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. 1998 Oct 1;102(7):1321–1331. doi: 10.1172/JCI1516

Matrilysin expression and function in airway epithelium.

S E Dunsmore 1, U K Saarialho-Kere 1, J D Roby 1, C L Wilson 1, L M Matrisian 1, H G Welgus 1, W C Parks 1
PMCID: PMC508979  PMID: 9769324

Abstract

We report that matrilysin, a matrix metalloproteinase, is constitutively expressed in the epithelium of peribronchial glands and conducting airways in normal lung. Matrilysin expression was increased in airway epithelial cells and was induced in alveolar type II cells in cystic fibrosis. Other metalloproteinases (collagenase-1, stromelysin-1, and 92-kD gelatinase) were not produced by normal or injured lung epithelium. These observations suggest that matrilysin functions in injury-mediated responses of the lung. Indeed, matrilysin expression was increased in migrating airway epithelial cells in wounded human and mouse trachea. In human tissue, epithelial migration was reduced by > 80% by a hydroxamate inhibitor, and in mouse tissue, reepithelialization in trachea from matrilysin-null mice was essentially blocked. In vivo observations and cell culture studies demonstrated that matrilysin was secreted lumenally by lung epithelium, but upon activation or while migrating over wounds, some matrilysin was released basally. The constitutive production of matrilysin in conducting airways, its upregulation after injury, its induction by alveolar epithelium, and its release into both lumenal and matrix compartments suggest that this metalloproteinase serves multiple functions in intact and injured lung, one of which is to facilitate reepithelialization.

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Selected References

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  1. Birkedal-Hansen H., Moore W. G., Bodden M. K., Windsor L. J., Birkedal-Hansen B., DeCarlo A., Engler J. A. Matrix metalloproteinases: a review. Crit Rev Oral Biol Med. 1993;4(2):197–250. doi: 10.1177/10454411930040020401. [DOI] [PubMed] [Google Scholar]
  2. Brinckerhoff C. E. Joint destruction in arthritis: metalloproteinases in the spotlight. Arthritis Rheum. 1991 Sep;34(9):1073–1075. doi: 10.1002/art.1780340902. [DOI] [PubMed] [Google Scholar]
  3. Brown-Augsburger P., Hartshorn K., Chang D., Rust K., Fliszar C., Welgus H. G., Crouch E. C. Site-directed mutagenesis of Cys-15 and Cys-20 of pulmonary surfactant protein D. Expression of a trimeric protein with altered anti-viral properties. J Biol Chem. 1996 Jun 7;271(23):13724–13730. doi: 10.1074/jbc.271.23.13724. [DOI] [PubMed] [Google Scholar]
  4. Buisson A. C., Gilles C., Polette M., Zahm J. M., Birembaut P., Tournier J. M. Wound repair-induced expression of a stromelysins is associated with the acquisition of a mesenchymal phenotype in human respiratory epithelial cells. Lab Invest. 1996 Mar;74(3):658–669. [PubMed] [Google Scholar]
  5. Busiek D. F., Baragi V., Nehring L. C., Parks W. C., Welgus H. G. Matrilysin expression by human mononuclear phagocytes and its regulation by cytokines and hormones. J Immunol. 1995 Jun 15;154(12):6484–6491. [PubMed] [Google Scholar]
  6. Busiek D. F., Ross F. P., McDonnell S., Murphy G., Matrisian L. M., Welgus H. G. The matrix metalloprotease matrilysin (PUMP) is expressed in developing human mononuclear phagocytes. J Biol Chem. 1992 May 5;267(13):9087–9092. [PubMed] [Google Scholar]
  7. Chin J. R., Werb Z. Matrix metalloproteinases regulate morphogenesis, migration and remodeling of epithelium, tongue skeletal muscle and cartilage in the mandibular arch. Development. 1997 Apr;124(8):1519–1530. doi: 10.1242/dev.124.8.1519. [DOI] [PubMed] [Google Scholar]
  8. Delacourt C., Le Bourgeois M., D'Ortho M. P., Doit C., Scheinmann P., Navarro J., Harf A., Hartmann D. J., Lafuma C. Imbalance between 95 kDa type IV collagenase and tissue inhibitor of metalloproteinases in sputum of patients with cystic fibrosis. Am J Respir Crit Care Med. 1995 Aug;152(2):765–774. doi: 10.1164/ajrccm.152.2.7633740. [DOI] [PubMed] [Google Scholar]
  9. Halpert I., Sires U. I., Roby J. D., Potter-Perigo S., Wight T. N., Shapiro S. D., Welgus H. G., Wickline S. A., Parks W. C. Matrilysin is expressed by lipid-laden macrophages at sites of potential rupture in atherosclerotic lesions and localizes to areas of versican deposition, a proteoglycan substrate for the enzyme. Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9748–9753. doi: 10.1073/pnas.93.18.9748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hayashi T., Stetler-Stevenson W. G., Fleming M. V., Fishback N., Koss M. N., Liotta L. A., Ferrans V. J., Travis W. D. Immunohistochemical study of metalloproteinases and their tissue inhibitors in the lungs of patients with diffuse alveolar damage and idiopathic pulmonary fibrosis. Am J Pathol. 1996 Oct;149(4):1241–1256. [PMC free article] [PubMed] [Google Scholar]
  11. Inoue M., Kratz G., Haegerstrand A., Ståhle-Bäckdahl M. Collagenase expression is rapidly induced in wound-edge keratinocytes after acute injury in human skin, persists during healing, and stops at re-epithelialization. J Invest Dermatol. 1995 Apr;104(4):479–483. doi: 10.1111/1523-1747.ep12605917. [DOI] [PubMed] [Google Scholar]
  12. Karelina T. V., Goldberg G. I., Eisen A. Z. Matrilysin (PUMP) correlates with dermal invasion during appendageal development and cutaneous neoplasia. J Invest Dermatol. 1994 Oct;103(4):482–487. doi: 10.1111/1523-1747.ep12395596. [DOI] [PubMed] [Google Scholar]
  13. Klein R. D., Borchers A. H., Sundareshan P., Bougelet C., Berkman M. R., Nagle R. B., Bowden G. T. Interleukin-1beta secreted from monocytic cells induces the expression of matrilysin in the prostatic cell line LNCaP. J Biol Chem. 1997 May 30;272(22):14188–14192. doi: 10.1074/jbc.272.22.14188. [DOI] [PubMed] [Google Scholar]
  14. Kronborg G., Hansen M. B., Svenson M., Fomsgaard A., Høiby N., Bendtzen K. Cytokines in sputum and serum from patients with cystic fibrosis and chronic Pseudomonas aeruginosa infection as markers of destructive inflammation in the lungs. Pediatr Pulmonol. 1993 May;15(5):292–297. doi: 10.1002/ppul.1950150506. [DOI] [PubMed] [Google Scholar]
  15. Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995 Jun 1;91(11):2844–2850. doi: 10.1161/01.cir.91.11.2844. [DOI] [PubMed] [Google Scholar]
  16. Librach C. L., Werb Z., Fitzgerald M. L., Chiu K., Corwin N. M., Esteves R. A., Grobelny D., Galardy R., Damsky C. H., Fisher S. J. 92-kD type IV collagenase mediates invasion of human cytotrophoblasts. J Cell Biol. 1991 Apr;113(2):437–449. doi: 10.1083/jcb.113.2.437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Matrisian L. M. The matrix-degrading metalloproteinases. Bioessays. 1992 Jul;14(7):455–463. doi: 10.1002/bies.950140705. [DOI] [PubMed] [Google Scholar]
  18. McDonnell S., Navre M., Coffey R. J., Jr, Matrisian L. M. Expression and localization of the matrix metalloproteinase pump-1 (MMP-7) in human gastric and colon carcinomas. Mol Carcinog. 1991;4(6):527–533. doi: 10.1002/mc.2940040617. [DOI] [PubMed] [Google Scholar]
  19. Monteagudo C., Merino M. J., San-Juan J., Liotta L. A., Stetler-Stevenson W. G. Immunohistochemical distribution of type IV collagenase in normal, benign, and malignant breast tissue. Am J Pathol. 1990 Mar;136(3):585–592. [PMC free article] [PubMed] [Google Scholar]
  20. Moore W. M., Spilburg C. A. Purification of human collagenases with a hydroxamic acid affinity column. Biochemistry. 1986 Sep 9;25(18):5189–5195. doi: 10.1021/bi00366a031. [DOI] [PubMed] [Google Scholar]
  21. Muller D., Breathnach R., Engelmann A., Millon R., Bronner G., Flesch H., Dumont P., Eber M., Abecassis J. Expression of collagenase-related metalloproteinase genes in human lung or head and neck tumours. Int J Cancer. 1991 Jun 19;48(4):550–556. doi: 10.1002/ijc.2910480412. [DOI] [PubMed] [Google Scholar]
  22. Murphy G., Cockett M. I., Ward R. V., Docherty A. J. Matrix metalloproteinase degradation of elastin, type IV collagen and proteoglycan. A quantitative comparison of the activities of 95 kDa and 72 kDa gelatinases, stromelysins-1 and -2 and punctuated metalloproteinase (PUMP). Biochem J. 1991 Jul 1;277(Pt 1):277–279. doi: 10.1042/bj2770277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Pardo A., Ridge K., Uhal B., Sznajder J. I., Selman M. Lung alveolar epithelial cells synthesize interstitial collagenase and gelatinases A and B in vitro. Int J Biochem Cell Biol. 1997 Jun;29(6):901–910. doi: 10.1016/s1357-2725(97)00030-7. [DOI] [PubMed] [Google Scholar]
  24. Pilcher B. K., Dumin J. A., Sudbeck B. D., Krane S. M., Welgus H. G., Parks W. C. The activity of collagenase-1 is required for keratinocyte migration on a type I collagen matrix. J Cell Biol. 1997 Jun 16;137(6):1445–1457. doi: 10.1083/jcb.137.6.1445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Prosser I. W., Stenmark K. R., Suthar M., Crouch E. C., Mecham R. P., Parks W. C. Regional heterogeneity of elastin and collagen gene expression in intralobar arteries in response to hypoxic pulmonary hypertension as demonstrated by in situ hybridization. Am J Pathol. 1989 Dec;135(6):1073–1088. [PMC free article] [PubMed] [Google Scholar]
  26. Quinton P. M. Cystic fibrosis: a disease in electrolyte transport. FASEB J. 1990 Jul;4(10):2709–2717. doi: 10.1096/fasebj.4.10.2197151. [DOI] [PubMed] [Google Scholar]
  27. Rennard S. I., Bitterman P. B., Crystal R. G. Response of the lower respiratory tract to injury. Mechanisms of repair of the parenchymal cells of the alveolar wall. Chest. 1983 Dec;84(6):735–739. doi: 10.1378/chest.84.6.735. [DOI] [PubMed] [Google Scholar]
  28. Rodgers W. H., Matrisian L. M., Giudice L. C., Dsupin B., Cannon P., Svitek C., Gorstein F., Osteen K. G. Patterns of matrix metalloproteinase expression in cycling endometrium imply differential functions and regulation by steroid hormones. J Clin Invest. 1994 Sep;94(3):946–953. doi: 10.1172/JCI117461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Rodgers W. H., Osteen K. G., Matrisian L. M., Navre M., Giudice L. C., Gorstein F. Expression and localization of matrilysin, a matrix metalloproteinase, in human endometrium during the reproductive cycle. Am J Obstet Gynecol. 1993 Jan;168(1 Pt 1):253–260. doi: 10.1016/s0002-9378(12)90922-9. [DOI] [PubMed] [Google Scholar]
  30. Saarialho-Kere U. K., Chang E. S., Welgus H. G., Parks W. C. Distinct localization of collagenase and tissue inhibitor of metalloproteinases expression in wound healing associated with ulcerative pyogenic granuloma. J Clin Invest. 1992 Nov;90(5):1952–1957. doi: 10.1172/JCI116073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Saarialho-Kere U. K., Chang E. S., Welgus H. G., Parks W. C. Expression of interstitial collagenase, 92-kDa gelatinase, and tissue inhibitor of metalloproteinases-1 in granuloma annulare and necrobiosis lipoidica diabeticorum. J Invest Dermatol. 1993 Mar;100(3):335–342. doi: 10.1111/1523-1747.ep12470032. [DOI] [PubMed] [Google Scholar]
  32. Saarialho-Kere U. K., Crouch E. C., Parks W. C. Matrix metalloproteinase matrilysin is constitutively expressed in adult human exocrine epithelium. J Invest Dermatol. 1995 Aug;105(2):190–196. doi: 10.1111/1523-1747.ep12317104. [DOI] [PubMed] [Google Scholar]
  33. Saarialho-Kere U. K., Kovacs S. O., Pentland A. P., Olerud J. E., Welgus H. G., Parks W. C. Cell-matrix interactions modulate interstitial collagenase expression by human keratinocytes actively involved in wound healing. J Clin Invest. 1993 Dec;92(6):2858–2866. doi: 10.1172/JCI116906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Saarialho-Kere U. K., Pentland A. P., Birkedal-Hansen H., Parks W. C., Welgus H. G. Distinct populations of basal keratinocytes express stromelysin-1 and stromelysin-2 in chronic wounds. J Clin Invest. 1994 Jul;94(1):79–88. doi: 10.1172/JCI117351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Saarialho-Kere U. K., Vaalamo M., Airola K., Niemi K. M., Oikarinen A. I., Parks W. C. Interstitial collagenase is expressed by keratinocytes that are actively involved in reepithelialization in blistering skin disease. J Invest Dermatol. 1995 Jun;104(6):982–988. doi: 10.1111/1523-1747.ep12606231. [DOI] [PubMed] [Google Scholar]
  36. Saarialho-Kere U. K., Vaalamo M., Puolakkainen P., Airola K., Parks W. C., Karjalainen-Lindsberg M. L. Enhanced expression of matrilysin, collagenase, and stromelysin-1 in gastrointestinal ulcers. Am J Pathol. 1996 Feb;148(2):519–526. [PMC free article] [PubMed] [Google Scholar]
  37. Salo T., Mäkelä M., Kylmäniemi M., Autio-Harmainen H., Larjava H. Expression of matrix metalloproteinase-2 and -9 during early human wound healing. Lab Invest. 1994 Feb;70(2):176–182. [PubMed] [Google Scholar]
  38. Sires U. I., Griffin G. L., Broekelmann T. J., Mecham R. P., Murphy G., Chung A. E., Welgus H. G., Senior R. M. Degradation of entactin by matrix metalloproteinases. Susceptibility to matrilysin and identification of cleavage sites. J Biol Chem. 1993 Jan 25;268(3):2069–2074. [PubMed] [Google Scholar]
  39. Sires U. I., Murphy G., Baragi V. M., Fliszar C. J., Welgus H. G., Senior R. M. Matrilysin is much more efficient than other matrix metalloproteinases in the proteolytic inactivation of alpha 1-antitrypsin. Biochem Biophys Res Commun. 1994 Oct 28;204(2):613–620. doi: 10.1006/bbrc.1994.2503. [DOI] [PubMed] [Google Scholar]
  40. Ståhle-Bäckdahl M., Parks W. C. 92-kd gelatinase is actively expressed by eosinophils and stored by neutrophils in squamous cell carcinoma. Am J Pathol. 1993 Apr;142(4):995–1000. [PMC free article] [PubMed] [Google Scholar]
  41. Sudbeck B. D., Pilcher B. K., Welgus H. G., Parks W. C. Induction and repression of collagenase-1 by keratinocytes is controlled by distinct components of different extracellular matrix compartments. J Biol Chem. 1997 Aug 29;272(35):22103–22110. doi: 10.1074/jbc.272.35.22103. [DOI] [PubMed] [Google Scholar]
  42. Talhouk R. S., Chin J. R., Unemori E. N., Werb Z., Bissell M. J. Proteinases of the mammary gland: developmental regulation in vivo and vectorial secretion in culture. Development. 1991 Jun;112(2):439–449. doi: 10.1242/dev.112.2.439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Tournier J. M., Polette M., Hinnrasky J., Beck J., Werb Z., Basbaum C. Expression of gelatinase A, a mediator of extracellular matrix remodeling, by tracheal gland serous cells in culture and in vivo. J Biol Chem. 1994 Oct 14;269(41):25454–25464. [PubMed] [Google Scholar]
  44. Urbanski S. J., Edwards D. R., Maitland A., Leco K. J., Watson A., Kossakowska A. E. Expression of metalloproteinases and their inhibitors in primary pulmonary carcinomas. Br J Cancer. 1992 Dec;66(6):1188–1194. doi: 10.1038/bjc.1992.434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Vu T. H., Shipley J. M., Bergers G., Berger J. E., Helms J. A., Hanahan D., Shapiro S. D., Senior R. M., Werb Z. MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell. 1998 May 1;93(3):411–422. doi: 10.1016/s0092-8674(00)81169-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Wilmott R. W., Frenzke M., Kociela V., Peng L. Plasma interleukin-1 alpha and beta, tumor necrosis factor-alpha, and lipopolysaccharide concentrations during pulmonary exacerbations of cystic fibrosis. Pediatr Pulmonol. 1994 Jul;18(1):21–27. doi: 10.1002/ppul.1950180107. [DOI] [PubMed] [Google Scholar]
  47. Wilson C. L., Heppner K. J., Labosky P. A., Hogan B. L., Matrisian L. M. Intestinal tumorigenesis is suppressed in mice lacking the metalloproteinase matrilysin. Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1402–1407. doi: 10.1073/pnas.94.4.1402. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Wilson C. L., Heppner K. J., Rudolph L. A., Matrisian L. M. The metalloproteinase matrilysin is preferentially expressed by epithelial cells in a tissue-restricted pattern in the mouse. Mol Biol Cell. 1995 Jul;6(7):851–869. doi: 10.1091/mbc.6.7.851. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Wilson M. J., Garcia B., Woodson M., Sinha A. A. Metalloproteinase activities expressed during development and maturation of the rat prostatic complex and seminal vesicles. Biol Reprod. 1992 Nov;47(5):683–691. doi: 10.1095/biolreprod47.5.683. [DOI] [PubMed] [Google Scholar]
  50. Wilson M. J., Strasser M., Vogel M. M., Sinha A. A. Calcium-dependent and calcium-independent gelatinolytic proteinase activities of the rat ventral prostate and its secretion: characterization and effect of castration and testosterone treatment. Biol Reprod. 1991 May;44(5):776–785. doi: 10.1095/biolreprod44.5.776. [DOI] [PubMed] [Google Scholar]
  51. Yao P. M., Buhler J. M., d'Ortho M. P., Lebargy F., Delclaux C., Harf A., Lafuma C. Expression of matrix metalloproteinase gelatinases A and B by cultured epithelial cells from human bronchial explants. J Biol Chem. 1996 Jun 28;271(26):15580–15589. doi: 10.1074/jbc.271.26.15580. [DOI] [PubMed] [Google Scholar]
  52. Yao P. M., Delclaux C., d'Ortho M. P., Maitre B., Harf A., Lafuma C. Cell-matrix interactions modulate 92-kD gelatinase expression by human bronchial epithelial cells. Am J Respir Cell Mol Biol. 1998 Jun;18(6):813–822. doi: 10.1165/ajrcmb.18.6.2984. [DOI] [PubMed] [Google Scholar]
  53. Yin H. Z., Vogel M. M., Schneider M., Ercole C., Zhang G., Sinha A. A., Wilson M. J. Gelatinolytic proteinase activities in human seminal plasma. J Reprod Fertil. 1990 Mar;88(2):491–501. doi: 10.1530/jrf.0.0880491. [DOI] [PubMed] [Google Scholar]
  54. d'Ortho M. P., Clerici C., Yao P. M., Delacourt C., Delclaux C., Franco-Montoya M. L., Harf A., Lafuma C. Alveolar epithelial cells in vitro produce gelatinases and tissue inhibitor of matrix metalloproteinase-2. Am J Physiol. 1997 Sep;273(3 Pt 1):L663–L675. doi: 10.1152/ajplung.1997.273.3.L663. [DOI] [PubMed] [Google Scholar]
  55. von Bredow D. C., Nagle R. B., Bowden G. T., Cress A. E. Cleavage of beta 4 integrin by matrilysin. Exp Cell Res. 1997 Oct 10;236(1):341–345. doi: 10.1006/excr.1997.3711. [DOI] [PubMed] [Google Scholar]

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