Skip to main content
SpringerLink
Log in

The protease-antiprotease balance within the human lung: Implications for the pathogenesis of emphysema

  • α1-Antitrypsin Deficiency: Diagnosis, Treatment, And Control
  • Published:
Lung Aims and scope Submit manuscript

Abstract

Critical elements of the mechanisms of emphysema remain to be clarified. However, taken together, the existing evidence supports the concept that alveolar matrix destruction ensues as the regulatory interplay between oxidant and protease expression is subverted. The final common pathway of matrix destruction links the inherited and acquired forms of emphysema through the ultimate expression of unimpeded neutrophil elastase.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Odeberg H, Olsson I (1976) Microbicidal mechanisms of human granulocytes: synergistic effects of granulocyte elastase and myeloperoxidase or chymotrypsinlike cationic protein. Infect Immun 14:1276–1283

    PubMed  CAS  Google Scholar 

  2. Pacht ER, Kaseki H, Gadek JE, Cornwell D, Davis WB (1987) Vitamin E in cigarette smokers: Relationship to alveolar macrophage mediated cytotoxicity. In: Mittman C, Taylor JC (eds) Pulmonary emphysema and proteolysis. Academic Press, Orlando, FL, pp 445–452

    Google Scholar 

  3. Wewers MD, Gadek JE (1987) The protease theory of emphysema. Ann Intern Med 107:761–763

    PubMed  CAS  Google Scholar 

  4. Kao RC, Wehner NG, Skubitz KM, Gray BH, Hoidal JR (1988) Proteinase 3: distinct human polymorphonuclear leukocyte proteinase that produces emphysema in hamsters. J Clin Invest 82:1963–1273

    Article  PubMed  CAS  Google Scholar 

  5. Gadek JE, Fells GA, Zimmerman RL, Rennard SI, Crystal RG (1981) Antielastases of the human alveolar structures. Implications for the protease-antiprotease theory of emphysema. J Clin Invest 68:889–898

    Article  PubMed  CAS  Google Scholar 

  6. Wewers MD, Herzyk DJ, Gadek JE. Alveolar fluid neutrophil elastase activity in the adult respiratory distress syndrome is complexed to alpha-2-macroglobulin. J Clin Invest (in press)

  7. Gadek JE, Fells GA, Zimmerman RL, Crystal RG (1984) Role of connective tissue proteases in the pathogenesis of chronic inflammatory lung disease. Environ Health Perspect 55:297–306

    Article  PubMed  CAS  Google Scholar 

  8. Campbell EJ, Senior RM, Welgus HG (1987) Extracellular matrix injury during lung inflammation. Chest 92:161–167

    Article  PubMed  CAS  Google Scholar 

  9. Senior RM, Tegner H, Kuhn C, Ohlsson K, Starcher BC, Pierce JA (1977) The induction of pulmonary emphysema with leukocyte elastase. Am Rev Respir Dis 116:469–475

    PubMed  CAS  Google Scholar 

  10. Janoff A, Sloan B, Weinbaum G, et al (1977) Experimental emphysema induced with purified human neutrophil elastase: tissue localization of the instilled protease. Am Rev Respir Dis 115:461–78

    PubMed  CAS  Google Scholar 

  11. Karlinsky JB, Snider GL (1978) Animal models of emphysema. Am Rev Respir Dis 117:1109–1133

    PubMed  CAS  Google Scholar 

  12. Johnson KJ, Ward PA (1981) Role of oxygen metabolites in immune complex injury of the lung. J Immunol 126:2365–2369

    PubMed  CAS  Google Scholar 

  13. Hunninghake GW, Gadek JE, Kawanami O, Ferrans VJ, Crystal RG (1979) Inflammatory and immune processes in the human lung in health and disease: evaluation by bronchoalveolar lavage. Am J Pathol 97:149–206

    PubMed  CAS  Google Scholar 

  14. Kindt GC, Gadek JE, Weiland JE (1989) Contrasting models of neutrophil recruitment to the lung: pneumonia vs. sepsis. Chest 95:203S-204S

    Article  Google Scholar 

  15. Weiland JE, Davis WB, Holter JF, Mohammed JR, Dorinsky PM, Gadek JE (1986) Lung neutrophils in the adult respiratory distress syndrome: clinical and pathophysiologic significance. Am Rev Respir Dis 133:218–225

    PubMed  CAS  Google Scholar 

  16. Hunninghake G, Gadek J, Crystal R (1980) Human alveolar macrophage neutrophil chemotactic factor: stimuli and partial characterization. J Clin Invest 66:473–483

    Article  PubMed  CAS  Google Scholar 

  17. Damiano VV, Tsang A, Kucich U, Abrams WR, Rosenbloom J, Kimbel P, et al. (1986) Immunolocalization of elastase in human emphysematous lungs. J Clin Invest 78:482–493

    Article  PubMed  CAS  Google Scholar 

  18. Weiss SJ, Peppin G, Ortiz X, Ragsdale C, Test ST (1985) Oxidative autoactivation of latent collagenase by human neutrophils. Science 227:747–749

    Article  PubMed  CAS  Google Scholar 

  19. Reilly CF, Travis J (1980) The degradation of human elastin by neutrophil proteinases. Biochem Biophys Acta 621:147–157

    PubMed  CAS  Google Scholar 

  20. Werb Z, Gordon S (1975) Elastase secretion by stimulated macrophages. J Exp Med 142:361–377

    Article  PubMed  CAS  Google Scholar 

  21. Senior RM, Campbell EJ, Landis JA, Cox RR, Kuhn C, Koren HS (1982) Elastase of U-937 monocyte-like cells. Comparisons with elastases derived from human monocytes and neutrophils and murine macrophage-like cells. J Clin Invest 69:384–393

    Article  PubMed  CAS  Google Scholar 

  22. Banda MJ, Clark EJ, Werb Z (1980) Limited proteolysis by macrophage elastase inactivates human alpha 1-proteinase inhibitor. J Exp Med 152:1563–1570

    Article  PubMed  CAS  Google Scholar 

  23. Chapman HA, Stone OL (1984) Comparison of live human neutrophil and alveolar macrophage elastolytic activity in vitro. Relative resistance of macrophage elastolytic activity to serum and alveolar proteinase inhibitors. J Clin Invest 74:1693–1700

    Article  PubMed  CAS  Google Scholar 

  24. Hunninghake GW, Crystal RG (1983) Cigarette smoking and lung destruction: accumulation of neutrophils in the lungs of cigarette smokers. Am Rev Respir Dis 128:833–838

    PubMed  CAS  Google Scholar 

  25. Welgus HG, Campbell EJ, Bar-Shavit Z, Senior RM, Teitelbaum SL (1985) Human alveolar macrophages produce a fibroblast-like collagenase and collagenase inhibitor. J Clin Invest 76:219–224

    Article  PubMed  CAS  Google Scholar 

  26. Takeuchi K, Wood H, Swank RT (1986) Lysosomal elastase and cathepsin G in beige mice. Neutrophils of beige (Chediak-Higachi) mice selectively lack lysosomal elastase and cathepsin G. J Exp Med 163:665–677

    Article  PubMed  CAS  Google Scholar 

  27. Fittschen C, Sandhaus RA, Worthen GS, Henson PM (1988) Bacterial lipopolysaccharide enhances chemoattractant-induced elastase secretion by human neutrophils. J Leukocyte Biol 43:547–556

    PubMed  CAS  Google Scholar 

  28. Gadek JE, Crystal RG (1982) Alpha 1-antitrypsin deficiency. In: Stanbury JB, Wyngaarden JB, Fredrickson DS, Goldstein JL, Brown MS (eds). Metabolic basis of inherited disease. McGraw-Hill, New York, pp 1450–1467

    Google Scholar 

  29. Carrell RW, Jeppsson J-O, Laurell C-B, et al. (1982) Structure and variation of human alpha 1-antitrypsin. Nature 298:329–334

    Article  PubMed  CAS  Google Scholar 

  30. Janoff A, Carp H (1977) Possible mechanism of emphysema in cigarette smokers: cigarette smoke condensate suppresses proteinase inhibitors in vitro. Am Rev Respir Dis 116:65–72

    PubMed  CAS  Google Scholar 

  31. Gadek JE, Fells GA, Crystal RG (1979) Cigarette smoking induces functional antiprotease deficiency in the lower respiratory tract of humans. Science 206:1315–1316

    Article  PubMed  CAS  Google Scholar 

  32. Carp H, Miller F, Hoidal J, Janoff A (1982) Alpha 1-proteinase inhibitor purified from lungs of cigarette smokers contains oxidized methionine and has decreased elastase inhibitory capacity. Proc Natl Acad Sci USA 779:2041–2045

    Article  Google Scholar 

  33. Stone PJ, Calore JD, McGowan SE, Bernardo J, Snider GL, Franzblau C (1983) Functional alpha 1-protease inhibitor in the lower respiratory tract of cigarette smokers is not decreased. Science 221:1187–1189

    Article  PubMed  CAS  Google Scholar 

  34. Boudier C, Pelletier A, Pauli G, Bieth JG (1983) The functional activity of alpha 1-proteinase inhibitor in bronchoalveolar lavage fluids from healthy human smokers and nonsmokers. Clin Chim Acta 132:309–315

    Article  PubMed  CAS  Google Scholar 

  35. Wewers MD, Herzyk DJ, Gadek JE (1989) Comparison of smoker and nonsmoker lavage fluid for the rate of association with neutrophil elastase. Am J Respir Cell Mol Biol 1:423–429

    PubMed  CAS  Google Scholar 

  36. Fells G, Ogushi F, Hubbard R, Crystal R (1987) Alpha 1-antitrypsin in the lower respiratory tract of cigarette smokers has a decreased association rate constant for neutrophil elastase. Am Rev Respir Dis 135:A291

    Google Scholar 

  37. Campbell EJ, Senior RM, McDonald JA, Cox DL (1982) Proteolysis by neutrophils. Relative importance of cell-substrate contact and oxidative inactivation of proteinase inhibitors in vitro. J Clin Invest 70:845–852

    Article  PubMed  CAS  Google Scholar 

  38. Weitz JI, Crowley KA, Landman SL, Lipman BI (1987) Increased neutrophil elastase activity in cigarette smokers. Ann Intern Med 107:680–682

    PubMed  CAS  Google Scholar 

  39. Wewers MD (1989) Pathogenesis of emphysema: Assessment of basic science concepts through clinical investigation. Chest 95:190–195

    Article  PubMed  CAS  Google Scholar 

  40. Hochstrasser K, Bretzel G, Wachter E, Heindl S (1975) The amino acid sequence of the double-headed proteinase inhibitor from canine submandibularis glands. Hoppe Seylers Z Physiol Chem 356:1855–1877

    Google Scholar 

  41. Wewers MD, Casolaro MA, Crystal RG (1987) Comparison of alpha 1-antitrypsin levels and antineutrophil elastase capacity of blood and lung in a patient with the alpha 1-antitrypsin phenotype Null-Null before and during alpha 1-antitrypsin augmentation therapy. Am Rev Respir Dis 135:539–543

    PubMed  CAS  Google Scholar 

  42. Ohlsson K, Fryksmark V, Tegner H (1980) The effect of cigarette smoker condensate on alpha 1-antitrypsin, antileukoprotease and granulocyte elastase. Eur J Clin Invest 10:373–379

    Article  PubMed  CAS  Google Scholar 

  43. Riley DJ, Kerr JS (1985) Oxidant injury of the extracellular matrix: potential role in the pathogenesis of pulmonary emphysema. Lung 163:1–13

    Article  PubMed  CAS  Google Scholar 

  44. Weiss SJ, Regiani S (1984) Neutrophils degrade subendothelial matrices in the presence of alpha 1-proteinase inhibitor: cooperative use of lysosomal proteinases and oxygen metabolites. J Clin Invest 73:1297–1303

    Article  PubMed  CAS  Google Scholar 

  45. Osman M, Cantor JO, Roffman S, Keller S, Turino GM, Mandl I Cigarette smoke impairs elastin resynthesis in lungs of hamsters with elastase-induced emphysema. Am Rev Respir Dis (in press).

  46. Laurent P, Janoff A, Kagan HM (1983) Cigarette smoke blocks cross-linking of elastin in vitro. Am Rev Respir Dis 127:189–192

    PubMed  CAS  Google Scholar 

  47. Janoff A (1985) State of the art: elastases and emphysema. Am Rev Respir Dis 132:417–433

    PubMed  CAS  Google Scholar 

  48. Rennard SI Personal communication.

  49. Pacht E, Kaseki H, Mohammed J, Cornwell D, Davis WB (1986) Deficiency of vitamin E in the alveolar fluid of cigarette smokers: Influence of alveolar macrophage cytotoxicity. J Clin Invest 77:789–796

    Article  PubMed  CAS  Google Scholar 

  50. Cantin AM, North SL, Hubbard RC, Crystal RG (1987) Normal alveolar epithelial lining fluid contains high levels of glutathione. J Appl Physiol 63:152–157

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Division of Pulmonary and Critical Care Medicine, Ohio State University College of Medicine, Columbus, Ohio, USA

    James E. Gadek & Eric R. Pacht

Authors
  1. James E. Gadek
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eric R. Pacht
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gadek, J.E., Pacht, E.R. The protease-antiprotease balance within the human lung: Implications for the pathogenesis of emphysema. Lung 168 (Suppl 1), 552–564 (1990). https://doi.org/10.1007/BF02718178

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02718178

Key words

Search

Navigation