肺表面活性物质对支气管哮喘小鼠治疗作用的研究
摘要
支气管哮喘是一种由多种炎症细胞、细胞组分及神经递质参与的气道慢性非特异性炎症。随着工业水平的提高,哮喘发病率呈全球性上升趋势,当前全世界大约有3亿人罹患哮喘病,每年死于哮喘病的人达18万多,哮喘正成为严重困扰人们健康生活的威胁。因此,对于哮喘的防治成为各国学者日益关心的话题。目前,支气管哮喘的治疗方法以抗炎、药物改善症状和免疫治疗为基本治疗方法[1]。肺表面活性物质(PS)主要应用于新生儿呼吸窘迫综合征(NRDS)。随着人们对PS的不断认识,PS还可应用于急性呼吸窘迫综合征(ARDS)、肺炎、胎粪吸入综合征(MAS)等疾病治疗。近10多年来,人们开始重视PS在哮喘病理生理中的作用。越来越多的证据表明,哮喘患者体内存在PS量的不足和功能的异常,因此人们也越来越重视PS在哮喘治疗上的应用。在本实验中,我们通过建立小鼠哮喘模型来观察PS干预前、后小鼠哮喘模型血清、肺组织中一氧化氮(NO)、丙二醛(MDA)含量和一氧化氮合成酶(NOS)、超氧化物歧化酶(SOD)活性变化;流式细胞术法检测CD4CD25阳性细胞数;应用免疫组织化学法检测PS治疗前后哮喘小鼠肺组织白介素-4(IL-4)、干扰素-γ(IFN-γ)、诱导型一氧化氮合成酶(iNOS)、肺表面活性蛋白-A(SP-A)、嗜酸性粒细胞趋化因子(Eotaxin)表达的改变,从而揭示哮喘小鼠体内上述指标的变化及PS对其影响,探讨哮喘治疗的新途径。
Bronchial asthma is a chronic airway inflammatory disease that involves many inflammatory cells, specially mast cell (MC), eosinophile granulocyte (EOS), T lymphocyte and it is accompanied by the airway hyperreactivity and the remodeling of the airway. The cause of asthma is complicated, the pathogenesis is not yet completely perspicuous. In asthma, the accumulation and activation of Eos in airway inflammation acts crucial function, but the display function of Eos needs chemotatic factor. Among the chemotatic factors, only the eotaxin is able to have specific chemotaxis and activation on Eos, is playing up the very important role in the asthmatic airway inflammation.The activate inflammatory cell may produce massive oxygen free radical (OFR). Malonal dehyde (MDA) is an important metabolite in the process of OFR inducing lipin peroxidation. MDA may make the asthma patient in vivo active oxygen to increase, the lipin peroxidation strengthens, destroy the biomembrane, thus aggravation inflammation responded does and harm to the airway epithelial cell, which has the vital role to asthma AHR production. Erythrocuprein (SOD) is the main antioxidasethe and ultra oxygen free radical scavenging agent in organism. Massive OFR consumes massive SOD, causes organism oxidation resistance ability to be low, the oxide compound to store up and the lipin peroxidation damage. MDA and SOD are together representing in vivo oxidation resistance-oxidation system condition. The nitrogen monoxide (NO) synthesis key enzyme is nitrogen monoxide synzyme (NOS). The activated inflammation cell and the inflammatory factor may cause iNOS to express obviously actively and synthesize massive NO, aggravates inflammatory reaction, then causes the lung damage. Moreover, NO and OFR may affect mutually, aggravate asthma outbreak. The T lymphocyte holds the important status in asthma morbidity. Most of the scholars thought the imbalance of two hypotypes kinds of auxiliary T lymphocyte (Th1 and Th2) is the important mechanism when asthma occurs. The Th1 cell mainly secretes interleukin-2 (IL-2), the interferon-gamma (IFN-γ) and the tumor necrosis factor-alpha (TNF-α), the Th2 cell mainly secretes IL-4, IL-5, IL-13 and granular cell-macrophage colony stimulation factor (GM-CSF) and so on. When asthma occurs, the Th2 cell activation accentuates and the Th1 function reduces, this is the pathogenesis key link in the asthma. But this theory could not explain all the asthmatic clinical manifestations and therapeutic reactions. The importance of Treg in asthma has been gradually recognized.Treg was the full-time suppressor, which has the role of immunological regulation. A great number of investigations revealed that Treg may demonstrate significant roles in the development of asthma.
Along with the deep explorationof asthma pathogenesis, it was found that in the bronchoalveolar lavage (BALF) of asthma animal experimentation and asthma patient, pulmonary surfactant (PS) not only has the quantity reduction and the ingredient unusual, moreover also has the function detuning. PS is synthesized and secreted by the pulmonary alveolus epidermisⅡCell (AT-Ⅱ), it is one kind of compound phosphatide which has high surface activity. The earliest discovery of PS was originated from the NRDS research, the people discovered that the PS quantity in NRDS was insufficient and the function was abnormal. Along with unceasing recognition and research to PS, the people discovered gradually besides NRDS, very many diseases like ARDS, pneumonia, bronchial asthma disease and so on all have abnormal PS.Pulmonary surfactant protein-A(SP-A) has the highest content, the most intense expression and the richest signal protein in PS, it is one of the important ingredients in pulmonary surfactant. Because PS can reduce the lung surface tension, prevent the pulmonary edema and has the immunity adjustment and the defense function, reduces airway hyperreactivity and so on, therefore PS possibly has the treatment function to asthma.
Until now in the world people have not found the permanent control method to asthma. At present, the overwhelming majority patient's asthma symptom may be under the good control after the standardized treatment. But asthma is one kind of heterogeneity disease, part of the patients are unsatisfactory to the conventional treatment. This experiment through the establishment bronchial asthma mice model, observe the changes before and after applying the therapy with PS, which concluded the content of NO, MDA and the vigor of NOS and SOD in serum and lung tissue with asthma. Detect CD4CD25 positive cells by the method of flow cytometry.The changes of expression in the lung tissue of asthma mouse before and after intervention with PS can be detected by immunohistochemical method, which included IL-4,IFN-γ, iNOS, SP-A and Eotaxin.
Method:
1. To discuss the treatment function of PS to the asthma mouse model, we randomly divided BALB/c mice into four groups: the PS-treated group, the hormone-treated group, the asthma group and the normal control group, and there were twelve mice in each group. Asthmatic mice were sensitized on days 1 and 14 by intraperitoneal injection of 10μg ovalbumin, and on days 21-27, after the initial sensitization, the mice were challenged for 30 min with an aerosol of 1% (w/v) OVA in saline (or with saline as a control) using an ultrasonic nebulizer. The PS-treated group and the hormone-treated group were treated for 30 min with PS or glucocorticoid (Budesonide) before each allergen challenge for 7 days. After the experiment each group of mice were beheaded to draw blood and the lung tissue. We observed bronchial pathological changes under the light microscope after the lung tissue pathological section were HE dyed.
2. We selected the BALB/c mouse, used the same method of randomization and model establishment as the above. Using the nitrate reductases and the spectrophotometric method determined and compared the NO content and the NOS vigor expression level in asthma mouse model blood serum and the lung before and after the PS was applied.
3. In the influence experimental study of PS to SOD and MDA in asthma mouse, we selected the BALB/C mouse, used the same method of randomization and model establishment as the above. Using the xanthine oxidase and the TBA color method examination, we detected SOD vigor and the MDA content change around asthma mouse model before and after PS was used, thus we discussed the influence of PS on resistance oxidation-oxidation system.
4. We chose CD_4~+CD_(25)~+Tr as the observation target and observed the change of CD_4~+CD_(25)~+Tr in asthma mouse serum applied around the PS atomization inspiration.
5. In this experiment we also chose 5 factors such as IFN-γ, IL-4, iNOS, SP-A and the eotaxin as judgement index. We applied immunohistochemical method to detect the change situation of IFN-γ, IL-4, iNOS, SP-A and the eotaxin expression level in the asthma mouse lung tissue around the PS treatment.
Results:
1. We found OVA sensitive and stimulation mouse had the behavior change, the lung tissue pathological section had massive inflammatory cell infiltration, the tracheal epithelial cell were destroyed obviously, the pipe wall accumulation, the lumen shrank narrowly, the beaker cell proliferation, the airway mucous plug formed and so on, all these results explained asthma model was established successfully.
2. Asthma mouse lung histology change demonstrated OVA sensitive and stimulation mouse presents the characteristic pathology of model asthma, compared with the normal control group, massive inflammatory cell infiltrated around bronchiole; After the PS atomization inspiration around the mouse bronchiole the inflammatory cell infiltration number compared the asthma group remarkably reduced, the pulmonary alveolar septum increased slightly.
3. The NO content and the NOS vigor in the lung tissue of asthma group were obviously higher than that of the normal control group, after applied PS and Budesonide atomization inspiration the NO content and the NOS vigor dropped obviously. Comparing the NO content and the NOS vigor in both the group of PS and BUD, that has no statistical difference. The NO content and the NOS vigor in the blood serum of asthma group were obviously higher, there was a significant difference between the asthma group and the PS-treatment group and the hormone-treated group. There was no significant difference between the PS-treatment group and the asthma group.
4. Comparing with the control group, the SOD vigor increased and the MDA content decreased in the group of asthma, which has obvious differences.And comparing with the asthma group, the SOD vigor increased and the MDA content decreased in both PS and BUD group.However, the comparison between in PS and BUD group has no obvious difference.The MDA content in asthma group, which compared with in PS, BUD and control group, has no obvious difference. It has statistical magnificance, comparing the SOD vigor in asthma with that in BUD and normal control group.While it has no obvious differenc between in asthma and PS group.
5. Compared with the normal control group, the PS-treatment group and the hormone-treated group, the level of CD_4~+CD_(25)~+Treg expression in the serum was not significantly higher in the asthma group.
6. Compared with the normal control group, the expression level of IL-4, iNOS and eotaxin was obviously higher in the asthma group. After PS and Budesonide atomization inspiration, the expression level of IL-4, iNOS and eotaxin was obviously decreased than that in the asthma group. In the asthma group IFN-γand SP-A expression level was lower than the normal control group obviously, after PS and Budesonide atomization inspiration, IFN-γand SP-A expression level was higher than the asthma group obviously.
Conclusion:
1. The PS atomization inspiration treatment in asthma can reduce the NOS vigor and the NO content in the mouse lung and decrease the expression of iNOS.
2. The PS atomization inspiration treatment in asthma can reduce the MDA content in the lung and increase the SOD vigor.
3. The PS atomization inspiration treatment can increase the IFN-γexpression and decrease the IL-4 expression in the mouse lung with asthma., which may adjust the unbalanced ratio of Th1/Th2.
4. The PS atomization inspiration treatment can decrease the Eotaxin expression and increase the SP-A expression in the mouse lung with asthma.
Bronchial asthma is a chronic airway inflammatory disease that involves many inflammatory cells, specially mast cell (MC), eosinophile granulocyte (EOS), T lymphocyte and it is accompanied by the airway hyperreactivity and the remodeling of the airway. The cause of asthma is complicated, the pathogenesis is not yet completely perspicuous. In asthma, the accumulation and activation of Eos in airway inflammation acts crucial function, but the display function of Eos needs chemotatic factor. Among the chemotatic factors, only the eotaxin is able to have specific chemotaxis and activation on Eos, is playing up the very important role in the asthmatic airway inflammation.The activate inflammatory cell may produce massive oxygen free radical (OFR). Malonal dehyde (MDA) is an important metabolite in the process of OFR inducing lipin peroxidation. MDA may make the asthma patient in vivo active oxygen to increase, the lipin peroxidation strengthens, destroy the biomembrane, thus aggravation inflammation responded does and harm to the airway epithelial cell, which has the vital role to asthma AHR production. Erythrocuprein (SOD) is the main antioxidasethe and ultra oxygen free radical scavenging agent in organism. Massive OFR consumes massive SOD, causes organism oxidation resistance ability to be low, the oxide compound to store up and the lipin peroxidation damage. MDA and SOD are together representing in vivo oxidation resistance-oxidation system condition. The nitrogen monoxide (NO) synthesis key enzyme is nitrogen monoxide synzyme (NOS). The activated inflammation cell and the inflammatory factor may cause iNOS to express obviously actively and synthesize massive NO, aggravates inflammatory reaction, then causes the lung damage. Moreover, NO and OFR may affect mutually, aggravate asthma outbreak. The T lymphocyte holds the important status in asthma morbidity. Most of the scholars thought the imbalance of two hypotypes kinds of auxiliary T lymphocyte (Th1 and Th2) is the important mechanism when asthma occurs. The Th1 cell mainly secretes interleukin-2 (IL-2), the interferon-gamma (IFN-γ) and the tumor necrosis factor-alpha (TNF-α), the Th2 cell mainly secretes IL-4, IL-5, IL-13 and granular cell-macrophage colony stimulation factor (GM-CSF) and so on. When asthma occurs, the Th2 cell activation accentuates and the Th1 function reduces, this is the pathogenesis key link in the asthma. But this theory could not explain all the asthmatic clinical manifestations and therapeutic reactions. The importance of Treg in asthma has been gradually recognized.Treg was the full-time suppressor, which has the role of immunological regulation. A great number of investigations revealed that Treg may demonstrate significant roles in the development of asthma.
Along with the deep explorationof asthma pathogenesis, it was found that in the bronchoalveolar lavage (BALF) of asthma animal experimentation and asthma patient, pulmonary surfactant (PS) not only has the quantity reduction and the ingredient unusual, moreover also has the function detuning. PS is synthesized and secreted by the pulmonary alveolus epidermisⅡCell (AT-Ⅱ), it is one kind of compound phosphatide which has high surface activity. The earliest discovery of PS was originated from the NRDS research, the people discovered that the PS quantity in NRDS was insufficient and the function was abnormal. Along with unceasing recognition and research to PS, the people discovered gradually besides NRDS, very many diseases like ARDS, pneumonia, bronchial asthma disease and so on all have abnormal PS.Pulmonary surfactant protein-A(SP-A) has the highest content, the most intense expression and the richest signal protein in PS, it is one of the important ingredients in pulmonary surfactant. Because PS can reduce the lung surface tension, prevent the pulmonary edema and has the immunity adjustment and the defense function, reduces airway hyperreactivity and so on, therefore PS possibly has the treatment function to asthma.
Until now in the world people have not found the permanent control method to asthma. At present, the overwhelming majority patient's asthma symptom may be under the good control after the standardized treatment. But asthma is one kind of heterogeneity disease, part of the patients are unsatisfactory to the conventional treatment. This experiment through the establishment bronchial asthma mice model, observe the changes before and after applying the therapy with PS, which concluded the content of NO, MDA and the vigor of NOS and SOD in serum and lung tissue with asthma. Detect CD4CD25 positive cells by the method of flow cytometry.The changes of expression in the lung tissue of asthma mouse before and after intervention with PS can be detected by immunohistochemical method, which included IL-4,IFN-γ, iNOS, SP-A and Eotaxin.
Method:
1. To discuss the treatment function of PS to the asthma mouse model, we randomly divided BALB/c mice into four groups: the PS-treated group, the hormone-treated group, the asthma group and the normal control group, and there were twelve mice in each group. Asthmatic mice were sensitized on days 1 and 14 by intraperitoneal injection of 10μg ovalbumin, and on days 21-27, after the initial sensitization, the mice were challenged for 30 min with an aerosol of 1% (w/v) OVA in saline (or with saline as a control) using an ultrasonic nebulizer. The PS-treated group and the hormone-treated group were treated for 30 min with PS or glucocorticoid (Budesonide) before each allergen challenge for 7 days. After the experiment each group of mice were beheaded to draw blood and the lung tissue. We observed bronchial pathological changes under the light microscope after the lung tissue pathological section were HE dyed.
2. We selected the BALB/c mouse, used the same method of randomization and model establishment as the above. Using the nitrate reductases and the spectrophotometric method determined and compared the NO content and the NOS vigor expression level in asthma mouse model blood serum and the lung before and after the PS was applied.
3. In the influence experimental study of PS to SOD and MDA in asthma mouse, we selected the BALB/C mouse, used the same method of randomization and model establishment as the above. Using the xanthine oxidase and the TBA color method examination, we detected SOD vigor and the MDA content change around asthma mouse model before and after PS was used, thus we discussed the influence of PS on resistance oxidation-oxidation system.
4. We chose CD_4~+CD_(25)~+Tr as the observation target and observed the change of CD_4~+CD_(25)~+Tr in asthma mouse serum applied around the PS atomization inspiration.
5. In this experiment we also chose 5 factors such as IFN-γ, IL-4, iNOS, SP-A and the eotaxin as judgement index. We applied immunohistochemical method to detect the change situation of IFN-γ, IL-4, iNOS, SP-A and the eotaxin expression level in the asthma mouse lung tissue around the PS treatment.
Results:
1. We found OVA sensitive and stimulation mouse had the behavior change, the lung tissue pathological section had massive inflammatory cell infiltration, the tracheal epithelial cell were destroyed obviously, the pipe wall accumulation, the lumen shrank narrowly, the beaker cell proliferation, the airway mucous plug formed and so on, all these results explained asthma model was established successfully.
2. Asthma mouse lung histology change demonstrated OVA sensitive and stimulation mouse presents the characteristic pathology of model asthma, compared with the normal control group, massive inflammatory cell infiltrated around bronchiole; After the PS atomization inspiration around the mouse bronchiole the inflammatory cell infiltration number compared the asthma group remarkably reduced, the pulmonary alveolar septum increased slightly.
3. The NO content and the NOS vigor in the lung tissue of asthma group were obviously higher than that of the normal control group, after applied PS and Budesonide atomization inspiration the NO content and the NOS vigor dropped obviously. Comparing the NO content and the NOS vigor in both the group of PS and BUD, that has no statistical difference. The NO content and the NOS vigor in the blood serum of asthma group were obviously higher, there was a significant difference between the asthma group and the PS-treatment group and the hormone-treated group. There was no significant difference between the PS-treatment group and the asthma group.
4. Comparing with the control group, the SOD vigor increased and the MDA content decreased in the group of asthma, which has obvious differences.And comparing with the asthma group, the SOD vigor increased and the MDA content decreased in both PS and BUD group.However, the comparison between in PS and BUD group has no obvious difference.The MDA content in asthma group, which compared with in PS, BUD and control group, has no obvious difference. It has statistical magnificance, comparing the SOD vigor in asthma with that in BUD and normal control group.While it has no obvious differenc between in asthma and PS group.
5. Compared with the normal control group, the PS-treatment group and the hormone-treated group, the level of CD_4~+CD_(25)~+Treg expression in the serum was not significantly higher in the asthma group.
6. Compared with the normal control group, the expression level of IL-4, iNOS and eotaxin was obviously higher in the asthma group. After PS and Budesonide atomization inspiration, the expression level of IL-4, iNOS and eotaxin was obviously decreased than that in the asthma group. In the asthma group IFN-γand SP-A expression level was lower than the normal control group obviously, after PS and Budesonide atomization inspiration, IFN-γand SP-A expression level was higher than the asthma group obviously.
Conclusion:
1. The PS atomization inspiration treatment in asthma can reduce the NOS vigor and the NO content in the mouse lung and decrease the expression of iNOS.
2. The PS atomization inspiration treatment in asthma can reduce the MDA content in the lung and increase the SOD vigor.
3. The PS atomization inspiration treatment can increase the IFN-γexpression and decrease the IL-4 expression in the mouse lung with asthma., which may adjust the unbalanced ratio of Th1/Th2.
4. The PS atomization inspiration treatment can decrease the Eotaxin expression and increase the SP-A expression in the mouse lung with asthma.
引文
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