中医药靶向干预气道非肾上腺素能非胆碱能神经治疗哮喘的研究进展(1)
[摘要] 哮喘的病因复杂，发病机制可概括为气道免疫-炎症机制、神经调节机制及其相互作用。气道非肾上腺素能非胆碱能(NANC)神经及其释放的神经递质可通过调节气道平滑肌收缩、黏液分泌、可逆性气道阻塞、气道高反应性干预哮喘发病。神经生长因子通过调节P物质等NANC神经释放的神经激肽，影响NANC神经的可塑性。哮喘在中医辨证为“哮病”“喘证”。时下有关中医药调控哮喘气道炎症的研究较为详实，而对中医药干预哮喘NANC神经及其释放的神经递质的的报道较为少见。本文就近年来中医药干预NANC神经及其释放的神经递质与相关下游通路、神经生长因子对NANC神经的影响做一简要的综述，以期为临床研究和实验研究开阔思路。
[关键词] 哮喘;非肾上腺素能胆碱能神经;血管活性肠肽;一氧化氮;P物质;神经生长因子
[中图分类号] R562 [文献标识码] A [文章编号] 1673-7210(2020)06(a)-0037-04
[Abstract] The etiology of asthma is complex， and the pathogenesis can be summarized as airway immune-inflammation mechanism， neuromodulation mechanism and their interaction. Airway non-adrenergic non-cholinergic (NANC) nerves and the neurotransmitters they release can interfere with the onset of asthma by regulating airway smooth muscle contraction， mucus secretion， reversible airway obstruction， and airway hyperresponsiveness. Nerve growth factor affects the plasticity of NANC nerve by regulating the neurokinin released by NANC nerve， such as substance P. The syndrome differentiation of asthma in traditional Chinese medicine is “wheezing disease” and “gasp syndrome”. Current studies on the regulation of airway inflammation in asthma by traditional Chinese medicine are more detailed， while reports on the intervention of traditional Chinese medicine in the NANC nerve and its neurotransmitters in asthma are rare. In this paper， the intervention of traditional Chinese medicine on the NANC nerve and its neurotransmitters and related downstream pathways， as well as the influence of nerve growth factor on the NANC nerve are briefly reviewed in recent years， in order to broaden the thinking for clinical and experimental studies.
[Key words] Asthma; Non-adrenergic non-cholinergic nerve; Vasoactive intestinal polypeptide; Nitric oxide; Substance P; Nerve growth factor
支气管哮喘是多种细胞及细胞组分参与的气道慢性炎症性疾病。全球超3亿人罹患此病，中国哮喘患者约3000万，且近年来全球哮喘患病率呈逐年增长的趋势[1]。一项流行病学调查显示[2]：2010～2011年中国哮喘患病率为1.24%，哮喘控制率仅为40.51%。控制气道炎症一直以来是治疗哮喘的中心环节。研究表明[3-4]，糖皮质激素作为改善气道炎症的主要药物，其治疗依从性不佳。哮喘神经调节机制的研究是时下的热点，气道神经纤维及其释放的神经递质靶向干预哮喘发病中气道上皮细胞，黏膜下腺体，气道平滑肌细胞，气道血管和炎症细胞等诸多环节[5]。非肾上腺素能非膽碱能(NANC)神经作为气道传出神经的一员，可分为抑制性非肾上腺素能非胆碱能(i-NANC)神经及兴奋性非肾上腺素能非胆碱能(e-NANC)神经。NANC神经释放的神经递质如血管活性肠肽(VIP)、一氧化氮(NO)、P物质(SP)可以加重或缓解哮喘病情。越来越多的研究表明，中医药通过调控NANC神经及其分泌的神经递质治疗哮喘，优势凸显[6-9]。
1 i-NANC神经
在哮喘的神经调节机制中，i-NANC神经是唯一具备舒张支气管功能的神经。i-NANC神经释放VIP和NO。VIP由i-NANC神经与免疫细胞所分泌，减弱炎症介质的释放;VIP特异性受体广泛存在于巨噬细胞、嗜酸性粒细胞、中性粒细胞等参与哮喘气道炎症的细胞中[10];VIP通过抑制小凹蛋白-1的表达与细胞外信号调节激酶1/2(ERK1/2)信号通路，减少气道平滑肌细胞增殖来避免哮喘发病过程中气道高反应性(AHR)[11]。因此，VIP直接或间接地参与哮喘气道免疫-炎症-神经等各个环节。VIP激活腺苷环磷酸酯(CAMP)及其蛋白激酶A(PKA)是抑制气道平滑肌增殖的经典途径。在此基础上，惠毅等[12]发现三拗汤合小承气汤通过增加哮喘小鼠肺组织VIP的表达，调控VIP-cAMP-PKA-水通道蛋白3、肿瘤坏死因子(TNF-α)、白细胞介素-1(IL-1)信号通路，对于哮喘的治疗有积极的意义。, http://www.100md.com(张硕 秦云普 毕明达)
[关键词] 哮喘;非肾上腺素能胆碱能神经;血管活性肠肽;一氧化氮;P物质;神经生长因子
[中图分类号] R562 [文献标识码] A [文章编号] 1673-7210(2020)06(a)-0037-04
[Abstract] The etiology of asthma is complex， and the pathogenesis can be summarized as airway immune-inflammation mechanism， neuromodulation mechanism and their interaction. Airway non-adrenergic non-cholinergic (NANC) nerves and the neurotransmitters they release can interfere with the onset of asthma by regulating airway smooth muscle contraction， mucus secretion， reversible airway obstruction， and airway hyperresponsiveness. Nerve growth factor affects the plasticity of NANC nerve by regulating the neurokinin released by NANC nerve， such as substance P. The syndrome differentiation of asthma in traditional Chinese medicine is “wheezing disease” and “gasp syndrome”. Current studies on the regulation of airway inflammation in asthma by traditional Chinese medicine are more detailed， while reports on the intervention of traditional Chinese medicine in the NANC nerve and its neurotransmitters in asthma are rare. In this paper， the intervention of traditional Chinese medicine on the NANC nerve and its neurotransmitters and related downstream pathways， as well as the influence of nerve growth factor on the NANC nerve are briefly reviewed in recent years， in order to broaden the thinking for clinical and experimental studies.
[Key words] Asthma; Non-adrenergic non-cholinergic nerve; Vasoactive intestinal polypeptide; Nitric oxide; Substance P; Nerve growth factor
支气管哮喘是多种细胞及细胞组分参与的气道慢性炎症性疾病。全球超3亿人罹患此病，中国哮喘患者约3000万，且近年来全球哮喘患病率呈逐年增长的趋势[1]。一项流行病学调查显示[2]：2010～2011年中国哮喘患病率为1.24%，哮喘控制率仅为40.51%。控制气道炎症一直以来是治疗哮喘的中心环节。研究表明[3-4]，糖皮质激素作为改善气道炎症的主要药物，其治疗依从性不佳。哮喘神经调节机制的研究是时下的热点，气道神经纤维及其释放的神经递质靶向干预哮喘发病中气道上皮细胞，黏膜下腺体，气道平滑肌细胞，气道血管和炎症细胞等诸多环节[5]。非肾上腺素能非膽碱能(NANC)神经作为气道传出神经的一员，可分为抑制性非肾上腺素能非胆碱能(i-NANC)神经及兴奋性非肾上腺素能非胆碱能(e-NANC)神经。NANC神经释放的神经递质如血管活性肠肽(VIP)、一氧化氮(NO)、P物质(SP)可以加重或缓解哮喘病情。越来越多的研究表明，中医药通过调控NANC神经及其分泌的神经递质治疗哮喘，优势凸显[6-9]。
1 i-NANC神经
在哮喘的神经调节机制中，i-NANC神经是唯一具备舒张支气管功能的神经。i-NANC神经释放VIP和NO。VIP由i-NANC神经与免疫细胞所分泌，减弱炎症介质的释放;VIP特异性受体广泛存在于巨噬细胞、嗜酸性粒细胞、中性粒细胞等参与哮喘气道炎症的细胞中[10];VIP通过抑制小凹蛋白-1的表达与细胞外信号调节激酶1/2(ERK1/2)信号通路，减少气道平滑肌细胞增殖来避免哮喘发病过程中气道高反应性(AHR)[11]。因此，VIP直接或间接地参与哮喘气道免疫-炎症-神经等各个环节。VIP激活腺苷环磷酸酯(CAMP)及其蛋白激酶A(PKA)是抑制气道平滑肌增殖的经典途径。在此基础上，惠毅等[12]发现三拗汤合小承气汤通过增加哮喘小鼠肺组织VIP的表达，调控VIP-cAMP-PKA-水通道蛋白3、肿瘤坏死因子(TNF-α)、白细胞介素-1(IL-1)信号通路，对于哮喘的治疗有积极的意义。, http://www.100md.com(张硕 秦云普 毕明达)