的反应， 以及CXC引发PMN活性和增强PMN活性的细胞机制。 人肺损伤后中性粒细胞对肺的攻击。 目的1：研究损伤后中性粒细胞对CXC [Ca ~（2+）]i反应的变化， 导致过度反应状态，易患创伤后ARDs，然后 将这些变化与人口统计学、损伤严重程度的临床指标以及 患者预后与ARDS有关。 目的2：探讨中性粒细胞（PMN）在细胞内的特异性体液、细胞和分子机制， [Ca2+]i对CXC的反应在创伤和易患创伤的情况下受到干扰 患者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.