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Involvement of gelatinases (MMP-2 and MMP-9) in the development of airway inflammation and pulmonary fibrosis

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Abstract

Pulmonary fibrosis has an aggressive course and is usually fatal an average of 3 to 6 years after the onset of symptoms. Pulmonary fibrosis is associated with deposition of extracellular matrix (ECM) components in the lung interstitium. Matrix metalloproteinases (MMPs) are a major group of proteinases known to regulate the ECM remodeling and so they are hypothesized to be important in the process of lung fibrosis. These led to the concept that modulation of airway remodeling including excessive proteolytic damage of the tissue may be of interest for future treatment. The excessive airway remodeling as a result of an imbalance in the equilibrium of the normal processes of synthesis and degradation of extracellular matrix components could argue in favor of antiprotease treatments. Moreover, these observations emphasize that effective therapies for these disorders must be given early in the natural history of the disease, prior to the development of expensive lung destruction and fibrosis.

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References

  • Belleguic C, Corbel M, Germain N, Boichot E, Delaval P, and Lagente V.Reduced gelatinase activity by the selective phosphodiesterase type 4 inhibitor, RP 73401, in sensitized mice. Eur J Pharmacol.2000:404:369-73.

    Article  PubMed  CAS  Google Scholar 

  • Belleguic C, Corbel M, Germain N, et al.Increased release of matrix metalloproteinase-9 in the plasma of acute severe asthmatic patients.Clin Exp Allergy.2002.[in press]

  • Betsuyaku T, Shipley JM, Liu Z, and Senior RM.Neutrophil emigration in the lungs, peritoneum, and skin does not require gelatinase B. Am J Respir Cell Mol Biol.1999;20: 1303-9.

    PubMed  CAS  Google Scholar 

  • Betsuyaku T, Fukuda Y, Parks WC, Shipley JM, and Senior RM.Gelatinase B is required for alveolar bronchiolization after intratracheal bleomycin. Am J Pathol.2000:157:525-35.

    PubMed  CAS  Google Scholar 

  • Birkedal-Hansen H.Proteolytic remodeling of extracellular matrix. Curr Opin Cell Biol.1995:7:728-35.

    Article  PubMed  CAS  Google Scholar 

  • Cataldo D, Munaut C, Noel A, et al.MMP-2-and MMP-9-linked gelatinolytic activity in the sputum from patients with asthma and chronic obstructive pulmonary disease. Int Arch Allergy Immunol.2000:123:259-67.

    Article  PubMed  CAS  Google Scholar 

  • Corbel M, Lagente V, Theret N, Germain N, Clement B, Boichot E.Comparative effects of betamethasone, cyclosporin and nedocromil sodium in acute pulmonary inflammation and metalloproteinase activities in bronchoalveolar lavage fluid from mice exposed to lipopolysaccharide. Pulm Pharmacol Ther.1999a;12:165-71.

    Article  PubMed  CAS  Google Scholar 

  • Corbel M, Caulet-Maugendre S, Germain N, et al.Increase activity of matrix metalloproteinase and collagen deposition after chronic administration of antigen in sensitized BP2 mouse. Am J Respir Crit Care Med.1999b;159:A189.

    Google Scholar 

  • Corbel M, Caulet-Maugendre S, Germain N, Molet S, Lagente V, and Boichot E.Inhibition of bleomycin-induced pulmonary fibrosis in mice by the matrix metalloproteinase inhibitor, Batimastat. J Pathol.2001a;193:538-45.

    Article  PubMed  CAS  Google Scholar 

  • Corbel M, Lanchou J, Germain N, Malledant Y, Boichot E, Lagente V.Modulation of airway remodeling-associated mediators by the antifibrotic compound pirfenidone and the matrix metalloproteinase inhibitor, batimastat, during acute lung injury. Eur J Pharmacol.2001b;426:l13-21.

    Article  Google Scholar 

  • Corbel M, Theret N, Caulet-Maugendre S, et al.Repeated endotoxin exposure induces intersitial fibrosis associated with enhanced gelatinase (MMP-2 and MMP-9) activity. Inflamm Res.2001c;50:129-35.

    Article  PubMed  CAS  Google Scholar 

  • Delclaux C, Delacourt C, D'Ortho MP, Boyer V, Lafuma C, Harf A.Role of gelatinase B and elastase in human polymorphonuclear neutrophil migration across basement membrane. Am J Respir Cell Mol Biol.1996:14:288-93.

    PubMed  CAS  Google Scholar 

  • De Nictolis M, Garbisa S, Lucarini G, et al.72-kilodalton type IV collagenase, type IV collagen, and Ki 67 antigen in serous tumors or the ovary: a clinicopathologic, immunohistochemical, and serological study. Int J Gynecol Pathol.1996;15(2):102-9.

    Article  PubMed  CAS  Google Scholar 

  • Denis U, Verweij J.Matrix metalloproteinase inhibitors: present achievements and future prospects. Invest New Drugs.1997;15:175-85.

    Article  PubMed  CAS  Google Scholar 

  • Fukuda Y, Ishizaki M, Kudoh S, Kitaichi M, Yamanaka N.Localisation of matrix metalloproteinases-1,-2, and-9 and tissue inhibitor of metalloproteinase-2 in interstitiallung diseases. Lab Invest.1998:78:687-98.

    PubMed  CAS  Google Scholar 

  • Gadeck JE, Kelman JA, Fens GA, Weinberger SE, Horwizt AL, Reynolds HY.Conagenase in the lower respiratory tract of patients with idiopathic pulmonary fibrosis. N Engl J Med.1979:301:737-42.

    Article  Google Scholar 

  • Germain N, Corbel M, Lanchou J, Boichot E, Lagente V.Effects of the phosphodiesterase 4 inhibitor, RP 73401, and interleukin-10 on acute pulmonary inflammation and metalloproteinase activity (MMP-9) in bronchoalveolar lavage fluid from mice exposed to lipopolysaccharide. Eur Respir J.2000;S31:557S.

    Google Scholar 

  • Hayashi T, Stetler-Stevenson WG, Fleming MY, et al.Immunohistochemical study ofmetalloproteinases and their tissue inhibitors in the lungs of patients with diffuse alveolar damage and idiopathic pulmonary fibrosis. Am J Pathol.1996:149:1241-56.

    PubMed  CAS  Google Scholar 

  • Hibbs MS, Hasty KA, Seyer IM, Kang AH, Mainardi CL.Biochemical and immunological characterization of the secreted forms of human neutrophil gelatinase. J Biol Chem.1985:260:2493-500.

    PubMed  CAS  Google Scholar 

  • Hoshino M, Nakamura Y, Sim J, Shimojo J, Isogai S.Bronchial subepithelial fibrosis and expression of matrix metalloproteinase-9 in asthmatic airway inflammation. J Allergy Clin Immunol.1998:102:783-8.

    Article  PubMed  CAS  Google Scholar 

  • lyer SN, Margolin SB, Hyde DM, Giri SN.Lung fibrosis is ameliorated by pirfenidone fed in diet after the second dose in a three-dose bleomycin-hamster model. Exp Lung Res.1998:24:119-32.

    Article  Google Scholar 

  • lyer SN, Wild JS, Schiedt MI, Hyde DM, Margolin SB and Giri SN.Dietary intake of pirfenidone ameliorates bleomycin-induced lung fibrosis in hamsters. J Lab Clin Med.1995; 125:779-85.

    Google Scholar 

  • Khalil N, Bereznay O, Spom M, and Greenberg AH.Macrophage production of transforming growth factor f3 and fibroblast collagen synthesis in chronic pulmonary inflammation. J Exp Med.1989:170:727-37.

    Article  PubMed  CAS  Google Scholar 

  • Khalil N, O'Connor RN, Unruh HW, et al.Increased production and immunohistochemical localization of transforming growth factor-f3 in idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol.1991:5:155-62.

    PubMed  CAS  Google Scholar 

  • Lanchou J, Corbel M, Boichot E, et al.Imbalance between matrix metalloproteinase (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) in the bronchoalveolar lavage of patients with long-lasting ARDS. Eur Respir J.2000;S31: 374S.

    Google Scholar 

  • Lemjabbar H, Gosset P, Lechapt-Zalcman E, et al.Over-expression of alveolar macrophage gelatinase B (MMP-9) in patients with idiopathic pulmonary fibrosis: effects of steroid and immunosuppressive treatment. Am J Respir Cell Mol Biol.1999:20:903-13.

    PubMed  CAS  Google Scholar 

  • Leppert D, Hauser SL, Kishiyama JL, An S, Zeng L, Goetzl EJ.Stimulation of matrix metalloproteinase-dependent migration of T cells by eicosanoids. FASEB J.1995:9:1473-81.

    PubMed  CAS  Google Scholar 

  • Llano E, Pendas AM, Freije JP, et al.Identification and characterization of human MT5-MMP (MMP-24), a new membrane-bound activator of pro-gelatinase a over-expressed in brain tumors.Cancer Res.1999;59(11):2570-6.

    PubMed  CAS  Google Scholar 

  • Mackarel AL, Cottell DC, Russell KJ, Fitzgerald MX, O'Connor CM.Migration of neutrophils across human pulmonary endothelial cells is not blocked by matrix metalloproteinase or serine protease inhibitors. Am J Respir Cell Mol Biol.1999:20:1209-19.

    PubMed  CAS  Google Scholar 

  • Madtes DK, Elston AL, Kaback LA, dark IG.Selective induction of tissue inhibitor of metalloproteinase-1 in bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol.2001:24:599-607.

    PubMed  CAS  Google Scholar 

  • Masure S, Proost P, Van DI, Opdenakker G.Purification and identification of 91-kDa neutrophil gelatinase.Release by the activating peptide interleukin-8. Eur J Biochem.1991; 198:391-8.

    Article  PubMed  CAS  Google Scholar 

  • Mautino G, Oliver N, Chanez P, Bousquet I, Capony F.Increased release of matrix metalloproteinase-9 in bronchoalveolar lavage fluid and by alveolar macrophages of asthmatics. Am J Respir Cell Mol Biol.1997:17:583-91.

    PubMed  CAS  Google Scholar 

  • Murphy G, Docherty AL.The matrix metalloproteinases and their inhibitors. Am J Respir Cell Mol Biol.1992:7:120-5.

    PubMed  CAS  Google Scholar 

  • O'Connor CM, Fitzgerald MX.Matrix metalloproteases and lung disease. Thorax.1994:49:602-9.

    PubMed  Google Scholar 

  • O'Connor C, Odium C, Van Breda A, Power C, Fitzgerald MX.Collagenase and fibronectin in bronchoalveolar lavage fluid in patients with sarcoidosis.Thorax.1988:43:393-400.

    PubMed  Google Scholar 

  • Ohno I, Ohtani H, Nitta Y, et al.Eosinophils as a source of matrix metalloproteinase-9 in asthmatic airway inflammation. Am J Respir Cell Mol Biol.1997:16:212-9.

    PubMed  CAS  Google Scholar 

  • Pardo A, Selman M, Ramirez R, et al.Production of collagenase and tissue inhibitor of metalloproteinases by fibroblasts derived from normal and fibrotic human lung.Chest.1992:102:1085-9.

    PubMed  CAS  Google Scholar 

  • Pardo A, Barrios R, Maldonado V, et al.Gelatinases A and B are up-regulated in rat lungs by subacute hyperoxia: pathogenetic implications. Am J Pathol.1998:153:833-44.

    PubMed  CAS  Google Scholar 

  • Parks WC, Shapiro SD.Matrix metalloproteinases in lung biology. Respir Res.2001:2:10-9.

    Article  PubMed  CAS  Google Scholar 

  • Pei D. Leukolysin/MMP-25/MT6-MMP: a novel matrix metalloproteinase specifically expressed in the leukocyte lineage.Cell Res.1999:9:291-303.

    Article  PubMed  CAS  Google Scholar 

  • Ricou B, Nicod L, Lacraz S, Welgus HG, Suter PM and Dayer JM.Matrix metalloproteinases and TIMP in acute respiratory distress syndrome. Am J Respir Crit Care Med.1996; 154:346-52.

    PubMed  CAS  Google Scholar 

  • Roche WR, Beasley R, Williams JH, Holgate ST. Subepithelial fibrosis in the bronchi of asthmatics.Lancet.1989:1:520-4.

    Article  PubMed  CAS  Google Scholar 

  • Selman M, Pardo A.Potential role of proteases in pulmonary fibrosis. Ann NYAcad Sci.1991:624:297-306.

    Article  CAS  Google Scholar 

  • Selman M, Ruiz V, Cabrem S, et al.TIMP-1,-2,-3, and-4 in idiopathic pulmonary fibrosis.A prevailing nondegradative lung microenvironment. Am J Physiol.2000;279:L562-74.

    CAS  Google Scholar 

  • Swiderski RE, Dencoff JE, Floerchinger CS, Shapiro SD, Hunninghake GW. Differential expression of extracellular matrix remodeling genes in a murine model of bleomycin-induced pulmonary fibrosis. Am J Pathol.1998:152:821-8.

    PubMed  CAS  Google Scholar 

  • Tetley TD.New perspectives on basic mechanisms in lung disease. 6. Proteinase imbalance: its role in lung disease.Thorax.1993:48:560-5.

    PubMed  CAS  Google Scholar 

  • Underwood DC, Osborn RR, Bochnowicz, et al. SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9 and fibrosis in lung. Am J Physiol Lung Cell Mol Physiol.2000;279:L895-902.

    PubMed  CAS  Google Scholar 

  • Velasco G, Pendas AM, Fueyo A, Knauper V, Murphy G, Lopez-Otin C. Cloning and characterization of human MMP-23, a new matrix metalloproteinase predominantly expressed in reproductive tissues and lacking conserved domains in other family members. J Biol Chem.1999:274 (8):4570-6.

    Article  PubMed  CAS  Google Scholar 

  • 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. Am J Respir Crit Care Med.1998:158: 1945-50.

    PubMed  CAS  Google Scholar 

  • Wang X, Fu X, Brown PD, Crimmin MI, Hoffinan RM. Matrix metalloproteinase inhibitor BB-94 (batimastat) inhibits human colon tumor growth and spread in a patient-like orthotopic model in nude mice. Cancer Res.1994:54:4726-8.

    PubMed  CAS  Google Scholar 

  • Watson SA, Morris TM, Robinson O, Crimmin MI, Brown PD, Hardcastle JD. Inhibition of organ invasion by the matrix metalloproteinase inhibitor batimastat (BB-94) in two human colon carcinoma metastasis models.Cancer Res.1995; 55:3629-33.

    PubMed  CAS  Google Scholar 

  • Yaguchi T, Fukuda Y, Ishizaki M, Yamanaka N. Immunohistochemical and gelatin zymography studies for matrix metalloproteinases in bleomycin-induced pulmonary fibrosis. Pathol Int.1998:48:954-63.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. INSERM U456, IFR 97, Université de Rennes I, Rennes, France

    M. Corbel, C. Belleguic, E. Boichot & V. Lagente

  2. Service de Pneumologie, CHU de Rennes, Hôpital de Pontchaillou, Rennes, France

    C. Belleguic

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  1. M. Corbel
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  3. E. Boichot
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  4. V. Lagente
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Corbel, M., Belleguic, C., Boichot, E. et al. Involvement of gelatinases (MMP-2 and MMP-9) in the development of airway inflammation and pulmonary fibrosis. Cell Biol Toxicol 18, 51–61 (2002). https://doi.org/10.1023/A:1014471213371

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