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，输注较老的储存的压缩红细胞(PRBC)与ALI/MOF的发生有关。急性器官损伤，如动物和体外模型所证明的，至少是两种临床事件的结果。第一个事件引起内皮细胞(EC)的激活，表现为黏附分子的增加以及趋化因子的合成和细胞外释放，导致PMN的启动和黏附。启动不仅最大限度地释放组成PMN杀菌武器库的氧化和非氧化细胞毒剂，而且启动还将PMN的表型改变为“高响应性”，这样不激活静止的PMN的刺激就会激活启动的PMN。第二个事件导致这些附着的“高响应性”PMN的激活，最终导致 内皮损伤，毛细血管渗漏，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)表明这些化合物与人肺微血管内皮细胞(HMVECs)的激活有关。因此，由于EC的激活是ALI/MOF的必要条件，而EC的去除在体外和体内都抑制了ALI/MOF，因此我们推测，血液中的中性亲脂化合物通过改变正常的PMN：EC生理学，使创伤患者容易发生损伤后的ALI/MOF。这种改变导致EC不分青红皂白地激活，导致高反应性PMN在特定器官床上隔离，从而导致损伤后ALI/MOF。这一假设将通过完成以下具体目标来检验。1：确定PRBC和LRPRBC在常规血液储存过程中积累并在复苏过程中输注的脂类。2：通过检测PMN和原代内皮细胞、HMVECs和人肝窦内皮细胞，描述这些亲脂化合物激活的导致PMN：EC生理学改变的信号通路。3：测试这些脂质在两个事件的PMN介导的ALI模型中作为第一个事件产生ALI的能力。4.阐明在常规储存过程中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可能会导致废除或改善这些脂类的临床效果的方法，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.