Mechanism and tissue specificity of nicotine-mediated lung S-adenosylmethionine reduction
Mechanism and tissue specificity of nicotine-mediated lung S-adenosylmethionine reduction
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DOI：
10.1074/jbc.m709399200
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发表时间：
2008-03-21
影响因子：
4.8
通讯作者：
Merali, Salim
中科院分区：
文献类型：
--
作者：
Moncada, Camilo A.;Clarkson, Allen;Merali, Salim
我们以前曾报道过慢性尼古丁输注阻断肺孢子虫肺炎的发展。这一发现源于我们的工作，证明了这种真菌病原体不能合成关键的代谢中间体S-腺苷甲硫氨酸，以及其他人的工作，表明尼古丁会导致豚鼠肺特异性S-腺苷甲硫氨酸减少。我们已经发现尼古丁输注导致肺鸟氨酸脱羧酶活性增加（多胺合成的速率控制酶），并假设S-腺苷甲硫氨酸减少是由上调的多胺生物合成驱动的。在这里，我们报告了我们的假设的一个关键测试，抑制鸟氨酸脱羧酶阻断尼古丁对肺S-腺苷甲硫氨酸的影响。代谢物分析提供了进一步的支持，表明尼古丁导致S-腺苷甲硫氨酸强烈转向多胺合成，远离甲基化反应;这些变化通过抑制鸟氨酸脱羧酶而逆转。由于尼古丁对肺孢子虫的作用是如此显著，我们考虑了组织特异性的可能性。使用激光捕获显微切割，我们收集了肺泡区域（感染部位）和呼吸道上皮细胞的样本作为对照。我们发现尼古丁引起肺泡区域但不是气道上皮细胞中的鸟氨酸脱羧酶蛋白增加;我们得出结论，组织特异性可能有助于尼古丁对肺孢子虫肺炎的影响。之前我们报道尼古丁的全部效果需要3周的治疗，这里我们显示恢复是对称的，也需要在治疗停止后3周。由于这一时间范围与肺细胞周转时间相似，多胺代谢的转变可能发生在新的肺细胞产生时。
We previously reported that chronic nicotine infusion blocks development of Pneumocystis pneumonia. This discovery developed from our work demonstrating the inability of this fungal pathogen to synthesize the critical metabolic intermediate S-adenosylmethionine and work by others showing nicotine to cause lung-specific reduction of S-adenosylmethionine in guinea pigs. We had found nicotine infusion to cause increased lung ornithine decarboxylase activity (rate-controlling enzyme of polyamine synthesis) and hypothesized that S-adenosylmethionine reduction is driven by up-regulated polyamine biosynthesis. Here we report a critical test of our hypothesis; inhibition of ornithine decarboxylase blocks the effect of nicotine on lung S-adenosylmethionine. Further support is provided by metabolite analyses showing nicotine to cause a strong diversion of S-adenosylmethionine toward polyamine synthesis and away from methylation reactions; these shifts are reversed by inhibition of ornithine decarboxylase. Because the nicotine effect on Pneumocystis is so striking, we considered the possibility of tissue specificity. Using laser capture microdissection, we collected samples of lung alveolar regions (site of infection) and respiratory epithelium for controls. We found nicotine to cause increased ornithine decarboxylase protein in alveolar regions but not airway epithelium; we conclude that tissue specificity likely contributes to the effect of nicotine on Pneumocystis pneumonia. Earlier we reported that the full effect of nicotine requires 3 weeks of treatment, and here we show recovery is symmetrical, also requiring 3 weeks after treatment cessation. Because this time frame is similar to pneumocyte turnover time, the shift in polyamine metabolism may occur as new pneumocytes are produced.