高分辨CT、生物标记物和肺功能评价哮喘患者气道重塑
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摘要
目的：探讨诱导痰中基质金属蛋白酶-9(MMP-9)及其抑制剂-1(TIMP-1)和转化生长因子-β1 (TGF-β1),高分辨CT (HRCT)和肺功能检查在评价支气管哮喘(简称哮喘)患者气道重塑方面的作用。
方法：2008年6月至12月就诊于山西医科大学第一医院的哮喘患者48例,根据应用β2-受体激动剂后是否出现气流可逆,将哮喘患者分为可逆气流阻塞组(24例)和不可逆气流阻塞组(24例),以及对照组(10名)。通过盐水诱导痰液,利用ELISA方法检测哮喘患者及对照者诱导痰中的MMP-9、TIMP-1和TGF-β1浓度。同时所有入选者进行常规肺功能及肺部HRCT检查,测定肺部HRCT的气道壁厚度与外径比值2倍的百分比(2T/D)和气道壁面积占气道总截面积百分比(WA%)。
结果：1.不可逆气流阻塞组和可逆气流阻塞组诱导痰中的MMP-9, TIMP-1和TGF-β1含量均高于对照组(P均<0.05),不可逆气流阻塞组含量均高于可逆气流阻塞组(P均<0.05)；不可逆气流阻塞组和可逆气流阻塞组MMP-9/TIMP-1比值均低于对照组(P均<0.05),不可逆气流阻塞组MMP-9/TIMP-1比值低于可逆气流阻塞组(P<0.05)。2.不可逆气流阻塞组和可逆气流阻塞组2T/D、WA%值高于对照组(P均<0.05)；不可逆气流阻塞组值高于可逆气流阻塞组(P<0.05)。3.诱导痰中MMP-9与2T/D、WA%呈正相关(r=0.755、0.751,P均< 0.05); TIMP-1与2T/D、WA%呈正相关(r=0.639、0.630,P均<0.05);TGF-β1与2T/D、WA%亦呈正相关(r=0.872、0.868,P均<0.05)。4.诱导痰中MMP-9、TIMP-1、TGF-β1,2T/D, WA%与肺功能FEV1%均呈负相关(r=-0.496、-0.468、-0.607、-0.599、-0.586,P均<0.05)；其与肺功能FVC%均呈负相关(r=-0.312、-0.359、-0.399、-0.407、-0.388,P均<0.05)；其与肺功能FEF25-75%亦均呈负相关(r=-0.558、-0.477、-0.649、-0.645、-0.651,P均<0.05)。
结论：1. HRCT可作为无创手段评估哮喘患者气道重塑情况。2.诱导痰中MMP-9、TIMP-1和TGF-β1可以作为气道重塑的生物标记物。3.诱导痰中MMP-9、TIMP-1、TGF-β1和HRCT能较早地发现气道重塑,其有可能指导临床早期治疗哮喘并监测治疗效果。4.采用诱导痰的方法获取气道信息是一种安全有效的方法。
Objective:To explore the roles of biomarkers of MMP-9,TIMP-1 and TGF-β1 in induced sputum,high-resolution CT and pulmonary function in assessing airway remodeling in asthma.
Method:Forty-eight patients with asthma were chosen in the first hospital of Shanxi medical university from June to December 2008. According whether airflow obstruction was reversible or not being used p2-receptor agonists,they were divided into two groups:irreversible airflow obstruction group and reversible airflow obstruction one,and 24 patients each group,and control group included 10 persons.The sputum was induced with Saline,and the MMP-9,TIMP-1 and TGF-β1 level of the sputum were determined with ELISA.All selected persons over the same period did pulmonary function and HRCT tests.The wall thickness two-fold to airway diameter ratio(2T/D) and the percentage of airway wall area to total airway cross sectional area(WA%) were calculated on high resolution computed tomography.
Result:(1) The levels of MMP-9, TIMP-1 and TGF-β1 in asthma group were higher than those in the controlled group (P＜0.05) respectively;and those in the irreversible airflow obstruction group were higher than ones in the reversible airflow obstruction group (P＜0.05) respectively.The MMP-9/TIMP-1 ratio in asthma group was lower than in control group (P＜0.05);and the irreversible airflow obstruction group was lower than the reversible airflow obstruction group,(P＜0.05).(2) 2T/D and WA%were higher in asthma group than in control group (P＜0.05) respectively;and the irreversible airflow obstruction group was higher than the reversible airflow obstruction group,(P＜0.05).(3) The MMP-9 level of induced sputum was positively correlated with 2T/D and WA%(r=0.755,0.751,P＜0.05);The TIMP-1 level was positively correlated with 2T/D and WA%(r=0.639,0.630,P＜0.05);The TGF-β1 level was also positively correlated with 2T/D and WA%(r=0.872,0.868,P＜0.05).(4) MMP-9, TIMP-1, TGF-β1,2T/D and WA%were negatively correlated with FEV1%(r=-0.496,-0.468,-0.607,-0.599,-0.586,P＜0.05);those were negatively correlated with FVC%(r=0.312、-0.359、-0.399、-0.407、-0.388,P＜0.05);those were also negatively correlated with FEF25-75%(r=-0.558、-0.477、-0.649、-0.645、-0.651,P＜0.05)
Conclusion:(1) The airway remodeling can be assessed by HRCT.(2) MMP-9, TIMP-1 and TGF-β1 in induced sputum could be as biomarkers as airway remodeling in asthma. (3) MMP-9,TIMP-1,TGF-β1 in induced sputum and HRCT could find airway remodeling earlier,which may be guiding clinical treatment and monitoring therapeutic effect. (4) It was a safe and effective way that airway secretions were obtained through the induced sputum.
方法：2008年6月至12月就诊于山西医科大学第一医院的哮喘患者48例,根据应用β2-受体激动剂后是否出现气流可逆,将哮喘患者分为可逆气流阻塞组(24例)和不可逆气流阻塞组(24例),以及对照组(10名)。通过盐水诱导痰液,利用ELISA方法检测哮喘患者及对照者诱导痰中的MMP-9、TIMP-1和TGF-β1浓度。同时所有入选者进行常规肺功能及肺部HRCT检查,测定肺部HRCT的气道壁厚度与外径比值2倍的百分比(2T/D)和气道壁面积占气道总截面积百分比(WA%)。
结果：1.不可逆气流阻塞组和可逆气流阻塞组诱导痰中的MMP-9, TIMP-1和TGF-β1含量均高于对照组(P均<0.05),不可逆气流阻塞组含量均高于可逆气流阻塞组(P均<0.05)；不可逆气流阻塞组和可逆气流阻塞组MMP-9/TIMP-1比值均低于对照组(P均<0.05),不可逆气流阻塞组MMP-9/TIMP-1比值低于可逆气流阻塞组(P<0.05)。2.不可逆气流阻塞组和可逆气流阻塞组2T/D、WA%值高于对照组(P均<0.05)；不可逆气流阻塞组值高于可逆气流阻塞组(P<0.05)。3.诱导痰中MMP-9与2T/D、WA%呈正相关(r=0.755、0.751,P均< 0.05); TIMP-1与2T/D、WA%呈正相关(r=0.639、0.630,P均<0.05);TGF-β1与2T/D、WA%亦呈正相关(r=0.872、0.868,P均<0.05)。4.诱导痰中MMP-9、TIMP-1、TGF-β1,2T/D, WA%与肺功能FEV1%均呈负相关(r=-0.496、-0.468、-0.607、-0.599、-0.586,P均<0.05)；其与肺功能FVC%均呈负相关(r=-0.312、-0.359、-0.399、-0.407、-0.388,P均<0.05)；其与肺功能FEF25-75%亦均呈负相关(r=-0.558、-0.477、-0.649、-0.645、-0.651,P均<0.05)。
结论：1. HRCT可作为无创手段评估哮喘患者气道重塑情况。2.诱导痰中MMP-9、TIMP-1和TGF-β1可以作为气道重塑的生物标记物。3.诱导痰中MMP-9、TIMP-1、TGF-β1和HRCT能较早地发现气道重塑,其有可能指导临床早期治疗哮喘并监测治疗效果。4.采用诱导痰的方法获取气道信息是一种安全有效的方法。
Objective:To explore the roles of biomarkers of MMP-9,TIMP-1 and TGF-β1 in induced sputum,high-resolution CT and pulmonary function in assessing airway remodeling in asthma.
Method:Forty-eight patients with asthma were chosen in the first hospital of Shanxi medical university from June to December 2008. According whether airflow obstruction was reversible or not being used p2-receptor agonists,they were divided into two groups:irreversible airflow obstruction group and reversible airflow obstruction one,and 24 patients each group,and control group included 10 persons.The sputum was induced with Saline,and the MMP-9,TIMP-1 and TGF-β1 level of the sputum were determined with ELISA.All selected persons over the same period did pulmonary function and HRCT tests.The wall thickness two-fold to airway diameter ratio(2T/D) and the percentage of airway wall area to total airway cross sectional area(WA%) were calculated on high resolution computed tomography.
Result:(1) The levels of MMP-9, TIMP-1 and TGF-β1 in asthma group were higher than those in the controlled group (P＜0.05) respectively;and those in the irreversible airflow obstruction group were higher than ones in the reversible airflow obstruction group (P＜0.05) respectively.The MMP-9/TIMP-1 ratio in asthma group was lower than in control group (P＜0.05);and the irreversible airflow obstruction group was lower than the reversible airflow obstruction group,(P＜0.05).(2) 2T/D and WA%were higher in asthma group than in control group (P＜0.05) respectively;and the irreversible airflow obstruction group was higher than the reversible airflow obstruction group,(P＜0.05).(3) The MMP-9 level of induced sputum was positively correlated with 2T/D and WA%(r=0.755,0.751,P＜0.05);The TIMP-1 level was positively correlated with 2T/D and WA%(r=0.639,0.630,P＜0.05);The TGF-β1 level was also positively correlated with 2T/D and WA%(r=0.872,0.868,P＜0.05).(4) MMP-9, TIMP-1, TGF-β1,2T/D and WA%were negatively correlated with FEV1%(r=-0.496,-0.468,-0.607,-0.599,-0.586,P＜0.05);those were negatively correlated with FVC%(r=0.312、-0.359、-0.399、-0.407、-0.388,P＜0.05);those were also negatively correlated with FEF25-75%(r=-0.558、-0.477、-0.649、-0.645、-0.651,P＜0.05)
Conclusion:(1) The airway remodeling can be assessed by HRCT.(2) MMP-9, TIMP-1 and TGF-β1 in induced sputum could be as biomarkers as airway remodeling in asthma. (3) MMP-9,TIMP-1,TGF-β1 in induced sputum and HRCT could find airway remodeling earlier,which may be guiding clinical treatment and monitoring therapeutic effect. (4) It was a safe and effective way that airway secretions were obtained through the induced sputum.
引文
[1]Aas K. Heterogeneity of bronchial asthma. Allergy 1981;36:3-14
[2]Djukanovic R, Roche WR, Wilson JW, et al. Mucosal inflammation in asthma. Am Rev Respir Dis 1990;142:434-457
[3]Brusasco V, Crimi E, Pellegrino R. Airway hyper responsiveness in asthma:not just a matter of airway inflammation. Thorax 1998;53:992-998
[4]Zhu Z, Lee G C, Zheng T, et al. Airway Inflammation and Remodeling in Asthma. Am. J. Respir. Crit. Care Med 2001 Volu; 164:S67-S70
[5]Awadh N, Muller NL, Park CS, et al. Airway wall thickness in subjects with near fatal asthma and control groups:assessment with high resolution computed scanning. Thorax 1998;53:248-253
[6]King GG, Muller NL, Pare PD. Evaluation of airways in obstructive pulmonary disease using high-resolution computed tomography. Am J Respir Crit Care Med 1999; 159:992-1004
[7]Vignola AM, Kips J, Bousquet J.Tissue remodeling as a feature of persistent asthma. J Allergy Clin Immunol 2000;105(6 Pt 1):1041-1053
[8]Waldo Mattos M,Sam Lim M, Richard Russell M, et al. Matrix Metalloproteinase-9 Expression in Asthma. CHEST 2002; 122:1543-1552
[9]M. Profital,R. Gagliardol,R,Di Giorgil,et al.In vitro effects of flunisolide on MMP-9, TIMP-1, fibronectin,TGF-bl release and apoptosis in sputum cells freshly isolated from mild to moderate asthmatics[J] Allergy 2004:59:927-932
[10]高衍新,王瑞.痰液诱导技术及其应用研究.中国职业医学October,2007, Vol.34, No.5
[11]中华医学会呼吸病学分会哮喘学组.支气管哮喘防治指南(支气管哮喘的定义、诊断、治疗及教育和管理方案)中华结核和呼吸杂志,2003,26：13221381
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[13]James AL.,Maxwell PS, Pearce-PG, et al.The Relationship of Reticular Basement Membrane Thickness to Airway Wall Remodeling in Asthma.Am.J.Respir.Crit.Care Med 2002; 166:1590-1595
[14]FitzGerald JM, Macklem PT. Fatal asthma. Annu Rev Med 1996;47:161-168
[15]H.Gono K,Fujimoto,S.Kawakami,et al.Evaluation of airway wall thickness and air trapping by HRCT in asymptomatic asthma.Eur Respir J 2003; 22:965-971.
[16]Kasahara K,Shiba K,Ozawa T,et al. Correlation between the bronchial subepithelial layer and whole airway wall thickness in patients with asthma. thorax; 2002:57:242-246
[17]Niimi A, Matsumoto H, Amitani R, et al. Effect of short-term treatment with inhaled corticosteroid on airway wall thickening in asthma. The American Journal of medicine.2004: 116：725-731
[18]张建,刘荣惠,刘文亚,等.高分辨率CT研究支气管哮喘患者的气道壁厚度与肺功能、病情严重度的相关性[J].医学影像学杂志,2004,14(6)：4982500.
[19]辛小燕,贺文,谭春婷.HRCT测量支气管哮喘的气道壁厚度与其病情严重度及肺功能的相关性研究.中国医学影像技术,2006,22(11)：166521667.
[20]辛晓峰,修清玉,施毅,等.高分辨率CT对慢性哮喘患者肺密度CT值测定的定量分析研究[J].医学研究生学报.2006,19(4).-352-355
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[1]Aas K. Heterogeneity of bronchial asthma. Allergy 1981;36:3-14
[2]Djukanovic R, Roche WR, Wilson JW, et al. Mucosal inflammation in asthma. Am Rev Respir Dis 1990; 142:434-457
[3]Brusasco V, Crimi E, Pellegrino R. Airway hyperresponsiveness in asthma:not just a matter of airway inflammation. Thorax 1998;53:992-998
[4]Zhu Z, Lee G C, Zheng T, et al. Airway Inflammation and Remodeling in Asthma. Am. J. Respir. Crit. Care Med 2001 Volu; 164:S67-S70.
[5]FitzGerald JM, Macklem PT. Fatal asthma. Annu Rev Med 1996;47:161-168
[6]James A L., Maxwell P S., Pearce-P G, et al. The Relationship of Reticular Basement Membrane Thickness to Airway Wall Remodeling in Asthma. Am. J. Respir. Crit. Care Med 2002; 166:1590-1595.
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[18]Niimi A, Matsumoto H, Amitani R, et al. Effect of short-term treatment with inhaled corticosteroid on airway wall thickening in asthma. The American Journal of medicine.2004: 116:725-731
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[2]Djukanovic R, Roche WR, Wilson JW, et al. Mucosal inflammation in asthma. Am Rev Respir Dis 1990;142:434-457
[3]Brusasco V, Crimi E, Pellegrino R. Airway hyper responsiveness in asthma:not just a matter of airway inflammation. Thorax 1998;53:992-998
[4]Zhu Z, Lee G C, Zheng T, et al. Airway Inflammation and Remodeling in Asthma. Am. J. Respir. Crit. Care Med 2001 Volu; 164:S67-S70
[5]Awadh N, Muller NL, Park CS, et al. Airway wall thickness in subjects with near fatal asthma and control groups:assessment with high resolution computed scanning. Thorax 1998;53:248-253
[6]King GG, Muller NL, Pare PD. Evaluation of airways in obstructive pulmonary disease using high-resolution computed tomography. Am J Respir Crit Care Med 1999; 159:992-1004
[7]Vignola AM, Kips J, Bousquet J.Tissue remodeling as a feature of persistent asthma. J Allergy Clin Immunol 2000;105(6 Pt 1):1041-1053
[8]Waldo Mattos M,Sam Lim M, Richard Russell M, et al. Matrix Metalloproteinase-9 Expression in Asthma. CHEST 2002; 122:1543-1552
[9]M. Profital,R. Gagliardol,R,Di Giorgil,et al.In vitro effects of flunisolide on MMP-9, TIMP-1, fibronectin,TGF-bl release and apoptosis in sputum cells freshly isolated from mild to moderate asthmatics[J] Allergy 2004:59:927-932
[10]高衍新,王瑞.痰液诱导技术及其应用研究.中国职业医学October,2007, Vol.34, No.5
[11]中华医学会呼吸病学分会哮喘学组.支气管哮喘防治指南(支气管哮喘的定义、诊断、治疗及教育和管理方案)中华结核和呼吸杂志,2003,26：13221381
[12]McNamara AE,Miiller NL,Kasahara K,et al.Airway narrowing in excised canine lungs measured by high resolution computed tomography[J].Appl Physiol,1992,73 (2):3072316
[13]James AL.,Maxwell PS, Pearce-PG, et al.The Relationship of Reticular Basement Membrane Thickness to Airway Wall Remodeling in Asthma.Am.J.Respir.Crit.Care Med 2002; 166:1590-1595
[14]FitzGerald JM, Macklem PT. Fatal asthma. Annu Rev Med 1996;47:161-168
[15]H.Gono K,Fujimoto,S.Kawakami,et al.Evaluation of airway wall thickness and air trapping by HRCT in asymptomatic asthma.Eur Respir J 2003; 22:965-971.
[16]Kasahara K,Shiba K,Ozawa T,et al. Correlation between the bronchial subepithelial layer and whole airway wall thickness in patients with asthma. thorax; 2002:57:242-246
[17]Niimi A, Matsumoto H, Amitani R, et al. Effect of short-term treatment with inhaled corticosteroid on airway wall thickening in asthma. The American Journal of medicine.2004: 116：725-731
[18]张建,刘荣惠,刘文亚,等.高分辨率CT研究支气管哮喘患者的气道壁厚度与肺功能、病情严重度的相关性[J].医学影像学杂志,2004,14(6)：4982500.
[19]辛小燕,贺文,谭春婷.HRCT测量支气管哮喘的气道壁厚度与其病情严重度及肺功能的相关性研究.中国医学影像技术,2006,22(11)：166521667.
[20]辛晓峰,修清玉,施毅,等.高分辨率CT对慢性哮喘患者肺密度CT值测定的定量分析研究[J].医学研究生学报.2006,19(4).-352-355
[21]F Mitsunobu, T Mifune, K Ashida,et al. Influence of age and disease severity on high resolution CT lung densitometry in asthma. Thorax 2001;56:851-856
[22]Hoshino M,Nakmura Y,Sim JJ,et al.Expression of growth factors and remodling of the airway wall in bronchial asthma. Thorax,1994,11:85-94.
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