Analysis for roles of complement and arachidonate metabolites in occurrence and progression of ARDS.

补体和花生四烯酸代谢物在ARDS发生和进展中的作用分析。

• 批准号: 03670403
• 负责人: ABE Masayoshi
• 金额: $ 1.28万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1991
• 资助国家: 日本
• 起止时间: 1991 至 1992
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-03670403/
• 关键词: ARDS metabolism; Endotoxin; Iipoxygenase-metabolism; C5a; サOサ2サ; alveolar macrophages; complement; peritoneal macrophages; 肺胞マクロファ-ジ; アラキドン酸; リポキシゲナ-ゼ; ス-パ-オキサイド

To elucidate roles of eicosanoids, complement, and endotoxins in pathogenesis of ARDS, we studied functional changes of AM by using a septic lung model of rats after the operation of cecal ligation and puncture. Septic AM generated significantly less amounts of leukotriene B_4' 12- and 5-HETEs by stimulation with A23187 than the control AM did. Immunoreactive LTC_4 in the bronchoalveolar lavage fluids from the septic rats was more than that from the control rats. Therefore, it was speculated that the AM of endotoxemic rats released lipoxygenase metabolites in alveoli and then these AM obtained showed reduced 5-1ipoxygenase activity. In contrast, these cells released enhanced amounts of O_2^- on stimulation with PMA.Next, we studied influences of the i.v. administration of E. coli LPS on the production of superoxide anion (O_2^-) and 5-lipoxygenase metabolism of arachidonic acid were evaluated in the alveolar (AM) and peritoneal macrophages (PM) on days 1 and 3 after the injection. The … More dose selected was that found to induce a significant leakage of ^<125> I-BSA in the pulmonary vasculature.AM obtained one day after the LPS-injection generated smaller amount of O^-_ on stimulation with C5a but generated same amounts with wheat germ lectin (WGA) or arachidonic acid (AA) compared to control AM. This result suggested a prior complement activation. On day 3, on the contrary, their production of O^-_ significantly exceeded that by the control AM with either of the three stimuli. PM collected on day 1 after the LPS-injection generated a significantly greater amount of O^-_ on stimulation with either WGA or AA than did control PM. The amount of O^-_, however, decreased from day 1 to day 3.AM collected one day after the injection of LPS generated significantly more LTB_4 and 5-HETE on stimulation with A23187 alone and in combination with AA than did the cells from untreated rats. Such activities returned to the control levels in the AM collected on day 3. In contrast, the PM collected on day 1 produced amounts of LTB_4 and 5-HETE similar to those of the control PM but the cells on day 3 produced significantly more LTB_4.Differing responses and time-courses in 5-1ipoxygenase and O^-_ generation system may indicate a difference in mechanisms that regulate the two production systems in macrophages following the injection of LPS. It is also suggested that early increase of endogenous AA availability in AM compared with PM induces more production of LTB_4 following second stimulation and consequently more leukocytes may be attracted to the lung. Less

为了阐明类二十烷酸、补体和内毒素在 ARDS 发病机制中的作用，我们利用盲肠结扎和穿刺手术后的大鼠脓毒症肺模型研究了 AM 的功能变化。脓毒症 AM 通过 A23187 刺激产生的白三烯 B_4' 12- 和 5-HETE 量明显少于对照 AM。脓毒症大鼠支气管肺泡灌洗液中免疫反应性LTC_4含量高于对照大鼠。因此，推测内毒素血症大鼠的AM在肺泡中释放脂氧合酶代谢物，然后获得的这些AM表现出5-1脂氧合酶活性降低。相反，这些细胞在 PMA 刺激下释放出更多的 O_2^-。 接下来，我们研究了静脉注射的影响。注射后第 1 天和第 3 天，在肺泡 (AM) 和腹膜巨噬细胞 (PM) 中评估大肠杆菌 LPS 对超氧阴离子 (O_2^-) 产生和花生四烯酸 5-脂氧合酶代谢的影响。所选择的剂量被发现会在肺脉管系统中诱导 ^<125> I-BSA 的显着渗漏。与对照 AM 相比，LPS 注射一天后获得的 AM 在用 C5a 刺激时产生较少量的 O^-_，但用麦芽凝集素 (WGA) 或花生四烯酸 (AA) 产生相同量的 O^-_。该结果表明补体先前被激活。相反，在第 3 天，在三种刺激中的任何一种刺激下，它们产生的 O^-_ 显着超过对照 AM。 LPS 注射后第 1 天收集的 PM 在 WGA 或 AA 刺激下产生的 O^-_ 量明显多于对照 PM。然而，O^-_的量从第1天到第3天减少。注射LPS一天后收集的AM在单独使用A23187以及与AA组合刺激时产生显着更多的LTB_4和5-HETE，比来自未处理的大鼠的细胞产生显着更多的LTB_4和5-HETE。这些活动恢复到第 3 天收集的 AM 中的对照水平。相比之下，第 1 天收集的 PM 产生的 LTB_4 和 5-HETE 量与对照 PM 相似，但第 3 天的细胞产生显着更多的 LTB_4。5-1ipoxygenase 和 O^-_ 生成系统中的不同反应和时间进程可能表明在注射 脂多糖。还表明，与 PM 相比，AM 中内源 AA 可用性的早期增加会在第二次刺激后诱导更多的 LTB_4 产生，因此可能会吸引更多的白细胞到肺部。较少的

项目成果

Yanaga,F.et al: "Signal transduction by tunor necrosis factor α is mediated through a guanine nucleotide binding protein in osteoblast-like cell line,MC3T3-El" Journal of Biological Chemistry. 267:. 5114-5121 (1992)

Yanaga，F.等人：“肿瘤坏死因子α的信号转导是通过成骨细胞样细胞系中的鸟嘌呤核苷酸结合蛋白介导的，MC3T3-E1”《生物化学杂志》267：5114-5121。

Masayoshi Abe, Tomomochi Gouya, Teizo Fujita, Masayuki Miyazaki, and Motomichi Torisu: "Evaluation of complement in patients with eosinophilic pneumonia" Int Med.Vol.31, No.6. 717-724 (1992)

Masayoshi Abe、Tomomochi Gouya、Teizo Fujita、Masayuki Miyazaki 和 Motomichi Torisu：“嗜酸性粒细胞性肺炎患者的补体评估”Int Med.Vol.31，No.6。

Tanaka,K.et al: "Effects of a 5ーlipoxygenase inhibitor,AA861,on lipoxygenase metabolism and superoxide anion generation by polymorphonucler leukocytes;potentiation of superoxide anion generation by LTB_4"

Tanaka, K. 等人：“5-脂氧合酶抑制剂 AA861 对脂氧合酶代谢和多形核白细胞产生超氧阴离子的影响；LTB_4 增强超氧阴离子的产生”

Abe,M.et al: "Evaluation of complement in patients with eosinophilic pneumonia" Internal Medicine. 31:. 717-724 (1992)

Abe，M.等人：“嗜酸性粒细胞性肺炎患者的补体评估”内科。

Fumi Yanaga, Masayoshi Abe, Toshitaka Koga, and Masato Hirata: "Signal transduction by tumor necrosis factor alpha is mediated through a guanine nucleotide binding protein in osteoblast-like cell line, MC3T3-E1" J.Biol Chem.267(8). 5114-5121 (1992)

Fumi Yanaga、Masayoshi Abe、Toshitaka Koga 和 Masato Hirata：“肿瘤坏死因子 α 的信号转导是通过成骨细胞样细胞系 MC3T3-E1 中的鸟嘌呤核苷酸结合蛋白介导的”J.Biol Chem.267(8)。