PROSTAGLANDIN G/H SYNTHASE 1 AND 2 LUNG INJURY

前列腺素G2/H2合成酶/环氧合酶的产物 花生四烯酸代谢途径(PGH合成酶)的作用 在调节炎症过程中起着至关重要的作用 肺和其他组织。有两个基因编码 对于两种相似的酶亚型，但PGH合成酶1 而PGH合成酶2基因包含独特的功能， 提示每种蛋白质在体内的特定作用 调节细胞功能。我们发现PGH合成酶 2的表达在内毒素诱导下特异性增加 兔肺泡巨噬细胞，兔肺，人 中性粒细胞(PMN)、THP-1原单核细胞 细胞和人肺泡巨噬细胞。前列腺素H合成酶1可以 用佛波醇肉豆蔻酸醋酸酯诱导THP-1细胞。 这项建议的目的是研究PGH 合酶1和2基因在人白细胞中的表达。目标 1将检验PGH合成酶1和2基因的假设 在人类血液白细胞中有不同的调节， THP-1细胞和人肺泡巨噬细胞，并在- 转录过程在调控中起着主要作用。 PGH合成酶2基因的表达。我们会比较一下 前列腺素H_1和前列环素合酶的合成和降解速率 BASIC条件下两个基因的mRNA及其翻译 条件和各种激动剂的后续刺激。 我们还将确定肾上腺皮质类固醇的作用。 关于这两个基因的表达。我们将进一步评估 基因的差异表达是否会改变 不同品种总二十烷类化合物合成能力的差异 电池，使用负离子化学电离气体 色谱质谱学。目标2将测试 假设PGH合成酶2是主要的 环氧合酶参与调节炎症反应 与某些类型的肺损伤相关的反应。我们 将定义PGH合成酶1和2在血液中的表达 患者外周血白细胞和肺泡白细胞 急性烧伤，成人呼吸窘迫 综合征(ARDS)和迟发性哮喘反应 患有特应性哮喘的患者。较长期目标 将解决相关的信号转导过程 在PGH合成酶1和2的分子调控下，我们 预计我们的研究将提供对 炎症性肺反应的发病机制 受二十烷类化合物生产的影响。

Products of the prostaglandin G2/H2 synthase/cyclooxygenase (PGH synthase) pathway of arachidonic metabolism play fundamentally important roles in modulating inflammation of lung and other tissues. There are two genes that encode for two similar enzymatic isoforms, but the PGH synthase 1 and the pGH synthase 2 genes contain unique features, suggesting specific roles for each of the proteins in modulating cellular functions. We find that PGH synthase 2 expression is specifically increased in endotoxin-primed rabbit alveolar macrophages, rabbit lung, human polymorphonuclear neutrophils (PMN), THP-1 promonocytic cells, and human alveolar macrophages. PGH synthase 1 can be induced in THP-1 cells by phorbol myristate acetate. The objective of this proposal is to investigate pGH synthase 1 and 2 gene expression in human leukocytes. Aim 1 will test the hypothesis that PGH synthase 1 and 2 genes are differentially regulated in human blood leukocytes, THP-1 cells, and human alveolar macrophages, and that post- transcriptional processes play a major role in regulating the expression of the pGH synthase 2 gene. We will compare rates of synthesis, and degradation of pGH 1 and 2 synthase mRNA's and translation of the two genes under basal conditions and following stimulation with various agonists. We also will determine the effects of adrenocorticosteroids on expression of the two genes. We will further assess whether differential expression of the genes alters the capacity for total eicosanoid synthesis in the different cells, using negative ion chemical ionization gas chromatographic mass spectroscopy. Aim 2 will test the hypothesis that pGH synthase 2 is the predominant cyclooxygenase involved in regulating inflammatory responses associated with certain types of lung injury. We will define the expression of PGH synthase 1 and 2 in blood leukocytes and alveolar leukocytes obtained from patients with acute burn injury, the Adult Respiratory Distress Syndrome (ARDS), and the late asthmatic response of patients with atopic forms of asthma. Longer-term goals will address the signal transduction processes associated with the molecular regulation of PGH synthase 1 and 2. We anticipate that our research will provide insight into the pathogenesis of inflammatory lung reactions that are influenced by eicosanoid production.