IMMUNOLOGICAL ASPECTS OF HEMORRHAGE

我们的研究表明出血会导致明显的抑郁 在液体复苏后仍然存在的细胞介导的免疫中， 增加对败血症的易感性。 初步研究表明：（a） 脾细胞中的ATP水平（通过31 P-NMR）在注射后几乎检测不到。 出血且甚至在复苏后2小时仍保持抑郁; B） 出血增加脾巨噬细胞（Mphi）细胞内Ca 2+， 降低对刺激物的反应; c）暴露于低氧后 环境（无出血），Mphi抗原呈递（AP）功能 降低，PGE 2的产生增加。 因此，我们的假设， 出血会产生局部缺氧，导致细胞ATP 降低，诱导钙稳态/第二信使改变 系统，细菌移位（即内毒素释放），以及 刺激枯否细胞产生炎性细胞因子。 净 上述事件的结果是PGE 2产生增加，其介导 抑制Mphi（AP和相关过程）和脾细胞 功能（增殖和淋巴因子生成），产生 免疫抑制和增加对脓毒症的易感性。 研究是 建议确定是否：1）出血和复苏， 而不进行免疫调节（使用诸如ATP-MgCl 2、钙 拮抗剂、抗内毒素、IL-6或TNF抗体、氯喹）， 与缺氧相比，产生脾细胞和Mphi ATP/钙的改变 水平和PGE 2生产; 2）出血或缺氧产生改变 第二信使系统的变化; 3）Mphi细胞因子的改变 出血和复苏后的生产，有和没有上述 免疫调节剂本质上是转录和/或翻译的。 等 研究将确定TNF和IL-6的基因表达是否 在出血/免疫调节后改变。 此外，在现场 将进行杂交以定位细胞区室， 改变细胞因子的产生;和4）消耗花生四烯酸储存 出血前使用欧米茄-3脂肪酸饮食可以预防抑郁症 Mphi和脾细胞功能的变化。 使用 生物化学、生理学、细胞和分子生物学技术， 确定免疫抑制的机制， 对出血和复苏后脓毒症的易感性应 提供有用的信息，用于治疗和护理患者 大量失血

Our studies have demonstrated that hemorrhage produces a marked depression in cell-mediated immunity which persists despite fluid resuscitation and increases susceptibility to sepsis. Preliminary studies indicate that: a) ATP levels (by 31P-NMR) in splenocytes are barely detectable after hemorrhage and remain depressed even 2 hrs after resuscitation; b) hemorrhage increases splenic macrophage (Mphi) intracellular Ca2+ while decreasing the response to stimulant; c) after exposure to hypoxic environment (without hemorrhage), Mphi antigen presentation (AP) function is depressed and PGE2 production is increased. Our hypothesis, therefore, is that hemorrhage produces regional hypoxia which causes cell ATP to decrease, inducing alterations in calcium homeostasis/second messenger systems, translocation of bacteria (i.e. endotoxin release), and stimulation of Kupffer cells to produce inflammatory cytokines. The net results of the above event(s) is increased PGE2 production, which mediates the depression of Mphi (AP and associated processes) and splenocyte function (proliferation and lymphokine generation), producing immunodepression and increasing susceptibility to sepsis. Studies are proposed to determine whether or not: 1) hemorrhage and resuscitation with and without immunomodulation (with agents such as ATP-MgCl2, calcium antagonists, anti-endotoxin, IL-6 or TNF antibodies, chloroquine), as compared to hypoxia, produce alterations in splenocyte and Mphi ATP/calcium levels and PGE2 production; 2) hemorrhage or hypoxia produces alterations in the second messenger system; 3) the alterations in Mphi cytokine production after hemorrhage and resuscitation with and without the above immunomodulators are transcriptional and/or translational in nature. Such studies will determine whether or not the gene expression for TNF and IL-6 is altered after hemorrhage/immunomodulation. Additionally, in situ hybridization will be carried out to localize the cellular compartments of altered cytokine production; and 4) depletion of arachidonic acid stores before hemorrhage using omega-3 fatty acid diet will prevent the depression of Mphi and splenocyte functions following hemorrhage. The use of biochemical, physiological, cellular and molecular biological techniques to determine the mechanism responsible for immunodepression and increased susceptibility to sepsis following hemorrhage and resuscitation should provide useful information for the treatment and care of patients with major blood loss.