Hyperinnervation of the airways in transgenic mice overexpressing nerve growth factor
Hyperinnervation of the airways in transgenic mice overexpressing nerve growth factor
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DOI：
10.1165/ajrcmb.18.2.2803m
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发表时间：
1998-02-01
影响因子：
6.4
通讯作者：
Friedman, M
中科院分区：
文献类型：
--
作者：
Hoyle, GW;Graham, RM;Friedman, M
感觉神经末梢释放的神经肽是哮喘气道炎症和吸入呼吸刺激物引起肺损伤的潜在介质。为了开发一种体内模型来评估神经源性炎症在这些过程中的作用，我们已经产生了肺神经支配改变的转基因小鼠。为了产生气道神经支配增加的小鼠，我们将编码神经生长因子（NGF）的基因置于肺特异性克拉拉细胞分泌蛋白（CCSP）启动子的控制下。两个谱系的CCSP-NGF转基因小鼠在肺中过度表达NGF，并产生了气道的神经支配过度。P物质的免疫组织化学，P物质的酶免疫分析，和儿茶酚胺组织荧光表明，速激肽的感觉纤维和交感神经纤维增加周围的CCSP-NGF小鼠的气道。用交感神经特异性神经毒素6-羟基多巴胺（6-OHDA）治疗CCSP-NGF小鼠，消除了气道神经支配的交感神经成分，留下了含速激肽的感觉纤维的特异性超神经支配。CCSP-NGF小鼠比正常小鼠对辣椒素诱导的呼吸系统阻力增加更敏感，这表明增加的感觉神经支配导致气道功能的变化。我们的结论是，从肺特异性启动子的NGF过表达产生肺神经支配的解剖和功能的变化，CCSP-NGF小鼠将是有用的研究神经源性炎症在气道疾病中的作用。
Neuropeptides released from sensory nerve endings are potential mediators of airway inflammation in asthma and lung injury induced by inhalation of respiratory irritants. To develop an in vivo model for assessing the contribution of neurogenic inflammation in these processes, we have generated transgenic mice with altered innervation of the lung. To generate mice with an increased innervation of the airways, we placed the gene that encodes nerve growth factor (NGF) under control of the lung-specific Clara-cell secretory protein (CCSP) promoter. Two lineages of CCSP-NGF transgenic mice overexpressed NGF in the lung and developed a hyperinnervation of the airways. Immunohistochemistry for substance P, a substance P enzyme immunoassay, and catecholamine histofluorescence indicated that both tachykinin-containing sensory fibers and sympathetic fibers were increased around the airways of CCSP-NGF mice. Treatment of CCSP-NGF mice with the sympathetic-specific neurotoxin 6-hydroxydopamine (6-OHDA) eliminated the sympathetic component of the airway innervation, leaving a specific hyperinnervation by tachykinin-containing sensory fibers. CCSP-NGF mice were more sensitive than normal mice to capsaicin-induced increases in respiratory system resistance, demonstrating that the increased sensory innervation led to a change in airway function. We conclude that NGF overexpression from a lung-specific promoter produces anatomic and functional changes in lung innervation, and that CCSP-NGF mice will be useful for studying the role of neurogenic inflammation in airway disease.