Prenatal Nicotine Exposure Increases GABA Signaling and Mucin Expression in Airway Epithelium
Prenatal Nicotine Exposure Increases GABA Signaling and Mucin Expression in Airway Epithelium
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DOI：
10.1165/rcmb.2010-0109oc
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发表时间：
2011-02-01
影响因子：
6.4
通讯作者：
Spindel, Eliot R.
中科院分区：
文献类型：
--
作者：
Fu, Xiao Wen;Wood, Kelsey;Spindel, Eliot R.
母亲在怀孕期间吸烟会增加后代患呼吸道疾病的风险，但令人惊讶的是，人们对潜在的机制知之甚少。支气管上皮细胞（BEC）中表达的烟碱乙酰胆碱受体（nAChRs）介导尼古丁对肺发育和功能的影响。最近，BEC也被证明表达GABA能旁分泌环，这与哮喘中的粘液过度产生有关。因此，我们研究了恒河猴BEC中胆碱能和GABA能信号之间的相互作用，发现尼古丁通过顺序激活BEC nAChR和GABA受体上调BEC中的GABA信号。恒河猴BEC原代培养物的孵育增加了GAD、GABA（A）受体和粘蛋白mRNA的浓度。尼古丁诱导的谷氨酸脱羧酶（GAD）和GABA（A）受体mRNA的增加导致GABA诱导的电流增加和粘蛋白表达增加。尼古丁和GABA（A）拮抗剂可阻断尼古丁增加粘蛋白表达的能力。这些结果暗示GABA信号作为尼古丁对粘液过量产生影响的中间人。在恒河猴长期暴露于尼古丁后，在体内观察到尼古丁对GABA信号传导和粘蛋白表达的类似影响。这些数据提供了一个新的机制，吸烟与哮喘和慢性阻塞性肺疾病中粘蛋白的增加，并提出了一个新的范例，BEC中的非神经元递质系统之间的通信。BEC中神经样递质相互作用的存在表明，一些在中枢神经系统中具有活性的药物可能在呼吸系统疾病中具有以前意想不到的效用。
Maternal smoking during pregnancy increases the risk of respiratory disease in offspring, but surprisingly little is known about the underlying mechanisms. Nicotinic acetylcholine receptors (nAChRs) expressed in bronchial epithelial cells (BECs) mediate the effects of nicotine on lung development and function. Recently, BECs were also shown to express a GABAergic paracrine loop that was implicated in mucus overproduction in asthma. We therefore investigated the interactions between cholinergic and GABAergic signaling in rhesus macaque BECs, and found that nicotine upregulated GABA signaling in BECs through the sequential activation of BEC nAChR and GABA receptors. The incubation of primary cultures of rhesus BECs increased concentrations of GAD, GABA(A) receptors, and mucin mRNA. The nicotine-induced increase in glutamatic acid decarboxylase (GAD) and GABA(A) receptor mRNA resulted in increased GABA-induced currents and increased expression of mucin. The ability of nicotine to increase mucin expression was blocked by nicotinic and GABA(A) antagonists. These results implicate GABA signaling as a middleman in nicotine's effects on mucus overproduction. Similar effects of nicotine on GABA signaling and the expression of mucin were seen in vivo after chronic exposure of rhesus monkeys to nicotine. These data provide a new mechanism linking smoking with the increased mucin seen in asthma and chronic obstructive pulmonary disorder, and suggest a new paradigm of communication between non-neuronal transmitter systems in BECs. The existence of neural-like transmitter interactions in BECs suggests that some drugs active in the central nervous system may possess previously unexpected utility in respiratory diseases.