Role of lipoxygenase products in murine pulmonary granuloma formation.
Role of lipoxygenase products in murine pulmonary granuloma formation.
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脂氧合酶产物在小鼠肺肉芽肿形成中的作用。
DOI：
10.1172/jci111449
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发表时间：
1984
期刊：
影响因子：
--
通讯作者：
Higashi,GI
中科院分区：
文献类型：
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作者：
Kunkel,SL;Chensue,SW;Mouton,C;Higashi,GI
已知各种花生四烯酸（AA）代谢物调节免疫细胞功能并决定急性和慢性炎症反应的进展。使用曼氏血吸虫虫卵诱导的超敏性肉芽肿模型，我们描绘了在体内的影响，抑制剂的环氧合酶（CO）和脂氧合酶（LO）的途径，肉芽肿的发展和肉芽肿巨噬细胞I区相关（Ia）抗原的表达。此外，通过高效液相色谱法（HPLC），我们已经分析了从肉芽肿病灶分离的巨噬细胞的AA代谢，并已生化特征的选择CO和LO抑制剂的体外特异性和活性。抗LO活性抑制剂（去甲二氢愈创木酸（NDGA），萘唑仑和BW 755 c）以剂量依赖性方式显着抑制小鼠超敏反应型肺肉芽肿的发展，而吲哚美辛，这主要是CO-选择性，没有显着的效果。此外，NDGA和nafazatrom深刻地阻止了预先形成的肉芽肿性病变的正常进展。LO通路的抑制剂也抑制了肉芽肿巨噬细胞表达Ia抗原的体内动力学。与此相反，吲哚美辛增加Ia抗原的表达。由肉芽肿巨噬细胞合成的主要AA代谢物显示为白三烯C4和单羟基二十碳四烯酸。用各种抑制剂处理的肉芽肿巨噬细胞的AA代谢物的HPLC分析证实，吲哚美辛是最CO选择性的，NDGA是最LO选择性的。Nafazatrom和BW 755 c通过两种途径抑制AA代谢。值得注意的是，高浓度的化合物（5 × 10（-5）M）倾向于抑制所有产物。我们的研究结果表明LO产物可能在免疫肉芽肿性炎症反应的产生和维持中起重要作用。
Various arachidonic acid (AA) metabolites are known to regulate immune cell function(s) and dictate the progression of both acute and chronic inflammatory reactions. Using a model of Schistosoma mansoni egg-induced hypersensitivity granulomas, we have delineated the in vivo effects of inhibitors of cyclooxygenase (CO) and lipoxygenase (LO) pathways on granuloma development and granuloma macrophage I-region-associated (Ia) antigen expression. In addition, by high performance liquid chromatography (HPLC) we have profiled the metabolism of AA by macrophages that are isolated from granulomatous foci, and have biochemically characterized the in vitro specificity and activity of selected CO and LO inhibitors. The development of hypersensitivity-type pulmonary granulomas in mice was dramatically suppressed by inhibitors with anti-LO activity (nordihydroguairetic acid (NDGA), nafazatrom, and BW755c) in a dose-dependent manner, while indomethacin, which is primarily CO-selective, had no significant effect. Furthermore, NDGA and nafazatrom profoundly arrested the normal progression of preformed granulomatous lesions. The inhibitors of the LO pathway also suppressed the in vivo kinetics of Ia antigen expression by granuloma macrophages. In contrast, indomethacin augmented Ia-antigen expression. The major AA metabolites that were synthesized by the granuloma macrophages were shown to be leukotriene C4 and mono-hydroxyeicosatetraenoic acids. HPLC analysis of AA metabolites from granuloma macrophages that were treated with the various inhibitors confirmed that indomethacin was most CO-selective and NDGA most LO-selective. Nafazatrom and BW755c inhibited AA metabolism by both pathways. Notably, high concentrations of the compounds (5 X 10(-5) M) tended to suppress all products. Our results suggest that LO products may be important in the generation and maintenance of immune granulomatous inflammatory responses.Images