Search JIM Advanced Search

Journal of Chinese Integrative Medicine ›› 2004, Vol. 2 ›› Issue (6): 435-439.doi: 10.3736/jcim20040610

• Original Experimental Research • Previous Articles     Next Articles

Function of MMP/TIMP on airway remodeling of bronchial asthma and treating effects of Zhichuan Capsule

Yin-gen Wu1, Li-xin Wang2   

  1. 1. Respiratory Department, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
    2. Respiratory Department, Shanghai Hospital of Traditional Chinese Medicine, Shanghai 200071, China
  • Received:2004-03-16 Online:2004-11-20 Published:2018-10-20

Objective: To explore the mechanism of the bronchial asthma and to study the treating effects of Zhichuan Capsule on the airway remodeling of asthmatic model rats.Methods: The rat model was established by being sensitized and activated with different density of ovalbumin through prolonged and repeated exposure for 8 weeks. The rats were randomly divided into model group, Zhichuan Capsule treated group, dexameson treated group, and Zhichuan Capsule and dexameson treated group. Another group of normal rats were taken as control. General histological changes were observed by hematoxylin and eosin stained sections. Being standardized by internal perimeter (Pi), the wall thickness (d), internal area (Ai), outer area (Ao) and wall area (WA) of the airway were quantified by computer-assisted image analysis system. The express of MMP-9, TIMP-1, ColⅠ, Col Ⅲ and ColⅤ in the airway were examined by immunocytochemical methods. During the course of airway remodeling, the dynamic changes of model rats were observed at different time points (2, 4, 6 and 8 weeks after the activating). Statistical comparison was performed by ANOVA followed by Fisher LSD test.Results: (1) Histologic examination showed eosinophil infiltration within the airway walls, epithelial damage, excessive mucus in the lumen and edema in the submucosa of the airways in model rats, and that the collagen deposition increased accompanied by increasing of TIMP-1. In the model rats, MMP-9 increased at the time point of 2 weeks, but it decreased in the late stage (8 weeks after activating) of airway remodeling. And the level of TIMP-1 was far higher than MMP-9 at the time point of 8 weeks. (2) Zhichuan Capsule could down-regulate the level of TIMP-1 in the airway wall, as well as the thickness of airway wall and the collagen deposition. And there were progressing effects when it was used together with dexameson.Conclusion: (1) The early increase of MMP-9 is a key point to start remodeling; and the increase of TIMP-1 in the late stage, which inhibits collagenase activity, may play an important role in developing airway fibrosis. Imbalance between MMP-9 and TIMP-1 is a marker of airway remodeling. (2) Zhichuan Capsule can decrease the deposition of collagen and suppress the airway remodeling by inhibiting the TIMP-1 expression.

Key words: asthma, matrix metalloproteinase, Zhichuan Capsule, airway remodeling, models, rats

CLC Number: 

  • R289.5

Tab 1

MMP-9 and TIMP-1 expression in airway of experimental rats($\bar{x}$±s)"

Group n MMP-9 expression TIMP-1 expression
Ratio of positive area (%) Staining intensity Ratio of positive area (%) Staining intensity
Normal control
2 weeks after activating 4 2.39±0.87 5.50±0.19
2.61±0.25 7.16±1.03
4 weeks after activating 4 2.64±0.43 6.50±0.33
2.37±0.22 7.33±0.72
6 weeks after activating 4 2.34±0.21 6.33±0.98
2.60±0.21 7.36±1.41
8 weeks after activating 4 2.84±0.47 6.16±0.89
2.38±0.27 7.25±0.83
2 weeks after activating 8 16.49±3.61* 13.46±1.17*
10.58±1.78* 17.12±1.32*
4 weeks after activating 8 26.70±3.23*Δ 19.04±1.21*Δ
26.31±3.51*Δ 21.75±1.09*Δ
6 weeks after activating 8 33.72±1.12*Δ 24.54±0.62*Δ
34.38±1.73*Δ 25.29±1.33*Δ
8 weeks after activating 8 16.72±2.26* 10.96±0.83*
40.39±1.26*ΔΔ 31.21±1.53*ΔΔ

Tab 2

Thickness and area of airway wall of rats in different groups($\bar{x}$±s, % )"

Group n Thickness (d/Pi) Area (WA/Pi2 )
Normal control 8 3.28±0.35 2.40±0.37
Model 8 9.66±1.11* 8.42±1.11*
Zhichuan Capsule treated 8 4.86±0.69*▲ 4.01±0.97*
Dexameson treated 8 5.15±0.91* 4.48±0.78*
Zhichuan Capsule and dexameson treated 8 4.72±1.08* 4.54±2.22*

Tab 3

Collagen expression (ratio of positive area) in airway of rats in different groups($\bar{x}$±s, % )"

Group n Collagen typeⅠ Collagen type Ⅲ Collagen type Ⅴ
Normal control 8 10.95±0.49 14.24±0.92 8.89±0.77
Model 8 37.24±1.58* 42.98±1.59* 43.84±2.09*
Zhichuan Capsule treated 8 13.53±0.85*▲□ 23.39±0.71*▲□■ 21.89±0.93*▲□■
Dexameson treated 8 16.14±1.66*▲■ 27.89±0.63*▲■ 24.52±1.07*▲■
Zhichuan Capsule and dexameson treated 8 14.27±0.80*▲□ 19.89±1.04*▲□ 19.06±0.72*▲□

Tab 4

TIMP-1 expression in airway of rats in different groups($\bar{x}$±s )"

Group n TIMP-1 expression
Ratio of positive area (%) Staining intensity
Normal control 8 2.38±0.27 7.25±0.83
Model 8 40.38±1.26* 31.20±1.53*
Zhichuan Capsule treated 8 15.08±0.95*▲□■ 15.45±0.87*▲□■
Dexameson treated 8 22.46±1.14*▲■ 16.91±0.58*▲■
Zhichuan Capsule and dexameson treated 8 10.78±2.05*▲□ 13.71±0.65*▲□
[1] 王丽新, 吴银根 . 实验性哮喘大鼠气道重塑的形态学变化[J]. 中西医结合学报, 2003,1(1):62-65
Wang LX, Wu YG . Morphological changes following airway remodeling in asthmatic rats[J]. Zhong Xi Yi Jie He Xue Bao, 2003,1(1):62-65
[2] Salmon M, Walsh DA, Koto H , et al. Repeated allergen exposure of sensitized Brown-Norway rats induces airway cell DNA synjournal and remodeling[J]. Eur Respir J, 1999,14(3):633-641
doi: 10.1034/j.1399-3003.1999.14c25.x
[3] Palmans E, Kips JC, Pauwels RA . Prolonged allergen exposure induces structural airway changes in sensitized rats[J]. Am J Respir Crit Care Med, 2000,161(2):627-635
doi: 10.1164/ajrccm.161.2.9902094 pmid: 10673209
[4] 陈奇 . 中药药理研究方法学(第1版)[M]. 北京: 人民卫生出版社, 1994,( 第1版):33-34
[5] James AL, Hogg JC, Dunn LA , et al. The use of the internal perimeter to compare airway size and to calculate smooth muscle shortening[J]. Am Rev Respir Dis, 1988,138(1):136-139
doi: 10.1164/ajrccm/138.1.136
[6] Wiggs BR, Bosken C, Pare PD , et al. A model of airway narrowing in asthma and in chronic obstructive pulmonary disease[J]. Am Rev Respir Dis, 1992,145(6):1251-1258
doi: 10.1164/ajrccm/145.6.1251 pmid: 1595987
[7] Fish JE, Peters SP . Airway remodeling and persistent airway obstruction in asthma[J]. J Allergy Clin Immunol, 1999,104(3 Pt 1):509-516
doi: 10.1016/S0091-6749(99)70315-5 pmid: 10482819
[8] Vignola AM, Riccobono L, Mirabella A , et al. Sputum metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio correlates with airflow obstruction in asthma and chronic bronchitis[J]. Am J Respir Crit Care Med, 1998,158(6):1945-1950
doi: 10.1164/ajrccm.158.6.9803014
[9] Bosse M, Chakir J, Rouabhia M , et al. Serum matrix metalloproteinase-9∶Tissue inhibitor of metalloproteinase-1 ratio correlates with steroid responsiveness in moderate to severe asthma[J]. Am J Respir Crit Care Med, 1999,159(2):596-602
doi: 10.1164/ajrccm.159.2.9802045
[1] Riska Siregar, Aris Setyawan, Syahruramdhani Syahruramdhani. A model to standardize safety and quality of care for cupping therapy. Journal of Integrative Medicine, 2021, 19(4): 327-332.
[2] Hao-cheng Zheng, Zi-rui Liu, Ya-lan Li, Yong-an Wang, Jing-wei Kong, Dong-yu Ge, Gui-ying Peng. Allium tuberosum alleviates pulmonary inflammation by inhibiting activation of innate lymphoid cells and modulating intestinal microbiota in asthmatic mice. Journal of Integrative Medicine, 2021, 19(2): 158-166.
[3] Bing-rong Li, Shi-yun Shao, Long Yuan, Ru Jia, Jian Sun, Qing Ji, Hua Sui, Li-hong Zhou, Yi Zhang, Hui Liu, Qi Li, Yan Wang, Bi-meng Zhang. Effects of mild moxibustion on intestinal microbiome and NLRP3 inflammasome in rats with 5-fluorouracil-induced intestinal mucositis. Journal of Integrative Medicine, 2021, 19(2): 144-157.
[4] Sitthichai Iamsaard, Supatcharee Arun, Jaturon Burawat, Supataechasit Yannasithinon, Saranya Tongpan, Sudtida Bunsueb, Natthapol Lapyuneyong, Pannawat Choowong-in, Nareelak Tangsrisakda, Chadaporn Chaimontri, Wannisa Sukhorum. Evaluation of antioxidant capacity and reproductive toxicity of aqueous extract of Thai Mucuna pruriens seeds. Journal of Integrative Medicine, 2020, 18(3): 265-273.
[5] Lena Grönblom Lundström, Ulrika Aasa, Yan Zhang, Tobias Sundberg. Health care in light of different theories of health—A proposed framework for integrating a social humanistic perspective into health care. Journal of Integrative Medicine, 2019, 17(5): 321-327.
[6] Morufu Eyitayo Balogun, Elizabeth Enohnyaket Besong, Jacinta Nkechi Obimma, Ogochukwu Sophia Mbamalu, Fankou Serges Athanase Djobissie. Protective roles of Vigna subterranea (Bambara nut) in rats with aspirin-induced gastric mucosal injury. Journal of Integrative Medicine, 2018, 16(5): 342-349.
[7] Lucky Legbosi Nwidu, Raphael Ellis Teme. Hot aqueous leaf extract of Lasianthera africana (Icacinaceae) attenuates rifampicin-isoniazid-induced hepatotoxicity. Journal of Integrative Medicine, 2018, 16(4): 263-272.
[8] Oluwakemi Josephine Awakan, Sylvia Omonirume Malomo, Abdullahi Adeyinka Adejare, Adedoyin Igunnu, Olubunmi Atolani, Abiodun Humphrey Adebayo, Bamidele Victor Owoyele . Anti-inflammatory and bronchodilatory constituents of leaf extracts of Anacardium occidentale L. in animal models. Journal of Integrative Medicine, 2018, 16(1): 62-70.
[9] Kylie Connolly, Douglas Jackson, Candice Pullen, Andrew Fenning. Alpha-adrenoceptor antagonism by Crassostrea gigas oyster extract inhibits noradrenaline-induced vascular contraction in Wistar rats. Journal of Integrative Medicine, 2015, 13(3): 194-200.
[10] Udhaya Lavinya Baskaran, Sherry Joseph Martin, Rasool Mahaboobkhan, Sabina Evan Prince. Protective role of Triphala, an Indian traditional herbal formulation, against the nephrotoxic effects of bromobenzene in Wistar albino rats. Journal of Integrative Medicine, 2015, 13(2): 115-121.
[11] Hussein O. B. Oloyede, Matthew C. Adaja, Taofeek O. Ajiboye, Musa O. Salawu. Anti-ulcerogenic activity of aqueous extract of Carica papaya seed on indomethacin-induced peptic ulcer in male albino rats. Journal of Integrative Medicine, 2015, 13(2): 105-114.
[12] Anirudha A. Lande, Shirishkumar D. Ambavade, Uma S. Swami, Prafulla P. Adkara Prashant D. Ambavade, Arun B. Waghamare. Saponins isolated from roots of Chlorophytum borivilianum reduce acute and chronic inflammation and histone deacetylase. Journal of Integrative Medicine, 2015, 13(1): 25-33.
[13] Vamsi Reddy, Arvind Sridhar, Roberto F. Machado, Jiwang Chen. High sodium causes hypertension: Evidence from clinical trials and animal experiments. Journal of Integrative Medicine, 2015, 13(1): 1-8.
[14] Elizabeth Abidemi Balogun, Sylvia Orume Malomo, Joseph Oluwatope Adebayo, Ahmed Adebayo Ishola, Ayodele Olufemi Soladoye, Lawrence Aderemi Olatunji, Olatunji Matthew Kolawole, Stephen Olubunmi Oguntoye, Abiola Samuel Babatunde, Oluwole Busayo Akinola . In vivo antimalarial activity and toxicological effects of methanolic extract of Cocos nucifera (Dwarf red variety) husk fibre. Journal of Integrative Medicine, 2014, 12(6): 504-511.
[15] Urmila Aswar, Mayuri Gurav, Ganesh More, Khaled Rashed, Manoj Aswar. Effect of aqueous extract of Solanum xanthocarpum Schrad. & Wendl. on postmenopausal syndrome in ovariectomized rats. Journal of Integrative Medicine, 2014, 12(5): 439-446.
Full text



[1] Jin-rong Fu. Establishment of multivariate diagnosis and treatment system of modern gynecology of traditional Chinese medicine. Journal of Chinese Integrative Medicine, 2008, 6(1): 22-24
[2] Hao Li, Ming-jiang Yao, Wen-ming Zhao, Jie Guan, Lin-lin Cai, Ling Cui. A randomized, controlled, double-blind trial of Huannao Yicong capsule in senile patients with mild cognitive impairment. Journal of Chinese Integrative Medicine, 2008, 6(1): 25-31
[3] Zhi-chun Jin. Problems in establishing clinical guideline for integrated traditional Chinese and Western medicine. Journal of Chinese Integrative Medicine, 2008, 6(1): 5-8
[4] SUN Ming-yu, ZUO Jian, DUAN Ji-feng, HAN Jun, FAN Shi-ming, ZHANG Wei, ZHU Li-fang, YAO Ming-hui. Antitumor activities of kushen flavonoids in vivo and in vitro. Journal of Chinese Integrative Medicine, 2008, 6(1): 51-59
[5] Min Cheng, Qiong Feng, Shu-wen Qian, Hui Gao, Cui-qing Zhu. Preliminary assay of p-amyloid binding elements in heart-beneficial recipe. Journal of Chinese Integrative Medicine, 2008, 6(1): 68-72
[6] Ning-qun Wang, Liang-duo Jiang, Zong-xing Li. Research progress in asthma-related quality of life. Journal of Chinese Integrative Medicine, 2008, 6(1): 93-97
[7] Jing-yuan Mao, Chang-xiao Liu, Heng-he Wang, Guang-li Wei , Zhen-peng Zhang, Jie Xing, Wang Xian liang , Ying-fei Bi . Effects of Shenmai Injection on serum concentration and pharmacokinetics of digoxin in dogs with heart failure. Journal of Chinese Integrative Medicine, 2010, 8(11): 1070-1074
[8] Zhi-mei Wang, Bin Zhang. A study on translation of ellipses in Huangdi Neijing from perspective of hermeneutic theory. Journal of Chinese Integrative Medicine, 2010, 8(11): 1097-1100
[9] Gui Yu, Jie Wang. Thinking on building the network cardiovasology of Chinese medicine. Journal of Chinese Integrative Medicine, 2012, 10(11): 1206-1210
[10] Pedro Saganha João, Doenitz Christoph, Greten Tobias, Efferth Thomas, J. Greten Henry. Qigong therapy for physiotherapists suffering from burnout: a preliminary study. Journal of Chinese Integrative Medicine, 2012, 10(11): 1233-1239