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

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。

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.