Skip to main content
Thorax logoLink to Thorax
. 2005 Apr;60(4):277–281. doi: 10.1136/thx.2004.028936

Relationship of airway wall thickening to an imbalance between matrix metalloproteinase-9 and its inhibitor in asthma

H Matsumoto 1, A Niimi 1, M Takemura 1, T Ueda 1, M Minakuchi 1, R Tabuena 1, K Chin 1, T Mio 1, Y Ito 1, S Muro 1, T Hirai 1, S Morita 1, S Fukuhara 1, M Mishima 1
PMCID: PMC1747359  PMID: 15790981

Abstract

Background: The balance between matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) may be critical in extracellular matrix remodelling, a characteristic of asthmatic airways. An excess of TIMP-1 over MMP-9 has been associated with chronic airflow obstruction but the mechanisms underlying this association remain unknown. Recent computed tomographic (CT) studies indicate that airway wall thickening is associated with chronic airflow obstruction.

Methods: Sputum levels of MMP-9, TIMP-1, and their molar ratio were examined in 26 patients with stable asthma and their relationship with pulmonary function and airway wall thickness, assessed by a validated CT technique which measured wall area corrected by body surface area (WA/BSA), the ratio of WA to outer wall area (WA%), and the absolute wall thickness corrected by √BSA of a segmental bronchus (T/√BSA), was examined.

Results: Sputum MMP-9 levels were inversely correlated with WA% and TIMP-1 levels were positively correlated with WA/BSA and T/√BSA. The MMP-9/TIMP-1 molar ratio was inversely correlated with WA% and T/√BSA and positively correlated with post-bronchodilator values of mid-forced expiratory flow and maximum expiratory flow at the quartile of lung volume.

Conclusion: Excess TIMP-1 may have a pathogenetic role in airway wall thickening in asthmatic patients which may result in chronic airflow obstruction.

Full Text

The Full Text of this article is available as a PDF (93.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bai T. R., Cooper J., Koelmeyer T., Paré P. D., Weir T. D. The effect of age and duration of disease on airway structure in fatal asthma. Am J Respir Crit Care Med. 2000 Aug;162(2 Pt 1):663–669. doi: 10.1164/ajrccm.162.2.9907151. [DOI] [PubMed] [Google Scholar]
  2. Bossé M., Chakir J., Rouabhia M., Boulet L. P., Audette M., Laviolette M. Serum matrix metalloproteinase-9:Tissue inhibitor of metalloproteinase-1 ratio correlates with steroid responsiveness in moderate to severe asthma. Am J Respir Crit Care Med. 1999 Feb;159(2):596–602. doi: 10.1164/ajrccm.159.2.9802045. [DOI] [PubMed] [Google Scholar]
  3. Corbel M., Caulet-Maugendre S., Germain N., Lagente V., Boichot E. Enhancement of gelatinase activity during development of subepithelial fibrosis in a murine model of asthma. Clin Exp Allergy. 2003 May;33(5):696–704. doi: 10.1046/j.1365-2222.2003.01581.x. [DOI] [PubMed] [Google Scholar]
  4. Cundall Meghan, Sun Yongchang, Miranda Christina, Trudeau John B., Barnes Stephen, Wenzel Sally E. Neutrophil-derived matrix metalloproteinase-9 is increased in severe asthma and poorly inhibited by glucocorticoids. J Allergy Clin Immunol. 2003 Dec;112(6):1064–1071. doi: 10.1016/j.jaci.2003.08.013. [DOI] [PubMed] [Google Scholar]
  5. Gershman N. H., Liu H., Wong H. H., Liu J. T., Fahy J. V. Fractional analysis of sequential induced sputum samples during sputum induction: evidence that different lung compartments are sampled at different time points. J Allergy Clin Immunol. 1999 Aug;104(2 Pt 1):322–328. doi: 10.1016/s0091-6749(99)70374-x. [DOI] [PubMed] [Google Scholar]
  6. Golden D. B. Discontinuation of venom immunotherapy. J Allergy Clin Immunol. 1998 Oct;102(4 Pt 1):703–704. doi: 10.1016/s0091-6749(98)70297-0. [DOI] [PubMed] [Google Scholar]
  7. Gruber B. L., Sorbi D., French D. L., Marchese M. J., Nuovo G. J., Kew R. R., Arbeit L. A. Markedly elevated serum MMP-9 (gelatinase B) levels in rheumatoid arthritis: a potentially useful laboratory marker. Clin Immunol Immunopathol. 1996 Feb;78(2):161–171. doi: 10.1006/clin.1996.0025. [DOI] [PubMed] [Google Scholar]
  8. Hayakawa T. Tissue inhibitors of metalloproteinases and their cell growth-promoting activity. Cell Struct Funct. 1994 Jun;19(3):109–114. doi: 10.1247/csf.19.109. [DOI] [PubMed] [Google Scholar]
  9. Hoshino M., Takahashi M., Takai Y., Sim J. Inhaled corticosteroids decrease subepithelial collagen deposition by modulation of the balance between matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 expression in asthma. J Allergy Clin Immunol. 1999 Aug;104(2 Pt 1):356–363. doi: 10.1016/s0091-6749(99)70379-9. [DOI] [PubMed] [Google Scholar]
  10. James Alan L., Maxwell Peta S., Pearce-Pinto Gladys, Elliot John G., Carroll Neil G. The relationship of reticular basement membrane thickness to airway wall remodeling in asthma. Am J Respir Crit Care Med. 2002 Dec 15;166(12 Pt 1):1590–1595. doi: 10.1164/rccm.2108069. [DOI] [PubMed] [Google Scholar]
  11. Jeffery P. K. Remodeling in asthma and chronic obstructive lung disease. Am J Respir Crit Care Med. 2001 Nov 15;164(10 Pt 2):S28–S38. doi: 10.1164/ajrccm.164.supplement_2.2106061. [DOI] [PubMed] [Google Scholar]
  12. Kasahara K., Shiba K., Ozawa T., Okuda K., Adachi M. Correlation between the bronchial subepithelial layer and whole airway wall thickness in patients with asthma. Thorax. 2002 Mar;57(3):242–246. doi: 10.1136/thorax.57.3.242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kelly E. A., Busse W. W., Jarjour N. N. Increased matrix metalloproteinase-9 in the airway after allergen challenge. Am J Respir Crit Care Med. 2000 Sep;162(3 Pt 1):1157–1161. doi: 10.1164/ajrccm.162.3.9908016. [DOI] [PubMed] [Google Scholar]
  14. Kikuchi K., Kubo M., Sato S., Fujimoto M., Tamaki K. Serum tissue inhibitor of metalloproteinases in patients with systemic sclerosis. J Am Acad Dermatol. 1995 Dec;33(6):973–978. doi: 10.1016/0190-9622(95)90289-9. [DOI] [PubMed] [Google Scholar]
  15. King G. G., Müller N. L., Paré P. D. Evaluation of airways in obstructive pulmonary disease using high-resolution computed tomography. Am J Respir Crit Care Med. 1999 Mar;159(3):992–1004. doi: 10.1164/ajrccm.159.3.9805064. [DOI] [PubMed] [Google Scholar]
  16. Little S. A., Sproule M. W., Cowan M. D., Macleod K. J., Robertson M., Love J. G., Chalmers G. W., McSharry C. P., Thomson N. C. High resolution computed tomographic assessment of airway wall thickness in chronic asthma: reproducibility and relationship with lung function and severity. Thorax. 2002 Mar;57(3):247–253. doi: 10.1136/thorax.57.3.247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Mautino G., Henriquet C., Jaffuel D., Bousquet J., Capony F. Tissue inhibitor of metalloproteinase-1 levels in bronchoalveolar lavage fluid from asthmatic subjects. Am J Respir Crit Care Med. 1999 Jul;160(1):324–330. doi: 10.1164/ajrccm.160.1.9808087. [DOI] [PubMed] [Google Scholar]
  18. Mautino G., Oliver N., Chanez P., Bousquet J., Capony F. Increased release of matrix metalloproteinase-9 in bronchoalveolar lavage fluid and by alveolar macrophages of asthmatics. Am J Respir Cell Mol Biol. 1997 Nov;17(5):583–591. doi: 10.1165/ajrcmb.17.5.2562. [DOI] [PubMed] [Google Scholar]
  19. McParland Brent E., Macklem Peter T., Pare Peter D. Airway wall remodeling: friend or foe? J Appl Physiol (1985) 2003 Jul;95(1):426–434. doi: 10.1152/japplphysiol.00159.2003. [DOI] [PubMed] [Google Scholar]
  20. Nakano Y., Muro S., Sakai H., Hirai T., Chin K., Tsukino M., Nishimura K., Itoh H., Paré P. D., Hogg J. C. Computed tomographic measurements of airway dimensions and emphysema in smokers. Correlation with lung function. Am J Respir Crit Care Med. 2000 Sep;162(3 Pt 1):1102–1108. doi: 10.1164/ajrccm.162.3.9907120. [DOI] [PubMed] [Google Scholar]
  21. Niimi A., Matsumoto H., Amitani R., Nakano Y., Mishima M., Minakuchi M., Nishimura K., Itoh H., Izumi T. Airway wall thickness in asthma assessed by computed tomography. Relation to clinical indices. Am J Respir Crit Care Med. 2000 Oct;162(4 Pt 1):1518–1523. doi: 10.1164/ajrccm.162.4.9909044. [DOI] [PubMed] [Google Scholar]
  22. Niimi Akio, Matsumoto Hisako, Amitani Ryoichi, Nakano Yasutaka, Sakai Hiroaki, Takemura Masaya, Ueda Tetsuya, Chin Kazuo, Itoh Harumi, Ingenito Edward P. Effect of short-term treatment with inhaled corticosteroid on airway wall thickening in asthma. Am J Med. 2004 Jun 1;116(11):725–731. doi: 10.1016/j.amjmed.2003.11.026. [DOI] [PubMed] [Google Scholar]
  23. Ohno I., Ohtani H., Nitta Y., Suzuki J., Hoshi H., Honma M., Isoyama S., Tanno Y., Tamura G., Yamauchi K. Eosinophils as a source of matrix metalloproteinase-9 in asthmatic airway inflammation. Am J Respir Cell Mol Biol. 1997 Mar;16(3):212–219. doi: 10.1165/ajrcmb.16.3.9070604. [DOI] [PubMed] [Google Scholar]
  24. Okada S., Kita H., George T. J., Gleich G. J., Leiferman K. M. Migration of eosinophils through basement membrane components in vitro: role of matrix metalloproteinase-9. Am J Respir Cell Mol Biol. 1997 Oct;17(4):519–528. doi: 10.1165/ajrcmb.17.4.2877. [DOI] [PubMed] [Google Scholar]
  25. Oshita Y., Koga T., Kamimura T., Matsuo K., Rikimaru T., Aizawa H. Increased circulating 92 kDa matrix metalloproteinase (MMP-9) activity in exacerbations of asthma. Thorax. 2003 Sep;58(9):757–760. doi: 10.1136/thorax.58.9.757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Pin I., Gibson P. G., Kolendowicz R., Girgis-Gabardo A., Denburg J. A., Hargreave F. E., Dolovich J. Use of induced sputum cell counts to investigate airway inflammation in asthma. Thorax. 1992 Jan;47(1):25–29. doi: 10.1136/thx.47.1.25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Roth Michael, Johnson Peter R. A., Borger Peter, Bihl Michel P., Rüdiger Jochen J., King Gregory G., Ge Qi, Hostettler Katrin, Burgess Janette K., Black Judith L. Dysfunctional interaction of C/EBPalpha and the glucocorticoid receptor in asthmatic bronchial smooth-muscle cells. N Engl J Med. 2004 Aug 5;351(6):560–574. doi: 10.1056/NEJMoa021660. [DOI] [PubMed] [Google Scholar]
  28. Segura-Valdez L., Pardo A., Gaxiola M., Uhal B. D., Becerril C., Selman M. Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death in COPD. Chest. 2000 Mar;117(3):684–694. doi: 10.1378/chest.117.3.684. [DOI] [PubMed] [Google Scholar]
  29. Takemura Masaya, Niimi Akio, Minakuchi Masayoshi, Matsumoto Hisako, Ueda Tetsuya, Chin Kazuo, Mishima Michiaki. Bronchial dilatation in asthma: relation to clinical and sputum indices. Chest. 2004 Apr;125(4):1352–1358. doi: 10.1378/chest.125.4.1352. [DOI] [PubMed] [Google Scholar]
  30. Takishima T., Hida W., Sasaki H., Suzuki S., Sasaki T. Direct-writing recorder of the dose-response curves of the airway to methacholine. Clinical application. Chest. 1981 Nov;80(5):600–606. doi: 10.1378/chest.80.5.600. [DOI] [PubMed] [Google Scholar]
  31. Tanaka H., Miyazaki N., Oashi K., Tanaka S., Ohmichi M., Abe S. Sputum matrix metalloproteinase-9: tissue inhibitor of metalloproteinase-1 ratio in acute asthma. J Allergy Clin Immunol. 2000 May;105(5):900–905. doi: 10.1067/mai.2000.105316. [DOI] [PubMed] [Google Scholar]
  32. Vignola A. M., Riccobono L., Mirabella A., Profita M., Chanez P., Bellia V., Mautino G., D'accardi P., Bousquet J., Bonsignore G. Sputum metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio correlates with airflow obstruction in asthma and chronic bronchitis. Am J Respir Crit Care Med. 1998 Dec;158(6):1945–1950. doi: 10.1164/ajrccm.158.6.9803014. [DOI] [PubMed] [Google Scholar]
  33. Wenzel Sally E., Balzar Silvana, Cundall Meghan, Chu Hong Wei. Subepithelial basement membrane immunoreactivity for matrix metalloproteinase 9: association with asthma severity, neutrophilic inflammation, and wound repair. J Allergy Clin Immunol. 2003 Jun;111(6):1345–1352. doi: 10.1067/mai.2003.1464. [DOI] [PubMed] [Google Scholar]
  34. Woessner J. F., Jr Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J. 1991 May;5(8):2145–2154. [PubMed] [Google Scholar]

Articles from Thorax are provided here courtesy of BMJ Publishing Group

RESOURCES