Tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone initiates and enhances pancreatitis responses
Tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone initiates and enhances pancreatitis responses
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DOI：
10.1152/ajpgi.00138.2012
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发表时间：
2012-09-01
影响因子：
4.5
通讯作者：
Thrower, E. C.
中科院分区：
文献类型：
--
作者：
Alexandre, M.;Uduman, A. K.;Thrower, E. C.
临床研究表明，吸烟会增加患急性胰腺炎的风险。尼古丁代谢产物4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）是一种主要的香烟烟雾毒素。我们假设NNK可以致敏胰腺炎，并在离体大鼠胰腺腺泡和体内研究其作用。在腺泡中，100 nM NNK分别引起胰蛋白酶原和胰凝乳蛋白酶原的三倍和五倍活化，高于对照。此外，NNK预处理腺泡增强了雨蛙素胰腺炎模型中的酶原激活。在腹膜内注射NNK（100 mg/kg体重）每周三次持续2周后，在体内检查NNK的长期作用。单独的NNK引起酶原活化（胰蛋白酶原是对照的6倍，胰凝乳蛋白酶原是对照的2倍）、空泡化、核固缩和水肿。与单独的雨蛙肽相比，NNK预处理后用雨蛙肽（40 μ g/kg）处理1小时诱导早期胰腺炎反应，增强胰蛋白酶原和胰凝乳蛋白酶原活化，以及胰腺炎的其他参数。NNK的潜在靶点包括烟碱乙酰胆碱受体和β-肾上腺素能受体;在腺泡细胞制剂中检测到两种受体类型的mRNA。对这些受体的药理学抑制剂的研究表明，NNK可以通过非神经元α（7）-烟碱乙酰胆碱受体（α（7）-nAChR）介导腺泡细胞反应。这些研究表明，长期暴露于这种烟草毒素可导致胰腺炎和对疾病敏感。靶向NNK介导的通路的疗法可能被证明在治疗吸烟相关胰腺炎中有用。
Clinical studies indicate that cigarette smoking increases the risk for developing acute pancreatitis. The nicotine metabolite 4-(methylnitrosamino)- 1-(3-pyridyl)-1-butanone (NNK) is a major cigarette smoke toxin. We hypothesized that NNK could sensitize to pancreatitis and examined its effects in isolated rat pancreatic acini and in vivo. In acini, 100 nM NNK caused three-and fivefold activation of trypsinogen and chymotrypsinogen, respectively, above control. Furthermore, NNK pretreatment in acini enhanced zymogen activation in a cerulein pancreatitis model. The long-term effects of NNK were examined in vivo after intraperitoneal injection of NNK (100 mg/kg body wt) three times weekly for 2 wk. NNK alone caused zymogen activation (6-fold for trypsinogen and 2-fold for chymotrypsinogen vs. control), vacuolization, pyknotic nuclei, and edema. This NNK pretreatment followed by treatment with cerulein (40 mu g/kg) for 1 h to induce early pancreatitis responses enhanced trypsinogen and chymotrypsinogen activation, as well as other parameters of pancreatitis, compared with cerulein alone. Potential targets of NNK include nicotinic acetylcholine receptors and beta-adrenergic receptors; mRNA for both receptor types was detected in acinar cell preparations. Studies with pharmacological inhibitors of these receptors indicate that NNK can mediate acinar cell responses through an nonneuronal alpha(7)-nicotinic acetylcholine receptor (alpha(7)-nAChR). These studies suggest that prolonged exposure to this tobacco toxin can cause pancreatitis and sensitize to disease. Therapies targeting NNK-mediated pathways may prove useful in treatment of smoking-related pancreatitis.