大气污染物二氧化硫对大鼠哮喘病模型气道平滑肌生物力学行为影响的研究
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摘要
哮喘(Asthma)作为一种慢性呼吸道疾病,正日益成为严重威胁人类健康的重大问题。令人遗憾的是,科学界对哮喘病的病因和发展过程至今还没有完全认识清楚,其病理机制也一直是医学上的重要难题。随着环境的不断恶化,大气中的污染物,包括二氧化硫(SO_2)与哮喘病的关系也日益受到关注。SO_2是大气中最常见的污染物之一,其对呼吸健康的危害早在上个世纪就引起了人们的重视。通过流行病学、免疫学等方面的大量研究,发现SO_2与哮喘病中包括免疫、炎症、氧化应激和氧化损伤等在内的多种病理机制有关。而有关SO_2对哮喘病中气道的生物力学特性的影响至今尚未见报道。与此对照的是,越来越多的研究表明,哮喘病人的气道组织,特别是气道平滑肌在病变过程中的结构与功能变化会导致其生物力学行为的改变,使其在受到外来刺激时发生过度收缩反应(AHR),从而引起气道过度狭窄和随之而来的呼吸阻碍,这是导致哮喘病成为高度危险疾病的共同的最终途径。由此,气道平滑肌收缩功能变异作为这一现象的终极原因成为目前研究的重点。因此,研究SO_2对于气道平滑肌生物力学特性的影响及其机理将有助于全面的认识和理解大气污染与哮喘病发生、发展的关系,为治理环境和有效防治哮喘病提供重要的参考依据。鉴于此,本文以四周龄Sprague Dawley(SD)大鼠为模型动物,以卵清蛋白(OVA)为致敏剂,建立了哮喘动物模型。在此基础上,以浓度为2 ppm(5.6 mg/m3)的SO_2对正常和哮喘模型动物进行长时间暴露刺激,并分别在个体、组织和细胞水平,研究了SO_2对气道平滑肌的影响,特别是SO_2对气道平滑肌细胞的生物力学行为的影响及其细胞骨架动力学机理。主要研究内容和结果如下:
1)根据模拟SO_2单因素大气污染环境的要求,设计并制作了内部空间SO_2浓度可控制的动物实验装置。该装置由气路管道系统、传感检测系统和智能控制等部分构成,不仅能够实现在局部封闭空间中模拟低浓度SO_2污染的大气环境,并具有操作性强和可靠性高的优点。经测试和较长时间的实际使用,结果表明该装置能够较好地模拟SO_2单因素大气污染环境,SO_2暴露刺激后的动物出现明显的生理病理变化,证明该装置为研究大鼠长时间暴露于低浓度SO_2环境后其生理病理变化过程和机制提供了一种可靠的技术平台。
2)研究了SO_2刺激对哮喘模型SD大鼠肺功能与气道组织结构的影响。首先以卵清蛋白(OVA)为致敏剂,刺激四周龄雄性SD大鼠,诱导其出现气道高反应性(AHR),并作为后续研究的哮喘动物模型。在此基础上,利用上述动物实验装置,对正常和哮喘模型SD大鼠进行长时间、低浓度的SO_2暴露刺激,并观察动物受SO_2刺激后的肺功能(Penh)和气道组织病理学变化。实验结果表明,与正常SD大鼠相比,哮喘模型SD大鼠在经受SO_2刺激后其Penh值显著提高(P<0.01),说明SO_2能显著地增强哮喘模型SD大鼠的气道高反应性,对正常SD大鼠的气道反应性则没有明显的作用。同时,肺组织病理切片苏木精-伊红(HE)染色观察和炎症因子检测结果均表明,SO_2能显著的恶化哮喘模型SD大鼠气道组织的炎症反应。
3)考察了SO_2刺激对SD大鼠气道平滑肌细胞收缩性的影响。首先采用酶消化法与组织块贴壁法相结合,获取SD大鼠原代气道平滑肌细胞,经细胞免疫化学方法鉴定并证明所获得原代气道平滑肌细胞的纯度较高,原代细胞经传代至2-5代时用于实验。结果证明,该方法具有高效、快捷、简单易操作、耗费低、细胞获取量高和纯度高等优点,为后续实验提供了充足的细胞来源。在此基础上,运用磁微粒扭转细胞测量系统(OMTC)测量SD大鼠原代气道平滑肌细胞的生物力学特性。气道平滑肌细胞分别取自正常SD大鼠(正常对照组),经受SO_2刺激的正常SD大鼠(SO_2组),哮喘模型SD大鼠(OVA组),经受SO_2刺激的哮喘模型SD大鼠(OVA+SO_2组)。细胞生物力学特性包括:细胞硬度、细胞硬度与频率的关系、细胞硬度对平滑肌收缩激动剂(氯化钾或组胺)的响应。实验结果表明,与正常对照组比较,其他三组SD大鼠(OVA组,OVA+SO_2组,SO_2组)的气道平滑肌细胞的硬度(G0)都显著增高(P<0.001,P<0.001和P<0.01),细胞硬度与频率之间呈较好的幂率关系且幂指数相差不大。更重要的是,在各实验组中只有OVA+SO_2组SD大鼠的气道平滑肌细胞对氯化钾(KCl)或组胺(histamine)作用的响应显著提高。
4)研究了SO_2衍生物在体外对正常SD大鼠气道平滑肌细胞生物力学特性的影响。由于大气中的SO_2在体内最终都是以其衍生物的形式作用于体内组织细胞,鉴于此,本文在体内实验的基础上,进一步研究了不同浓度下,SO_2衍生物(亚硫酸钠和亚硫酸氢钠的混合物,二者摩尔比为3:1)对体外培养的正常SD大鼠气道平滑肌细胞生物力学特性的效应。实验表明,在10-4~10-1 mmol/L的浓度范围内,SD大鼠气道平滑肌细胞的增殖能力、迁移能力、细胞收缩性都随SO_2衍生物浓度的增高而增强,同时细胞骨架蛋白F-actin的表达量也随之增加,并且这四者之间存在一定的相关性。这些实验结果提示,SO_2有可能通过增强气道平滑肌细胞的增殖能力、迁移能力和收缩性,引发气道组织的重构和气道高反应性,进而加剧哮喘症状的恶化。
综上所述,本课题针对大气污染物SO_2对正常或哮喘模型SD大鼠气道平滑肌生物力学行为的影响,分别在个体、组织和细胞水平上进行了研究。结果表明,SO_2刺激对于正常SD大鼠作用不大,但对哮喘模型SD大鼠气道平滑肌却有显著的影响,主要表现为哮喘模型SD大鼠在受到SO_2刺激时出现气道高反应性加剧,气道平滑肌组织增生,气道平滑肌细胞收缩性增强等症状。此外,体外培养的SD大鼠气道平滑肌细胞在受到SO_2衍生物直接刺激时,出现平滑肌细胞增殖、迁移和收缩能力增强的现象。这些结果提示,除了炎症反应外,SO_2有可能通过改变气道平滑肌的生物力学行为,特别是气道平滑肌细胞对收缩激动剂的响应来加剧气道高反应性等哮喘典型症状,这为从生物力学角度认识大气污染在哮喘病病理机制中的作用提供了有价值的参考依据,为提高哮喘病的防治水平提供了新的思路。
As a chronic respiratory disease, asthma is becoming an increasingly serious threat to human health. Unfortunately, the etiology and development of asthma are still not well understood, while the pathological mechanism of asthma remains difficult to elucidate. As the environment keeps deteriorating, the roles of air pollutants including sulfur dioxide (SO_2) in the pathogenesis of asthma are increasingly interested among investigators. SO_2 is one of the most common air pollutants,and its hazardous effects on respiratory health, especially on asthma has been concerned by many researchers as early as in the last century. Early studies focused on epidemiology, immunology and other aspects, which uncovered various roles of SO_2 in asthma pathology including immunology, oxidative stress and damage, and inflammatory mechanisms. However, there has been no pulished report regarding the effects of SO_2 on biomechanical behavior of the airway smmoth muscle (ASM). In contrast, there are more and more reports demonstrating that the structure and function of ASM are altered in asthma, which leads to changes of ASM biomechanical behaviors and ultimately results in airway hyperresponsiveness (AHR). In order to fully understand what does SO_2 do to asthmatics, therefore, it is imperative to study the effects of SO_2 exposure on ASM biomechanical behaviors. Motivated by this question, we established the animal model of asthma using newborn Sprague Dawley (SD) rats that were sensitized by ovalbumin (OVA). Based on this animal model, we exposed either normal or sensitized SD rats to a 2 ppm (5.6 mg/m3) low dose SO_2 for up to 4 wks, and suqsequently investigated the biomechanical behaviors of the ASM at either organism, tissue, or cell level. The specific and primary findings are described as follows:
1) According to the requirement to mimic SO_2 in the environment, we design and build a device that can control the concentration of SO_2 for animal model experiment. This device consists of gas pipeline system, sensor detection systems and intelligent control system, then we can simulate low concentration of SO_2 pollution in the micro-environment with the use of the device, and it has the maneuverability and high reliability properties. After being tested and used for a long period, the result shows that the device can well simulate the single factor of atmospheric SO_2 pollution, animals after being exposed to SO_2 showed significant changes in physiology, all these results proved that this device provided a strong technology platform for investigating the pathogenesis of SD rats, which were exposd to low concentration of SO_2 for a long time.
2) The effects of SO_2 exposure on the lung function and airway tissue structure of asthmatic SD rats. First, we used ovalbumin (OVA) as sensitization agent to stimulate the newborn male SD rats, induced airway hyperresponsiveness (AHR), and took them as the asthmatic animal model for the latter study. On this basis, we used the device talked above to stimulate the normal and asthmatic SD rats with low concentration of SO_2 for a long time, and then observed the lung function (Penh) and airway tissue pathological changes. The results show that, compared with the normal SD rats, after being exposed to SO_2, the values of Penh of asthmatic SD rats increased signicanctly (P<0.01), which indicates that SO_2 can significantly enhance the hyperresponsiveness of asthmatic SD rats, however, there is no significanct changes for the normal SD rats. Meanwhile, the lung histology hematoxylin-eosin (H&E) staining and the inflammatory factors assay results show that SO_2 can sinnificantly aggravate the inflammatory reaction of asthmatic SD rats.
3) The effects of SO_2 exposure on the contractility of airway smooth muscle cells from SD rats. First, we harvested primary airway smooth muscle cells from SD rat successfully by combining the enzymatic digestion method and tissue adherent method, and the immunocytochemistry test proved that the primary airway smooth muscle cells we obtained is relatively high purity, primary cells were passaged to 2-5 generations for the experiments. The results show that this method has the advantages of efficient, fast, easy to operate, low cost, and high volum and purity cells to obtain, and provides sufficient cell sources for the later experiments. On this basis, we measured the biomechanical properties of airway smooth muscle cells by using the optical magnetic twisting cytometry (OMTC). Airway smooth muscle cells were harvested from normal SD rats (control group), normal SD rat which were exposed to SO_2(SO_2 group), asthmatic SD rats(OVA group), and asthimatic SD rat which were exposed to SO_2(OVA+SO_2 group). Biomechanical properties including: cell stiffiness, relationship between cell stiffness and frequency, and cell stiffness response to smooth muscle contraction agonist (KCL, histamine). The results show that, compared with the control group, airway smooth muscle cell stiffness (G0) of the other three groups (OVA+SO_2 group, OVA group, and SO_2 group) was rank ordered and all significantly greater (P<0.001, P<0.001, or P<0.01), it shows a good power law relationship between cell stiffness and frequency, and there is no significant change in the power-law responses to different frequences. More importantly, among the four groups, only the airway smooth muscle cells from OVA+SO_2 group showed a significant response to postassium chloride (KCL) or histamine.
4) The effects of SO_2 derivatives on the biomechanical properties of normal airway smooth muscle cells in vitro. The SO_2 in the atmosphere are ultimately in the form of its derivatives affect the tissues in the body, therefore, on the basis of animal experiments, we investigated different concentrations of SO_2 derivatives (sodium sulfite and sodidum bisulfite, the molar tatio is 3:1) on normal SD rat primary airway smooth muscle cells in vitro. The results show that between 10-4 to 10-1 mmol/L, SO_2 derivatives can enhance the proliferation, migration and contraction of primary airway smooth muscle cells from SD rat, also they can increase the amount of the F-actins, and there exists correlations among the four factors. These results further suggest us a possible pathogenic mechanism which SO_2 worsening the symptoms of asthma can be explained that, by enhancing the proliferation, migration and contraction of airway smooth muscle cells, SO_2 causes remodeling of the airway, hyperresponsiveness, and then in turn exacerbate asthmatic symptoms.
In summary, in this paper, we described the biomechanical behavior of airway smooth muscle cells from normal and/or asthmatic SD rats affected by SO_2, respectively, and we studied in individuals, organizations, and celluar level. The results show that, SO_2 exposure can little affect normal SD rats, but it can significantly impact the airway smooth muscle cells from asthmatic SD rats, mainly on the aspects of increasing hyperresponsiveness, the layer of airway smooth muscle, and contractility of airway smooth muscle cells when the asthmatic SD rats were exposured to SO_2. In addition, SO_2 derivatives can enhance the proliferation, migration and contraction of primary airway smooth muscle cells from SD rat cultured in vitro. All these results suggest that, besides of inflammatory response, SO_2 can change the biomechanical behavior of airway smooth muscle cells, especially the response of airway smooth muscle cell to contraction agonist, then increase airway hyperresponsiveness and other typical symptoms of asthma, which providing valuable reference for understanding the role of air pollution in the pathogenesis of asthma on the aspects of biomechanics, also it provides a new way of thinking for improving prevention and treatment of asthma.
1)根据模拟SO_2单因素大气污染环境的要求,设计并制作了内部空间SO_2浓度可控制的动物实验装置。该装置由气路管道系统、传感检测系统和智能控制等部分构成,不仅能够实现在局部封闭空间中模拟低浓度SO_2污染的大气环境,并具有操作性强和可靠性高的优点。经测试和较长时间的实际使用,结果表明该装置能够较好地模拟SO_2单因素大气污染环境,SO_2暴露刺激后的动物出现明显的生理病理变化,证明该装置为研究大鼠长时间暴露于低浓度SO_2环境后其生理病理变化过程和机制提供了一种可靠的技术平台。
2)研究了SO_2刺激对哮喘模型SD大鼠肺功能与气道组织结构的影响。首先以卵清蛋白(OVA)为致敏剂,刺激四周龄雄性SD大鼠,诱导其出现气道高反应性(AHR),并作为后续研究的哮喘动物模型。在此基础上,利用上述动物实验装置,对正常和哮喘模型SD大鼠进行长时间、低浓度的SO_2暴露刺激,并观察动物受SO_2刺激后的肺功能(Penh)和气道组织病理学变化。实验结果表明,与正常SD大鼠相比,哮喘模型SD大鼠在经受SO_2刺激后其Penh值显著提高(P<0.01),说明SO_2能显著地增强哮喘模型SD大鼠的气道高反应性,对正常SD大鼠的气道反应性则没有明显的作用。同时,肺组织病理切片苏木精-伊红(HE)染色观察和炎症因子检测结果均表明,SO_2能显著的恶化哮喘模型SD大鼠气道组织的炎症反应。
3)考察了SO_2刺激对SD大鼠气道平滑肌细胞收缩性的影响。首先采用酶消化法与组织块贴壁法相结合,获取SD大鼠原代气道平滑肌细胞,经细胞免疫化学方法鉴定并证明所获得原代气道平滑肌细胞的纯度较高,原代细胞经传代至2-5代时用于实验。结果证明,该方法具有高效、快捷、简单易操作、耗费低、细胞获取量高和纯度高等优点,为后续实验提供了充足的细胞来源。在此基础上,运用磁微粒扭转细胞测量系统(OMTC)测量SD大鼠原代气道平滑肌细胞的生物力学特性。气道平滑肌细胞分别取自正常SD大鼠(正常对照组),经受SO_2刺激的正常SD大鼠(SO_2组),哮喘模型SD大鼠(OVA组),经受SO_2刺激的哮喘模型SD大鼠(OVA+SO_2组)。细胞生物力学特性包括:细胞硬度、细胞硬度与频率的关系、细胞硬度对平滑肌收缩激动剂(氯化钾或组胺)的响应。实验结果表明,与正常对照组比较,其他三组SD大鼠(OVA组,OVA+SO_2组,SO_2组)的气道平滑肌细胞的硬度(G0)都显著增高(P<0.001,P<0.001和P<0.01),细胞硬度与频率之间呈较好的幂率关系且幂指数相差不大。更重要的是,在各实验组中只有OVA+SO_2组SD大鼠的气道平滑肌细胞对氯化钾(KCl)或组胺(histamine)作用的响应显著提高。
4)研究了SO_2衍生物在体外对正常SD大鼠气道平滑肌细胞生物力学特性的影响。由于大气中的SO_2在体内最终都是以其衍生物的形式作用于体内组织细胞,鉴于此,本文在体内实验的基础上,进一步研究了不同浓度下,SO_2衍生物(亚硫酸钠和亚硫酸氢钠的混合物,二者摩尔比为3:1)对体外培养的正常SD大鼠气道平滑肌细胞生物力学特性的效应。实验表明,在10-4~10-1 mmol/L的浓度范围内,SD大鼠气道平滑肌细胞的增殖能力、迁移能力、细胞收缩性都随SO_2衍生物浓度的增高而增强,同时细胞骨架蛋白F-actin的表达量也随之增加,并且这四者之间存在一定的相关性。这些实验结果提示,SO_2有可能通过增强气道平滑肌细胞的增殖能力、迁移能力和收缩性,引发气道组织的重构和气道高反应性,进而加剧哮喘症状的恶化。
综上所述,本课题针对大气污染物SO_2对正常或哮喘模型SD大鼠气道平滑肌生物力学行为的影响,分别在个体、组织和细胞水平上进行了研究。结果表明,SO_2刺激对于正常SD大鼠作用不大,但对哮喘模型SD大鼠气道平滑肌却有显著的影响,主要表现为哮喘模型SD大鼠在受到SO_2刺激时出现气道高反应性加剧,气道平滑肌组织增生,气道平滑肌细胞收缩性增强等症状。此外,体外培养的SD大鼠气道平滑肌细胞在受到SO_2衍生物直接刺激时,出现平滑肌细胞增殖、迁移和收缩能力增强的现象。这些结果提示,除了炎症反应外,SO_2有可能通过改变气道平滑肌的生物力学行为,特别是气道平滑肌细胞对收缩激动剂的响应来加剧气道高反应性等哮喘典型症状,这为从生物力学角度认识大气污染在哮喘病病理机制中的作用提供了有价值的参考依据,为提高哮喘病的防治水平提供了新的思路。
As a chronic respiratory disease, asthma is becoming an increasingly serious threat to human health. Unfortunately, the etiology and development of asthma are still not well understood, while the pathological mechanism of asthma remains difficult to elucidate. As the environment keeps deteriorating, the roles of air pollutants including sulfur dioxide (SO_2) in the pathogenesis of asthma are increasingly interested among investigators. SO_2 is one of the most common air pollutants,and its hazardous effects on respiratory health, especially on asthma has been concerned by many researchers as early as in the last century. Early studies focused on epidemiology, immunology and other aspects, which uncovered various roles of SO_2 in asthma pathology including immunology, oxidative stress and damage, and inflammatory mechanisms. However, there has been no pulished report regarding the effects of SO_2 on biomechanical behavior of the airway smmoth muscle (ASM). In contrast, there are more and more reports demonstrating that the structure and function of ASM are altered in asthma, which leads to changes of ASM biomechanical behaviors and ultimately results in airway hyperresponsiveness (AHR). In order to fully understand what does SO_2 do to asthmatics, therefore, it is imperative to study the effects of SO_2 exposure on ASM biomechanical behaviors. Motivated by this question, we established the animal model of asthma using newborn Sprague Dawley (SD) rats that were sensitized by ovalbumin (OVA). Based on this animal model, we exposed either normal or sensitized SD rats to a 2 ppm (5.6 mg/m3) low dose SO_2 for up to 4 wks, and suqsequently investigated the biomechanical behaviors of the ASM at either organism, tissue, or cell level. The specific and primary findings are described as follows:
1) According to the requirement to mimic SO_2 in the environment, we design and build a device that can control the concentration of SO_2 for animal model experiment. This device consists of gas pipeline system, sensor detection systems and intelligent control system, then we can simulate low concentration of SO_2 pollution in the micro-environment with the use of the device, and it has the maneuverability and high reliability properties. After being tested and used for a long period, the result shows that the device can well simulate the single factor of atmospheric SO_2 pollution, animals after being exposed to SO_2 showed significant changes in physiology, all these results proved that this device provided a strong technology platform for investigating the pathogenesis of SD rats, which were exposd to low concentration of SO_2 for a long time.
2) The effects of SO_2 exposure on the lung function and airway tissue structure of asthmatic SD rats. First, we used ovalbumin (OVA) as sensitization agent to stimulate the newborn male SD rats, induced airway hyperresponsiveness (AHR), and took them as the asthmatic animal model for the latter study. On this basis, we used the device talked above to stimulate the normal and asthmatic SD rats with low concentration of SO_2 for a long time, and then observed the lung function (Penh) and airway tissue pathological changes. The results show that, compared with the normal SD rats, after being exposed to SO_2, the values of Penh of asthmatic SD rats increased signicanctly (P<0.01), which indicates that SO_2 can significantly enhance the hyperresponsiveness of asthmatic SD rats, however, there is no significanct changes for the normal SD rats. Meanwhile, the lung histology hematoxylin-eosin (H&E) staining and the inflammatory factors assay results show that SO_2 can sinnificantly aggravate the inflammatory reaction of asthmatic SD rats.
3) The effects of SO_2 exposure on the contractility of airway smooth muscle cells from SD rats. First, we harvested primary airway smooth muscle cells from SD rat successfully by combining the enzymatic digestion method and tissue adherent method, and the immunocytochemistry test proved that the primary airway smooth muscle cells we obtained is relatively high purity, primary cells were passaged to 2-5 generations for the experiments. The results show that this method has the advantages of efficient, fast, easy to operate, low cost, and high volum and purity cells to obtain, and provides sufficient cell sources for the later experiments. On this basis, we measured the biomechanical properties of airway smooth muscle cells by using the optical magnetic twisting cytometry (OMTC). Airway smooth muscle cells were harvested from normal SD rats (control group), normal SD rat which were exposed to SO_2(SO_2 group), asthmatic SD rats(OVA group), and asthimatic SD rat which were exposed to SO_2(OVA+SO_2 group). Biomechanical properties including: cell stiffiness, relationship between cell stiffness and frequency, and cell stiffness response to smooth muscle contraction agonist (KCL, histamine). The results show that, compared with the control group, airway smooth muscle cell stiffness (G0) of the other three groups (OVA+SO_2 group, OVA group, and SO_2 group) was rank ordered and all significantly greater (P<0.001, P<0.001, or P<0.01), it shows a good power law relationship between cell stiffness and frequency, and there is no significant change in the power-law responses to different frequences. More importantly, among the four groups, only the airway smooth muscle cells from OVA+SO_2 group showed a significant response to postassium chloride (KCL) or histamine.
4) The effects of SO_2 derivatives on the biomechanical properties of normal airway smooth muscle cells in vitro. The SO_2 in the atmosphere are ultimately in the form of its derivatives affect the tissues in the body, therefore, on the basis of animal experiments, we investigated different concentrations of SO_2 derivatives (sodium sulfite and sodidum bisulfite, the molar tatio is 3:1) on normal SD rat primary airway smooth muscle cells in vitro. The results show that between 10-4 to 10-1 mmol/L, SO_2 derivatives can enhance the proliferation, migration and contraction of primary airway smooth muscle cells from SD rat, also they can increase the amount of the F-actins, and there exists correlations among the four factors. These results further suggest us a possible pathogenic mechanism which SO_2 worsening the symptoms of asthma can be explained that, by enhancing the proliferation, migration and contraction of airway smooth muscle cells, SO_2 causes remodeling of the airway, hyperresponsiveness, and then in turn exacerbate asthmatic symptoms.
In summary, in this paper, we described the biomechanical behavior of airway smooth muscle cells from normal and/or asthmatic SD rats affected by SO_2, respectively, and we studied in individuals, organizations, and celluar level. The results show that, SO_2 exposure can little affect normal SD rats, but it can significantly impact the airway smooth muscle cells from asthmatic SD rats, mainly on the aspects of increasing hyperresponsiveness, the layer of airway smooth muscle, and contractility of airway smooth muscle cells when the asthmatic SD rats were exposured to SO_2. In addition, SO_2 derivatives can enhance the proliferation, migration and contraction of primary airway smooth muscle cells from SD rat cultured in vitro. All these results suggest that, besides of inflammatory response, SO_2 can change the biomechanical behavior of airway smooth muscle cells, especially the response of airway smooth muscle cell to contraction agonist, then increase airway hyperresponsiveness and other typical symptoms of asthma, which providing valuable reference for understanding the role of air pollution in the pathogenesis of asthma on the aspects of biomechanics, also it provides a new way of thinking for improving prevention and treatment of asthma.
引文
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