Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1981 Oct;68(4):889–898. doi: 10.1172/JCI110344

Antielastases of the human alveolar structures. Implications for the protease-antiprotease theory of emphysema.

J E Gadek, G A Fells, R L Zimmerman, S I Rennard, R G Crystal
PMCID: PMC370876  PMID: 6169740

Abstract

The current concepts of the pathogenesis of emphysema hold that progressive, chronic destruction of the alveolar structures occurs because there was in imbalance between the proteases and antiproteases in the lower respiratory tract. In this context, proteases, particularly neutrophil elastase, work unimpeded to destroy the alveolar structures. This concept has evolved from consideration of patients with alpha 1-antitrypsin deficiency, who have decreased levels of serum alpha 1-antitrypsin and who have progressive panacinar emphysema. To directly assess the antiprotease side of this equation, the lower respiratory tract of non-smoking individuals with normal serum antiproteases and individuals with PiZ homozygous alpha 1-antitrypsin deficiency underwent bronchoalveolar lavage to evaluate the antiprotease screen of their lower respiratory tract. These studies demonstrated that: (a) alpha 1-antitrypsin is the major antielastase of the normal human lower respiratory tract; (b) alpha 2-macroglobulin, a large serum antielastase, and the bronchial mucous inhibitor, an antielastase of the central airways, do not contribute to the antielastase protection of the human alveolar structures; (c) individuals with PiZ alpha 1-antitrypsin deficiency have little or no alpha 1-antitrypsin in their lower respiratory tract and have no alternative antiprotease protection against neutrophil elastase; and (d) the lack of antiprotease protection of the lower respiratory tract of PiZ individuals is a chronic process, suggesting their vulnerability to neutrophil elastase is always present.

Full text

PDF
889

Selected References

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

  1. Allen R. C., Harley R. A., Talamo R. C. A new method for determination of alpha-1-antitrypsin phenotypes using isoelectric focusing on polyacrylamide gel slabs. Am J Clin Pathol. 1974 Dec;62(6):732–739. doi: 10.1093/ajcp/62.6.732. [DOI] [PubMed] [Google Scholar]
  2. Carp H., Janoff A. In vitro suppression of serum elastase-inhibitory capacity by reactive oxygen species generated by phagocytosing polymorphonuclear leukocytes. J Clin Invest. 1979 Apr;63(4):793–797. doi: 10.1172/JCI109364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cohen A. B. Opportunities for the development of specific therapeutic agents to treat emphysema. Am Rev Respir Dis. 1979 Oct;120(4):723–727. doi: 10.1164/arrd.1979.120.4.723. [DOI] [PubMed] [Google Scholar]
  4. Cohen A. B. The effects in vivo and in vitro of oxidative damage to purified alpha1-antitrypsin and to the enzyme-inhibiting activity of plasma. Am Rev Respir Dis. 1979 Jun;119(6):953–960. doi: 10.1164/arrd.1979.119.6.953. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. 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]
  7. Gadek J. E., Fulmer J. D., Gelfand J. A., Frank M. M., Petty T. L., Crystal R. G. Danazol-induced augmentation of serum alpha 1-antitrypsin levels in individuals with marked deficiency of this antiprotease. J Clin Invest. 1980 Jul;66(1):82–87. doi: 10.1172/JCI109838. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gadek J. E., Hosea S. W., Gelfand J. A., Frank M. M. Response of variant hereditary angioedema phenotypes to danazol therapy. Genetic implications. J Clin Invest. 1979 Jul;64(1):280–286. doi: 10.1172/JCI109449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. 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]
  10. Gelfand J. A., Sherins R. J., Alling D. W., Frank M. M. Treatment of hereditary angioedema with danazol. Reversal of clinical and biochemical abnormalities. N Engl J Med. 1976 Dec 23;295(26):1444–1448. doi: 10.1056/NEJM197612232952602. [DOI] [PubMed] [Google Scholar]
  11. Hochstrasser K. Proteinase (elastase) inhibitors from the ciliated membranes of the human respiratory tract. Methods Enzymol. 1976;45:869–874. doi: 10.1016/s0076-6879(76)45080-2. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. 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]
  14. 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]
  15. 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]
  16. 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]
  17. Kueppers F., Black L. F. Alpha1-antitrypsin and its deficiency. Am Rev Respir Dis. 1974 Aug;110(2):176–194. doi: 10.1164/arrd.1974.110.2.176. [DOI] [PubMed] [Google Scholar]
  18. LAURELL C. B. ANTIGEN-ANTIBODY CROSSED ELECTROPHORESIS. Anal Biochem. 1965 Feb;10:358–361. doi: 10.1016/0003-2697(65)90278-2. [DOI] [PubMed] [Google Scholar]
  19. Larsson C. Natural history and life expectancy in severe alpha1-antitrypsin deficiency, Pi Z. Acta Med Scand. 1978;204(5):345–351. doi: 10.1111/j.0954-6820.1978.tb08452.x. [DOI] [PubMed] [Google Scholar]
  20. Lieberman J. Elastase, collagenase, emphysema, and alpha1-antitrypsin deficiency. Chest. 1976 Jul;70(1):62–67. doi: 10.1378/chest.70.1.62. [DOI] [PubMed] [Google Scholar]
  21. Mancini G., Carbonara A. O., Heremans J. F. Immunochemical quantitation of antigens by single radial immunodiffusion. Immunochemistry. 1965 Sep;2(3):235–254. doi: 10.1016/0019-2791(65)90004-2. [DOI] [PubMed] [Google Scholar]
  22. Morse J. O. alpha1-antitrypsin deficiency (first of two parts). N Engl J Med. 1978 Nov 9;299(19):1045–1048. doi: 10.1056/NEJM197811092991905. [DOI] [PubMed] [Google Scholar]
  23. Ohlsson K. Neutral leucocyte proteases and elastase inhibited by plasma alpha 1 -antitrypsin. Scand J Clin Lab Invest. 1971 Nov;28(3):251–253. doi: 10.3109/00365517109095696. [DOI] [PubMed] [Google Scholar]
  24. Ohlsson K., Tegner H., Akesson U. Isolation and partial characterization of a low molecular weight acid stable protease inhibitor from human bronchial secretion. Hoppe Seylers Z Physiol Chem. 1977 May;358(5):583–589. doi: 10.1515/bchm2.1977.358.1.583. [DOI] [PubMed] [Google Scholar]
  25. Ohlsson K., Tegner H. Inhibition of elastase from granulocytes by the low molecular weight bronchial protease inhibitor. Scand J Clin Lab Invest. 1976 Sep;36(5):437–445. doi: 10.3109/00365517609054461. [DOI] [PubMed] [Google Scholar]
  26. Rennard S. I., Berg R., Martin G. R., Foidart J. M., Robey P. G. Enzyme-linked immunoassay (ELISA) for connective tissue components. Anal Biochem. 1980 May 1;104(1):205–214. doi: 10.1016/0003-2697(80)90300-0. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. Stockley R. A., Burnett D. Alpha,-antitrypsin and leukocyte elastase in infected and noninfected sputum. Am Rev Respir Dis. 1979 Nov;120(5):1081–1086. doi: 10.1164/arrd.1979.120.5.1081. [DOI] [PubMed] [Google Scholar]
  29. Takahashi S., Seifter S., Yang F. C. A new radioactive assay for enzymes with elastolytic activity using reduced tritiated elastin. The effect of sodium dodecyl sulfate on elastolysis. Biochim Biophys Acta. 1973 Nov 15;327(1):138–145. doi: 10.1016/0005-2744(73)90111-3. [DOI] [PubMed] [Google Scholar]
  30. Taylor J. C., Crawford I. P. Purification and preliminary characterization of human leukocyte elastasel. Arch Biochem Biophys. 1975 Jul;169(1):91–101. doi: 10.1016/0003-9861(75)90320-3. [DOI] [PubMed] [Google Scholar]
  31. Tegner H. Quantitation of human granulocyte protease inhibitors in non-purulent bronchial lavage fluids. Acta Otolaryngol. 1978 Mar-Apr;85(3-4):282–289. doi: 10.3109/00016487809111936. [DOI] [PubMed] [Google Scholar]
  32. Virca G. D., Travis J., Hall P. K., Roberts R. C. Purification of human alpha-2-macroglobulin by chromatography on Cibacron Blue Sepharose. Anal Biochem. 1978 Aug 15;89(1):274–278. doi: 10.1016/0003-2697(78)90750-9. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES