瞬时受体电位通道和神经肽表达上调在甲醛诱导型支气管哮喘小鼠模型中的作用
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摘要
甲醛是一种常见的装修型化学性室内空气污染物,也是一种全球性的环境污染物。它具有污染来源广、时间长、水平高、毒性种类多等特点。甲醛对健康的影响主要包括：呼吸道和眼部急性刺激作用、神经行为改变、生殖毒性、免疫毒性、氧化损伤、遗传毒性等诸多方面。近年来,世界各地哮喘发病率都在快速增长,但致敏原的种类和数量并未发生显著变化。非过敏原性空气污染物的大量增加被认为是原因之一,但其分子机制尚不清楚。不断有研究表明,甲醛暴露可以引起哮喘或哮喘样症状。为了探讨甲醛是否可以诱发哮喘和其可能的发病机理,本论文进行了如下体内研究：
1.甲醛导致中枢神经系统神经源性炎症及氧化性损伤发生：对Balb/c小鼠连续甲醛气态暴露7天,每天8小时,设(a)对照组；(b)0.5mg/m3甲醛组；(c)3.0mg/m3甲醛组,在3.0mg/m3水平甲醛作用下,与对照组相比较：(1)脑组织谷胱甘肽(GSH)含量呈极显著性降低(p<0.01),脊髓组织GSH含量呈显著性降低(p<0.05)；(2)脑组织丙二醛(MDA)含量呈极显著性增高(p<0.01),脊髓组织MDA含量呈显著性增高(p<0.05)；(3)脑组织促炎症细胞因子白介素-IL-1β含量呈显著性增高(p<0.05),脊髓组织IL-1β含量呈极显著性增高(p<0.01)；(4)脑组织速激肽物质P含量(substance P)呈极显著增高(p<0.01),脊髓组织substance P含量呈极显著性增高(p<0.01)。本实验说明甲醛可以导致中枢神经系统神经性炎症及氧化损伤发生。
2. TRPA1介导甲醛所致气道炎症发生：对Balb/c小鼠连续甲醛气态暴露10天,每天8小时。设(a)对照组；(b)0.5mg/m3甲醛组；(c)1.0mg/m3甲醛组；(d)3.0mg,/m3甲醛组；(e)3.0mg/m3+HC-030031[瞬时受体电位通道亚型A1(TRPA1)拮抗剂]组,发现在3.0mg/m3甲醛水平作用下,与对照组相比较：(1)血清中免疫球蛋白E(1gE)水平显著上升(p<0.01)；(2)小鼠肺泡灌洗液中白介素-4(IL-4)含量显著上调(p<0.01)；(3)血清中超氧化物歧化酶(SOD)活力显著下降(p<0.01),MDA含量显著上升(p<0.01)；对3.0mg/m3甲醛给予HC-030031(50mg/kg)处理,发现IgE水平下调(p<0.01),IL-4水平下调(p<0.01), SOD活力上升(p<0.05),MDA含量下降(p<0.05)；本实验说明TRPA1可以介导甲醛所致气道炎症发生和氧化损伤作用。
3. TRPA1和TRPV1通道蛋白介导气态甲醛诱导哮喘作用：对Balb/c雄性小鼠甲醛动态式气态暴露4周,每天6小时,卵清蛋白(OVA)致敏并激发1周建立甲醛诱导哮喘模型。设(a)对照组；(b) OVA组；(c)3.0mg/m3甲醛组；(d)3.Omg/m3甲醛+OVA组；(e)3.0mg/m3甲醛+OVA+HC-030031组；(f)3.0mg/m3甲醛+OVA+capsazepine(瞬时受体电位通道亚型V1拮抗剂)组,分别测定气道高反应性、气道重塑、气道炎症相关指标。与对照组相比,甲醛组气道反应性和肺部病理学变化并不明显,但嗜酸性粒细胞计数显著增高(p<0.05),血清总IgE含量明显上调(p<0.01),IL-4含量显著升高(p<0.01), substance P表达上调(p<0.01),降钙素基因相关肽(CGRP)表达上调(p<0.05),IL-1p水平升高(p<0.01)；与OVA组相比,甲醛+OVA组呈现显著气道高反应性和气道重塑现象,嗜酸性粒细胞计数显著增高(p<0.01),血清中总IgE水平显著上调(p<0.01),肺组织IL-4含量显著升高(p<0.01)；substance P表达上调(p<0.01)、CGRP表达上调(p<0.01), IL-1β水平升高(p<0.01)。对FA+OVA组给予TRPA1通道拮抗剂HC-030031和TRPV1通道拮抗剂CPZ,结果显示：拮抗组与模型组相比,(1)气道高反应性显著降低：(2)肺组织病理变化明显好转；(3)小鼠肺泡灌洗液中嗜酸性粒细胞计数降低(p<0.01),肺组织IL-4含量显著降低(p<0.01),血清中IgE水平降低(p<0.01)；(4)substance P表达下调(p<0.01)、CGRP表达下调(p<0.05), IL-1β水平无显著变化(p>0.05)。结果说明甲醛可以提高哮喘的发病风险,它可以直接导致神经源性气道炎症,并以免疫佐剂身份加重OVA过敏原导致气道炎症；Substance P和CGRP参与甲醛诱导哮喘的病理生理过程,TRPA1和TRPV1通道蛋白介导气态甲醛诱导哮喘作用并调控神经肽的释放。
Formaldehyde (FA), a kind of popular indoor air pollutant, and it is a global environmental pollutant. The effects of formaldehyde on human health include eyes and upper respiratory irritancy, neurotoxicity, reproductive toxicity, allery and immunological effects, oxidative damage, genotoxicity. Asthma disease rates keep on increasing all over the world, especially in western societies over last40years.Discoveryof risk factors for the rise in asthma cases is essentially important, although some studies have indicated that indoor formaldehyde might worsen allergies andbe an underlying factor for increasing incidence andseverity of asthma, the mechanism was not clear and needs to be further investigated. In order to explore whether formaldehyde could involve in asthma and its molecular mechanism in the process of asthma, experiments in vivo were employed.
1. Balb/c mice in three experimental groups were exposed to:(a) vehicle control;(b) formaldehyde (0.5mg/m3);(c) formaldehyde (3.0mg/m3). The mice were exposed to FA for8h and7day respectively. Then evaluate the content of malonyldialdehyde (MDA), glutathione (GSH), interleukin-1β (IL-1β) and substance P in brain and spinal cord.3.0mg/m3formaldehyde exposure led to a significant increase in levels of MDA, IL-1β and substance P, decreases in GSH level in two tissues. The result showed that high concentration of gaseous formaldehyde induced neurotoxicity of central nervous system. The mechanism of it perhaps relate to oxidative damage of brain and spinal cord.
2. Balb/c mice in five experimental groups were exposed to:(a) vehicle control;(b) formaldehyde (0.5mg/m3);(c) formaldehyde (1.0mg/m3);(d) formaldehyde (3.0mg/m3);(e) formaldehyde (3.0mg/m3)+HC-030031[antagonist of transient receptor potential ankyrin1(TRPA1)]. The mice were exposed to FA for8h and10day respectively. Then evaluate the content of MDA, superoxide dismutase (SOD) and immunoglobulin E (IgE) in serum, interleukin-4(IL-4) in bronchialveolar lavage fluid.3.0mg/m3formaldehyde exposure led to a significant increase in such biomarker and changes in the levels of biomarker could be inhibited by HC-030031. The result showed that TRPA1receptor channel mediated formaldehyde induced airway inflammation and caused oxidative damage, chronic respiratory disease induced by formaldehyde may associate with the TRPA1receptor channel.
3. The irritant effect and immune adjuvant effect are the two possible pathways for formaldehyde to promote asthma. Balb/c mice in six experimental groups were exposed to:(a) vehicle control;(b) ovalbumin;(c) formaldehyde (3.0mg/m3);(d) ovalbumin+formaldehyde (3.0mg/m3);(e) ovalbumin+formaldehyde (3.0mg/m3)+HC-030031(antagonist of transient receptor potential ankyrin1);(f) ovalbumin+formaldehyde (3.0mg/m3)+capsazepine (antagonist of transient receptor potential vanilloid1). Experiments were conductedafter4weeks of exposure and1-week challenge with aerosolized ovalbumin. Airway hyper-responsiveness, pulmonary tissue damage, eosinophil infiltration, and increased levels of IL-4, IL-1β, IgE, substance P and calcitonin gene-related peptide (CGRP) in lung tissues werefound in the ovalbumin+formaldehyde (3.0mg/m3) group compared with the values seen in ovalbumin-only immunized mice. Except for interleukin-1β levels, other changesin the levels of biomarker could be inhibited by HC-030031and capsazepine. Formaldehyde might be one of key risk factor for the rise in asthma cases. Transient receptor potential ion channels and neuropeptides have important roles in formaldehyde promoted-asthma.
1.甲醛导致中枢神经系统神经源性炎症及氧化性损伤发生：对Balb/c小鼠连续甲醛气态暴露7天,每天8小时,设(a)对照组；(b)0.5mg/m3甲醛组；(c)3.0mg/m3甲醛组,在3.0mg/m3水平甲醛作用下,与对照组相比较：(1)脑组织谷胱甘肽(GSH)含量呈极显著性降低(p<0.01),脊髓组织GSH含量呈显著性降低(p<0.05)；(2)脑组织丙二醛(MDA)含量呈极显著性增高(p<0.01),脊髓组织MDA含量呈显著性增高(p<0.05)；(3)脑组织促炎症细胞因子白介素-IL-1β含量呈显著性增高(p<0.05),脊髓组织IL-1β含量呈极显著性增高(p<0.01)；(4)脑组织速激肽物质P含量(substance P)呈极显著增高(p<0.01),脊髓组织substance P含量呈极显著性增高(p<0.01)。本实验说明甲醛可以导致中枢神经系统神经性炎症及氧化损伤发生。
2. TRPA1介导甲醛所致气道炎症发生：对Balb/c小鼠连续甲醛气态暴露10天,每天8小时。设(a)对照组；(b)0.5mg/m3甲醛组；(c)1.0mg/m3甲醛组；(d)3.0mg,/m3甲醛组；(e)3.0mg/m3+HC-030031[瞬时受体电位通道亚型A1(TRPA1)拮抗剂]组,发现在3.0mg/m3甲醛水平作用下,与对照组相比较：(1)血清中免疫球蛋白E(1gE)水平显著上升(p<0.01)；(2)小鼠肺泡灌洗液中白介素-4(IL-4)含量显著上调(p<0.01)；(3)血清中超氧化物歧化酶(SOD)活力显著下降(p<0.01),MDA含量显著上升(p<0.01)；对3.0mg/m3甲醛给予HC-030031(50mg/kg)处理,发现IgE水平下调(p<0.01),IL-4水平下调(p<0.01), SOD活力上升(p<0.05),MDA含量下降(p<0.05)；本实验说明TRPA1可以介导甲醛所致气道炎症发生和氧化损伤作用。
3. TRPA1和TRPV1通道蛋白介导气态甲醛诱导哮喘作用：对Balb/c雄性小鼠甲醛动态式气态暴露4周,每天6小时,卵清蛋白(OVA)致敏并激发1周建立甲醛诱导哮喘模型。设(a)对照组；(b) OVA组；(c)3.0mg/m3甲醛组；(d)3.Omg/m3甲醛+OVA组；(e)3.0mg/m3甲醛+OVA+HC-030031组；(f)3.0mg/m3甲醛+OVA+capsazepine(瞬时受体电位通道亚型V1拮抗剂)组,分别测定气道高反应性、气道重塑、气道炎症相关指标。与对照组相比,甲醛组气道反应性和肺部病理学变化并不明显,但嗜酸性粒细胞计数显著增高(p<0.05),血清总IgE含量明显上调(p<0.01),IL-4含量显著升高(p<0.01), substance P表达上调(p<0.01),降钙素基因相关肽(CGRP)表达上调(p<0.05),IL-1p水平升高(p<0.01)；与OVA组相比,甲醛+OVA组呈现显著气道高反应性和气道重塑现象,嗜酸性粒细胞计数显著增高(p<0.01),血清中总IgE水平显著上调(p<0.01),肺组织IL-4含量显著升高(p<0.01)；substance P表达上调(p<0.01)、CGRP表达上调(p<0.01), IL-1β水平升高(p<0.01)。对FA+OVA组给予TRPA1通道拮抗剂HC-030031和TRPV1通道拮抗剂CPZ,结果显示：拮抗组与模型组相比,(1)气道高反应性显著降低：(2)肺组织病理变化明显好转；(3)小鼠肺泡灌洗液中嗜酸性粒细胞计数降低(p<0.01),肺组织IL-4含量显著降低(p<0.01),血清中IgE水平降低(p<0.01)；(4)substance P表达下调(p<0.01)、CGRP表达下调(p<0.05), IL-1β水平无显著变化(p>0.05)。结果说明甲醛可以提高哮喘的发病风险,它可以直接导致神经源性气道炎症,并以免疫佐剂身份加重OVA过敏原导致气道炎症；Substance P和CGRP参与甲醛诱导哮喘的病理生理过程,TRPA1和TRPV1通道蛋白介导气态甲醛诱导哮喘作用并调控神经肽的释放。
Formaldehyde (FA), a kind of popular indoor air pollutant, and it is a global environmental pollutant. The effects of formaldehyde on human health include eyes and upper respiratory irritancy, neurotoxicity, reproductive toxicity, allery and immunological effects, oxidative damage, genotoxicity. Asthma disease rates keep on increasing all over the world, especially in western societies over last40years.Discoveryof risk factors for the rise in asthma cases is essentially important, although some studies have indicated that indoor formaldehyde might worsen allergies andbe an underlying factor for increasing incidence andseverity of asthma, the mechanism was not clear and needs to be further investigated. In order to explore whether formaldehyde could involve in asthma and its molecular mechanism in the process of asthma, experiments in vivo were employed.
1. Balb/c mice in three experimental groups were exposed to:(a) vehicle control;(b) formaldehyde (0.5mg/m3);(c) formaldehyde (3.0mg/m3). The mice were exposed to FA for8h and7day respectively. Then evaluate the content of malonyldialdehyde (MDA), glutathione (GSH), interleukin-1β (IL-1β) and substance P in brain and spinal cord.3.0mg/m3formaldehyde exposure led to a significant increase in levels of MDA, IL-1β and substance P, decreases in GSH level in two tissues. The result showed that high concentration of gaseous formaldehyde induced neurotoxicity of central nervous system. The mechanism of it perhaps relate to oxidative damage of brain and spinal cord.
2. Balb/c mice in five experimental groups were exposed to:(a) vehicle control;(b) formaldehyde (0.5mg/m3);(c) formaldehyde (1.0mg/m3);(d) formaldehyde (3.0mg/m3);(e) formaldehyde (3.0mg/m3)+HC-030031[antagonist of transient receptor potential ankyrin1(TRPA1)]. The mice were exposed to FA for8h and10day respectively. Then evaluate the content of MDA, superoxide dismutase (SOD) and immunoglobulin E (IgE) in serum, interleukin-4(IL-4) in bronchialveolar lavage fluid.3.0mg/m3formaldehyde exposure led to a significant increase in such biomarker and changes in the levels of biomarker could be inhibited by HC-030031. The result showed that TRPA1receptor channel mediated formaldehyde induced airway inflammation and caused oxidative damage, chronic respiratory disease induced by formaldehyde may associate with the TRPA1receptor channel.
3. The irritant effect and immune adjuvant effect are the two possible pathways for formaldehyde to promote asthma. Balb/c mice in six experimental groups were exposed to:(a) vehicle control;(b) ovalbumin;(c) formaldehyde (3.0mg/m3);(d) ovalbumin+formaldehyde (3.0mg/m3);(e) ovalbumin+formaldehyde (3.0mg/m3)+HC-030031(antagonist of transient receptor potential ankyrin1);(f) ovalbumin+formaldehyde (3.0mg/m3)+capsazepine (antagonist of transient receptor potential vanilloid1). Experiments were conductedafter4weeks of exposure and1-week challenge with aerosolized ovalbumin. Airway hyper-responsiveness, pulmonary tissue damage, eosinophil infiltration, and increased levels of IL-4, IL-1β, IgE, substance P and calcitonin gene-related peptide (CGRP) in lung tissues werefound in the ovalbumin+formaldehyde (3.0mg/m3) group compared with the values seen in ovalbumin-only immunized mice. Except for interleukin-1β levels, other changesin the levels of biomarker could be inhibited by HC-030031and capsazepine. Formaldehyde might be one of key risk factor for the rise in asthma cases. Transient receptor potential ion channels and neuropeptides have important roles in formaldehyde promoted-asthma.
引文
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