Geng Y, Savage S M, Johnson L J, Seagrave J, Sopori M L
Immunotoxicology Section, Lovelace Institutes, Albuquerque, New Mexico 87108, USA.
Toxicol Appl Pharmacol. 1995 Dec;135(2):268-78. doi: 10.1006/taap.1995.1233.
Previous work has demonstrated that chronic exposure of rats to cigarette smoke causes inhibition of the antibody-forming cell (AFC) response and that the particulate phase of cigarette smoke, containing most of the nicotine in cigarette smoke, is essential for immunosuppression. Using intradermally implanted miniosmotic pumps, LEW rats were exposed to nicotine or its principal metabolite, cotinine, at the rate of about 14 micrograms/hr for 3-4 weeks. Serum cotinine levels in nicotine-treated (NT) animals of 219 +/- 40 ng/ml (on Day 10) were comparable to average human smokers. No significant differences between control (CON) and NT animals were observed in the distribution of lymphocyte subsets. However, nicotine, but not cotinine, treatment for 3 to 4 weeks inhibited both the T-dependent and T-independent AFC responses and proliferation to anti-CD3. Con A response was observed in 4-week but not in 3-week NT animals. Cell cycle analysis revealed that upon stimulation with Con A or anti-CD3, in spite of comparable surface expression of IL-2 receptors and class II MHC molecules, significantly fewer NT T cells entered the S and G2/M phases than CON T cells, indicating an arrest in the G0/G1 phase. Furthermore, B and T cells from NT animals were unable to elevate the intracellular calcium levels normally in response to ligation of antigen receptors, although Ca2+ responses of salivary gland cells to acetylcholine were normal. Thus, nicotine may significantly contribute to the immunosuppressive effects of chronic smoking by inducing a state of anergy in lymphocytes and may be related to their impaired response to antigen-induced signaling.
先前的研究表明，大鼠长期暴露于香烟烟雾中会导致抗体形成细胞（AFC）反应受到抑制，并且香烟烟雾的颗粒相（包含香烟烟雾中的大部分尼古丁）对于免疫抑制至关重要。使用皮下植入的微型渗透泵，将LEW大鼠以约14微克/小时的速率暴露于尼古丁或其主要代谢产物可替宁中，持续3 - 4周。尼古丁处理（NT）组动物在第10天的血清可替宁水平为219±40纳克/毫升，与人类吸烟者的平均水平相当。在淋巴细胞亚群的分布上，未观察到对照组（CON）和NT组动物之间存在显著差异。然而，尼古丁而非可替宁处理3至4周会抑制T细胞依赖性和T细胞非依赖性AFC反应以及对抗CD3的增殖反应。在4周龄的NT组动物中观察到了刀豆蛋白A反应，但3周龄的NT组动物未观察到。细胞周期分析显示，在用刀豆蛋白A或抗CD3刺激后，尽管IL - 2受体和II类主要组织相容性复合体分子的表面表达相当，但进入S期和G2/M期的NT组T细胞明显少于CON组T细胞，表明细胞停滞在G0/G1期。此外，NT组动物的B细胞和T细胞在抗原受体连接后无法正常升高细胞内钙水平，尽管唾液腺细胞对乙酰胆碱的Ca2+反应正常。因此，尼古丁可能通过诱导淋巴细胞无反应状态而显著促成慢性吸烟的免疫抑制作用，并且可能与其对抗原诱导信号的反应受损有关。
