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. 1984 Apr;55:297–306. doi: 10.1289/ehp.8455297

Role of connective tissue proteases in the pathogenesis of chronic inflammatory lung disease.

J E Gadek, G A Fells, R L Zimmerman, R G Crystal
PMCID: PMC1568367  PMID: 6329673

Abstract

The normal structure and function of the human lung is dependent on the maintenance of the connective tissue matrix. These structural macromolecules provide the template for normal parenchymal cell architecture on which efficient gas exchange depends. In addition, the organization and amount of this extracellular matrix accounts for much of the mechanical behavior of the lung parenchyma during the respiratory cycle. The preservation of this intricate connective tissue scaffold depends on the lung's capacity to prevent enzymatic disruption of the component matrix proteins. Specifically, the integrity of the normal connective tissue skeleton of the lung is determined by the maintenance of a balance between proteases capable of cleaving these structural elements and the specific protease inhibitors. The normal extracellular matrix is preserved when the local concentrations of protease inhibitors prohibits expression of active connective tissue proteases within the lung parenchyma. Conversely, the disruption of lung structure during the course of acute and chronic inflammatory diseases of the lung is often associated with an imbalance of protease-antiprotease activity. The consequence is the expression of unimpeded proteolytic attack on the connective tissue matrix of the lung. In this context, the nature of the pulmonary lesion and its physiologic consequences, reflect the specificity of the expressed proteases for the individual connective tissue components. Experimental evidence suggests that the differential expression of collagenase and elastase, prototypes of connective tissue proteases, may determine whether the pathologic outcome is fibrosis (e.g., idiopathic pulmonary fibrosis) or destruction (e.g., emphysema) of the alveolar structures.

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Selected References

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

  1. Adnet J. J., Pinteaux A., Pousse G., Caulet T. Caractérisation du tissu élastique normal et pathologique en microscope électronique. (Sur coupes semi-fines et coupes fines) Pathol Biol (Paris) 1976 Apr;24(4):293–296. [PubMed] [Google Scholar]
  2. Bell D. Y., Haseman J. A., Spock A., McLennan G., Hook G. E. Plasma proteins of the bronchoalveolar surface of the lungs of smokers and nonsmokers. Am Rev Respir Dis. 1981 Jul;124(1):72–79. doi: 10.1164/arrd.1981.124.1.72. [DOI] [PubMed] [Google Scholar]
  3. Bradley K. H., Kawanami O., Ferrans V. J., Crystal R. G. The fibroblast of human lung alveolar structures: a differentiated cell with a major role in lung structure and function. Methods Cell Biol. 1980;21A:37–64. doi: 10.1016/s0091-679x(08)60757-8. [DOI] [PubMed] [Google Scholar]
  4. Brissie R. M., Spicer S. S., Hall B. J., Thompson N. T. Ultrastructural staining of thin sections with iron hematoxylin. J Histochem Cytochem. 1974 Sep;22(9):895–907. doi: 10.1177/22.9.895. [DOI] [PubMed] [Google Scholar]
  5. Campbell E. J., White R. R., Senior R. M., Rodriguez R. J., Kuhn C. Receptor-mediated binding and internalization of leukocyte elastase by alveolar macrophages in vitro. J Clin Invest. 1979 Sep;64(3):824–833. doi: 10.1172/JCI109530. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Carp H., Janoff A. Possible mechanisms of emphysema in smokers. In vitro suppression of serum elastase-inhibitory capacity by fresh cigarette smoke and its prevention by antioxidants. Am Rev Respir Dis. 1978 Sep;118(3):617–621. doi: 10.1164/arrd.1978.118.3.617. [DOI] [PubMed] [Google Scholar]
  7. Crystal R. G., Fulmer J. D., Roberts W. C., Moss M. L., Line B. R., Reynolds H. Y. Idiopathic pulmonary fibrosis. Clinical, histologic, radiographic, physiologic, scintigraphic, cytologic, and biochemical aspects. Ann Intern Med. 1976 Dec;85(6):769–788. doi: 10.7326/0003-4819-85-6-769. [DOI] [PubMed] [Google Scholar]
  8. Crystal R. G., Gadek J. E., Ferrans V. J., Fulmer J. D., Line B. R., Hunninghake G. W. Interstitial lung disease: current concepts of pathogenesis, staging and therapy. Am J Med. 1981 Mar;70(3):542–568. doi: 10.1016/0002-9343(81)90577-5. [DOI] [PubMed] [Google Scholar]
  9. GROSS P., PFITZER E. A., TOLKER E., BABYAK M. A., KASCHAK M. EXPERIMENTAL EMPHYSEMA: ITS PRODUCTION WITH PAPAIN IN NORMAL AND SILICOTIC RATS. Arch Environ Health. 1965 Jul;11:50–58. doi: 10.1080/00039896.1965.10664169. [DOI] [PubMed] [Google Scholar]
  10. Gadek J. E., Fells G. A., Crystal R. G. Cigarette smoking induces functional antiprotease deficiency in the lower respiratory tract of humans. Science. 1979 Dec 14;206(4424):1315–1316. doi: 10.1126/science.316188. [DOI] [PubMed] [Google Scholar]
  11. Gadek J. E., Fells G. A., Wright D. G., Crystal R. G. Human neutrophil elastase functions as a type III collagen "collagenase". Biochem Biophys Res Commun. 1980 Aug 29;95(4):1815–1822. doi: 10.1016/s0006-291x(80)80110-0. [DOI] [PubMed] [Google Scholar]
  12. Gadek J. E., Fells G. A., Zimmerman R. L., Rennard S. I., Crystal R. G. Antielastases of the human alveolar structures. Implications for the protease-antiprotease theory of emphysema. J Clin Invest. 1981 Oct;68(4):889–898. doi: 10.1172/JCI110344. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gadek J. E., Hunninghake G. W., Fells G. A., Zimmerman R. L., Keogh B. A., Crystal R. G. Evaluation of the protease-antiprotease theory of human destructive lung disease. Bull Eur Physiopathol Respir. 1980;16 (Suppl):27–40. doi: 10.1016/b978-0-08-027379-2.50005-3. [DOI] [PubMed] [Google Scholar]
  14. Gadek J. E., Hunninghake G. W., Zimmerman R. L., Crystal R. G. Regulation of the release of alveolar macrophage-derived neutrophil chemotactic factor. Am Rev Respir Dis. 1980 Apr;121(4):723–733. doi: 10.1164/arrd.1980.121.4.723. [DOI] [PubMed] [Google Scholar]
  15. Gadek J. E., Kelman J. A., Fells G., Weinberger S. E., Horwitz A. L., Reynolds H. Y., Fulmer J. D., Crystal R. G. Collagenase in the lower respiratory tract of patients with idiopathic pulmonary fibrosis. N Engl J Med. 1979 Oct 4;301(14):737–742. doi: 10.1056/NEJM197910043011401. [DOI] [PubMed] [Google Scholar]
  16. Hance A. J., Crystal R. G. The connective tissue of lung. Am Rev Respir Dis. 1975 Nov;112(5):657–711. doi: 10.1164/arrd.1975.112.5.657. [DOI] [PubMed] [Google Scholar]
  17. Horwitz A. L., Crystal R. C. Content and synthesis of glycosaminoglycans in the developing lung. J Clin Invest. 1975 Nov;56(5):1312–1318. doi: 10.1172/JCI108207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Horwitz A. L., Hance A. J., Crystal R. G. Granulocyte collagenase: selective digestion of type I relative to type III collagen. Proc Natl Acad Sci U S A. 1977 Mar;74(3):897–901. doi: 10.1073/pnas.74.3.897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Horwitz A. L., Kelman J. A., Crystal R. G. Activation of alveolar macrophage collagenase by a neutral protease secreted by the same cell. Nature. 1976 Dec 23;264(5588):772–774. doi: 10.1038/264772a0. [DOI] [PubMed] [Google Scholar]
  20. Hunninghake G. W., Davidson J. M., Rennard S., Szapiel S., Gadek J. E., Crystal R. G. Elastin fragments attract macrophage precursors to diseased sites in pulmonary emphysema. Science. 1981 May 22;212(4497):925–927. doi: 10.1126/science.7233186. [DOI] [PubMed] [Google Scholar]
  21. Hunninghake G. W., Gadek J. E., Kawanami O., Ferrans V. J., Crystal R. G. Inflammatory and immune processes in the human lung in health and disease: evaluation by bronchoalveolar lavage. Am J Pathol. 1979 Oct;97(1):149–206. [PMC free article] [PubMed] [Google Scholar]
  22. Hunninghake G. W., Gadek J. E., Lawley T. J., Crystal R. G. Mechanisms of neutrophil accumulation in the lungs of patients with idiopathic pulmonary fibrosis. J Clin Invest. 1981 Jul;68(1):259–269. doi: 10.1172/JCI110242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hunninghake G., Gadek J., Crystal R. Mechanism by which cigarette smoke attracts polymorphonuclear leukocytes to lung. Chest. 1980 Feb;77(2 Suppl):273–273. doi: 10.1378/chest.77.2_supplement.273. [DOI] [PubMed] [Google Scholar]
  24. Janoff A., Carp H., Lee D. K., Drew R. T. Cigarette smoke inhalation decreases alpha 1-antitrypsin activity in rat lung. Science. 1979 Dec 14;206(4424):1313–1314. doi: 10.1126/science.316187. [DOI] [PubMed] [Google Scholar]
  25. Janoff A., Feinstein G., Malemud C. J., Elias J. M. Degradation of cartilage proteoglycan by human leukocyte granule neutral proteases--a model of joint injury. I. Penetration of enzyme into rabbit articular cartilage and release of 35SO4-labeled material from the tissue. J Clin Invest. 1976 Mar;57(3):615–624. doi: 10.1172/JCI108317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Janoff A., Sloan B., Weinbaum G., Damiano V., Sandhaus R. A., Elias J., Kimbel P. Experimental emphysema induced with purified human neutrophil elastase: tissue localization of the instilled protease. Am Rev Respir Dis. 1977 Mar;115(3):461–478. doi: 10.1164/arrd.1977.115.3.461. [DOI] [PubMed] [Google Scholar]
  27. Janoff A., White R., Carp H., Harel S., Dearing R., Lee D. Lung injury induced by leukocytic proteases. Am J Pathol. 1979 Oct;97(1):111–136. [PMC free article] [PubMed] [Google Scholar]
  28. Karlinsky J. B., Snider G. L. Animal models of emphysema. Am Rev Respir Dis. 1978 Jun;117(6):1109–1133. doi: 10.1164/arrd.1978.117.6.1109. [DOI] [PubMed] [Google Scholar]
  29. Kitagawa S., Takaku F., Sakamoto S. Serine protease inhibitors inhibit superoxide production by human polymorphonuclear leukocytes and monocytes stimulated by various surface active agents. FEBS Lett. 1979 Nov 15;107(2):331–334. doi: 10.1016/0014-5793(79)80401-9. [DOI] [PubMed] [Google Scholar]
  30. Liotta L. A., Goldfarb R. H., Terranova V. P. Cleavage of laminin by thrombin and plasmin: alpha thrombin selectively cleaves the beta chain of laminin. Thromb Res. 1981 Mar 15;21(6):663–673. doi: 10.1016/0049-3848(81)90268-1. [DOI] [PubMed] [Google Scholar]
  31. Madri J. A., Furthmayr H. Isolation and tissue localization of type AB2 collagen from normal lung parenchyma. Am J Pathol. 1979 Feb;94(2):323–331. [PMC free article] [PubMed] [Google Scholar]
  32. Mainardi C. L., Dixit S. N., Kang A. H. Degradation of type IV (basement membrane) collagen by a proteinase isolated from human polymorphonuclear leukocyte granules. J Biol Chem. 1980 Jun 10;255(11):5435–5441. [PubMed] [Google Scholar]
  33. Mainardi C. L., Seyer J. M., Kang A. H. Type-specific collagenolysis: a type V collagen-degrading enzyme from macrophages. Biochem Biophys Res Commun. 1980 Dec 16;97(3):1108–1115. doi: 10.1016/0006-291x(80)91490-4. [DOI] [PubMed] [Google Scholar]
  34. McDonald J. A., Baum B. J., Rosenberg D. M., Kelman J. A., Brin S. C., Crystal R. G. Destruction of a major extracellular adhesive glycoprotein (fibronectin) of human fibroblasts by neutral proteases from polymorphonuclear leukocyte granules. Lab Invest. 1979 Mar;40(3):350–357. [PubMed] [Google Scholar]
  35. Miller E. J., Finch J. E., Jr, Chung E., Butler W. T., Robertson P. B. Specific cleavage of the native type III collagen molecule with trypsin. Similarity of the cleavage products to collagenase-produced fragments and primary structure at the cleavage site. Arch Biochem Biophys. 1976 Apr;173(2):631–637. doi: 10.1016/0003-9861(76)90300-3. [DOI] [PubMed] [Google Scholar]
  36. Paz M. A., Keith D. A., Traverso H. P., Gallop P. M. Isolation, purification, and cross-linking profiles of elastin from lung and aorta. Biochemistry. 1976 Nov 2;15(22):4912–4918. doi: 10.1021/bi00667a025. [DOI] [PubMed] [Google Scholar]
  37. Reilly C. F., Travis J. The degradation of human lung elastin by neutrophil proteinases. Biochim Biophys Acta. 1980 Jan 24;621(1):147–157. doi: 10.1016/0005-2795(80)90070-7. [DOI] [PubMed] [Google Scholar]
  38. Senior R. M., Griffin G. L., Mecham R. P. Chemotactic activity of elastin-derived peptides. J Clin Invest. 1980 Oct;66(4):859–862. doi: 10.1172/JCI109926. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Senior R. M., Tegner H., Kuhn C., Ohlsson K., Starcher B. C., Pierce J. A. The induction of pulmonary emphysema with human leukocyte elastase. Am Rev Respir Dis. 1977 Sep;116(3):469–475. doi: 10.1164/arrd.1977.116.3.469. [DOI] [PubMed] [Google Scholar]
  40. Starkey P. M., Barrett A. J., Burleigh M. C. The degradation of articular collagen by neutrophil proteinases. Biochim Biophys Acta. 1977 Aug 11;483(2):386–397. doi: 10.1016/0005-2744(77)90066-3. [DOI] [PubMed] [Google Scholar]
  41. Timpl R., Rohde H., Robey P. G., Rennard S. I., Foidart J. M., Martin G. R. Laminin--a glycoprotein from basement membranes. J Biol Chem. 1979 Oct 10;254(19):9933–9937. [PubMed] [Google Scholar]
  42. Werb Z., Gordon S. Elastase secretion by stimulated macrophages. Characterization and regulation. J Exp Med. 1975 Aug 1;142(2):361–377. doi: 10.1084/jem.142.2.361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. White R., Janoff A., Godfrey H. P. Secretion of Alpha-2-macroglobulin by human alveolar macrophages. Lung. 1980;158(1):9–14. doi: 10.1007/BF02713697. [DOI] [PubMed] [Google Scholar]
  44. Woolley D. E., Roberts D. R., Evanson J. M. Small molecular weight beta 1 serum protein which specifically inhibits human collagenases. Nature. 1976 May 27;261(5558):325–327. doi: 10.1038/261325a0. [DOI] [PubMed] [Google Scholar]

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