Treatment of acute lung injury by inhibition of gene induction of NO synthase in alveolar macrophages.

通过抑制肺泡巨噬细胞中 NO 合酶的基因诱导来治疗急性肺损伤。

• 批准号: 12670579
• 负责人: TAMAOKI Jun
• 金额: $ 2.56万
• 依托单位: Tokyo Woman's Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670579/
• 关键词: Macrophage; Nitric Oxide; Gene therapy; Lung injury; Cytokines; Macrolide; Erythromycin; Clarithromycin; 遺伝子治療; 急性肺傷害; クラリスロマイシン; ポーラログラフィー

Macrolide antibiotics have unique immunomodulatory actions apart from antimicrobial properties. We studied the effects of macrolides on immunoglobulin G immune complex (IgG-ICx)-induced lung injury in rats in vivo and in vitro. Intrapulmonary deposition of IgG-ICx produced a time-dependent increase in the concentration of NO in exhaled air. There were corresponding increases in the number of neutrophils accumulated into alveolar spaces, and lung wet-to-dry weight ratio. All of these changes were inhibited by pretreatment with erythromycin or josamycin, but not by amoxicillin or cephaclor. Incubation of cultured pulmonary alveolar macrophages (PAM) caused upregulation of NO production and expression of inducible NO synthase (iNOS) mRNA, an effect that was dose dependently inhibited by erythromycin, roxithromycin, or josamycin. The macrolides also reduced IgG-ICx-induced release of IL-1* and TNF-α, but did not alter the release of NO induced by exogenously added IL-1β and TNF-α. These results suggest that macrolide antibiotics specifically inhibit immune complex-induced lung injury presumably by inhibiting cytokine release and the resultant downregulation of iNOS gene expression and NO production by rat PAM.

大环内酯类抗生素除了具有抗菌特性外，还具有独特的免疫调节作用。本实验在体内外研究了大环内酯类药物对免疫球蛋白G免疫复合物（IgG-ICx）诱导的大鼠肺损伤的影响。肺内沉积的IgG-ICx产生了一个时间依赖性的增加，在呼出气中的NO浓度。有相应的增加，中性粒细胞的数量积聚到肺泡腔，肺湿干重比。红霉素或交沙霉素预处理可抑制上述变化，但阿莫西林或头孢克洛不能抑制上述变化。培养的肺泡巨噬细胞（PAM）的孵育引起的诱导型一氧化氮合酶（iNOS）的mRNA的表达和NO的产生的上调，红霉素，罗红霉素，交沙霉素的剂量依赖性抑制的效果。大环内酯类药物还可减少IgG-ICx诱导的IL-1* 和TNF-α的释放，但不改变外源性IL-1β和TNF-α诱导的NO释放。这些结果表明，大环内酯类抗生素特异性抑制免疫复合物诱导的肺损伤，大概是通过抑制细胞因子的释放和由此产生的下调iNOS基因的表达和NO的生产大鼠PAM。

项目成果

玉置淳: "呼吸器疾患とマクロライド療法"分子呼吸器病. 4. 413-418 (2000)

Jun Tamaki：“呼吸系统疾病和大环内酯治疗”《分子呼吸系统疾病》4. 413-418 (2000)。

Tamaoki J: "Effects of macrolides on lung injufy induced by lgG immune complex."Jap J Antibiot. 54. 83-86 (2001)

Tamaoki J：“大环内酯类药物对 IgG 免疫复合物诱导的肺损伤的影响。”Jap J Antibiot。

Tamaoki Jun: "Impairment of airway mucociliary transport in patients with sinobronchial syndrome"Journal of Aerosol Medicine. 13. 239-244 (2000)

Tamaoki Jun：“窦支气管综合征患者气道粘液纤毛运输受损”气溶胶医学杂志。

玉置 淳: "呼吸器疾患とマクロライド療法"分子呼吸器病. 4. 413-418 (2000)

Jun Tamaki：“呼吸系统疾病和大环内酯治疗”《分子呼吸系统疾病》4. 413-418 (2000)。

玉置 淳: "IgG免疫複合体(IgG-ICx)肺傷害モデルに対するマクロライドの効果と作用機序"Japanese Journal of Antibiotics. 54. 83-86 (2001)

Jun Tamaki：“大环内酯类药物对 IgG 免疫复合物 (IgG-ICx) 肺损伤模型的作用和机制”，日本抗生素杂志 54. 83-86 (2001)。