Inflammatory Eicosanoids

输血与急性肺损伤和损伤后多器官衰竭（ALI/MOF）的发生有关。流行病学研究表明，输注储存时间较长的浓缩红细胞（PRBC）与ALI/MOF的发生有关。正如动物和体外模型所证明的那样，急性器官损伤是至少两种临床事件的结果。第一个事件导致内皮细胞（EC）活化，如粘附分子的增加和趋化因子的合成和细胞外释放所证明的，导致PMN启动和粘附。引发不仅最大限度地释放构成中性粒细胞杀微生物武器库的氧化性和非氧化性细胞毒性剂，而且引发还将中性粒细胞表型改变为“超反应性”，使得不激活静息中性粒细胞的刺激激活引发的中性粒细胞。第二个事件导致这些粘附的“高反应性”中性粒细胞激活，最终导致 内皮损伤、毛细血管渗漏和器官损伤。脂质在血液的常规储存过程中积累，初步数据（我们的）表明这些化合物参与了人肺微血管内皮细胞（HMVEC）的活化。因此，由于EC激活是ALI/MOF的必要条件，并且其废除在体外和体内抑制ALI/MOF，我们假设储存血液中的中性亲脂性化合物通过改变正常PMN：EC生理学使受伤患者易患损伤后ALI/MOF。这种改变导致不分青红皂白的EC激活，导致在特定器官床中的高反应性PMN的隔离，导致损伤后ALI/MOF。这一假设将通过完成以下具体目标来检验。1：鉴定PRBC和LRPRBC中在常规血液储存期间积累并在复苏期间输注的脂质。第二章：通过检测中性粒细胞和原代内皮细胞、高巨噬细胞内皮细胞和人肝窦内皮细胞，描述这些亲脂性化合物激活的信号通路，这些信号通路导致中性粒细胞：内皮细胞生理学改变。3：测试这些脂质产生ALI作为两事件PMN介导的ALI模型中的第一事件的能力。4.阐明在常规储存期间抑制这些化合物积累的方法， PRBC和LR-PRBC。这些特定目标的完成将可能导致消除或改善这些脂质的临床作用的方法，并最终使输血更安全。

Blood transfusions are linked to the development of acute lung injury and post-injury multiple organ failure (ALI/MOF). Epidemiological studies have associated infusion of older stored packed red blood cells (PRBCs) to the development of ALI/MOF. Acute organ injury, as demonstrated in both animal and in vitro models, is the result of at least two clinical events. The first event causes endothelial cell (EC) activation as evidenced by an increase in adhesion molecules and the synthesis and extracellular release of chemokines, resulting in PMN priming and adherence. Priming not only maximizes the release of both oxidative and nonoxidative cytotoxic agents that comprise the microbicidal arsenal of the PMN, but priming also changes the PMN phenotype to "hyper-responsive", such that stimuli that do not activate resting PMNs activate primed PMNs. The second event causes activation of these adherent "hyper-responsive" PMNs culminating in endothelial damage, capillary leak, and organ injury. Lipids accumulate during the routine storage of blood, and preliminary data (ours) have implicated these compounds in the activation of human pulmonary microvascular endothelial cells (HMVECs). Thus, because EC activation is a requirement for ALI/MOF and its abrogation inhibits ALI/MOF in vitro and in vivo, we hypothesize that the neutral lipophilic compounds in stored blood predispose injured patients to post-injury ALI/MOF by alteration of normal PMN: EC physiology. This alteration causes indiscriminant EC activation resulting in sequestration of hyper-reactive PMNs in specific organ beds that leads to post-injury ALI/MOF. This hypothesis will be tested by completion of the following specific aims. 1: To identify the lipids that accumulate during routine blood storage and are infused during resuscitation in both PRBCs and LRPRBCs. 2: To delineate the signaling pathways activated by these lipophilic compounds that cause altered PMN: EC physiology by examining PMNs and primary ECs, HMVECs and human liver sinusoidal ECs. 3: To test the ability of these lipids to produce ALI as the first event in a two-event, PMN- mediated model of ALI. 4. To elucidate methods to inhibit the accumulation of these compounds during routine storage of both PRBCs and LR-PRBCs. Completion of these specific aims will likely result in methods to abrogate or to ameliorate the clinical effects of these lipids and will ultimately make transfusions safer.