Schreiber A A, Frei K, Lichtensteiger W, Schlumpf M
Institute of Pharmacology, University of Zürich, Switzerland.
Agents Actions. 1993 Mar;38(3-4):265-72. doi: 10.1007/BF01976219.
Prenatal exposure to diazepam and other benzodiazepines (BDZ) has been found to result in a marked reduction of T-lymphocyte proliferation during postnatal development of rats. In search for pathogenic changes underlying this effect, we investigated the mitogen lipopolysaccharide (LPS) and concanavalin A (ConA) stimulated release of tumour necrosis factor (TNF)-alpha by mixed splenocytes of male offspring from Long Evans rats treated with 1.25 mg/kg per day diazepam from gestational day 14 to 20. In response to LPS, TNF-alpha release was found to be significantly lower in mixed splenocytes of two- and four-week-old treated than in control offspring. However, at eight weeks of age, prenatally diazepam-treated animals showed a significantly higher LPS-induced TNF-alpha release than control rats. Since monocytes/macrophages represent a major source of TNF-alpha, additional experiments were performed on purified spleen macrophages and lymphocytes stimulated with LPS. TNF-alpha release was only detectable in supernatants of adherent spleen macrophages and not in supernatants of lymphocytes. Thus, our data indicate that a disturbance in TNF-alpha release from macrophages is involved in the deficient immune response of prenatally diazepam-exposed rats.
研究发现，产前接触地西泮和其他苯二氮䓬类药物（BDZ）会导致大鼠出生后发育过程中T淋巴细胞增殖显著减少。为了寻找这种效应背后的致病变化，我们研究了从妊娠第14天至20天每天用1.25毫克/千克地西泮处理的Long Evans大鼠雄性后代的混合脾细胞在有丝分裂原脂多糖（LPS）和伴刀豆球蛋白A（ConA）刺激下肿瘤坏死因子（TNF）-α的释放情况。结果发现，在LPS刺激下，两周龄和四周龄经处理的混合脾细胞中TNF-α的释放量显著低于对照后代。然而，在八周龄时，产前经地西泮处理的动物LPS诱导的TNF-α释放量显著高于对照大鼠。由于单核细胞/巨噬细胞是TNF-α的主要来源，因此我们对纯化的脾巨噬细胞和经LPS刺激的淋巴细胞进行了额外实验。仅在贴壁脾巨噬细胞的上清液中检测到TNF-α的释放，而淋巴细胞的上清液中未检测到。因此，我们的数据表明，巨噬细胞TNF-α释放的紊乱与产前接触地西泮的大鼠免疫反应缺陷有关。
