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Logo of jcinvestThe Journal of Clinical Investigation
J Clin Invest. 1988 October; 82(4): 1260–1267.
PMCID: PMC442677

Alveolar fluid neutrophil elastase activity in the adult respiratory distress syndrome is complexed to alpha-2-macroglobulin.


We characterized the elastase and antielastase activity of the alveolar fluid of seven patients with the adult respiratory distress syndrome (ARDS) and thirteen normal volunteers. Alpha-1-antitrypsin (A1AT) concentrations were 60-fold higher in ARDS as compared to normal lavage fluid (2,140 +/- 498 nM; 36.1 +/- 4.2 nM, respectively). ARDS fluid antineutrophil elastase activity was also considerably higher than that of normals (979 +/- 204 nM; 31.3 +/- 2.9 nM, respectively). Despite the antineutrophil elastase excess, 5 of 7 ARDS lavage samples contained elastase activity (mean, 6.1 +/- 2.4 pM) as assayed using low-molecular-mass substrate, while only 1 of 13 normal subjects had detectable elastase activity (0.2 pM) (P less than 0.01, compared with ARDS). That this activity was due to alpha-2-macroglobulin (A2MG)-complexed neutrophil elastase was evidenced by (a) the Sephadex G-75 elution profile; (b) the inactivity against insoluble [3H]elastin; (c) the inhibitory profile with phenylmethylsulfonyl fluoride, methoxy-succinyl-alanyl-alanyl-prolyl-valyl-chloromethylketone, ethylene diamine tetraacetic acid, and A1AT; and (d) the immobilization by A2MG antibody bound to polystyrene plates. Furthermore, in agreement with the predicted affinity of A1AT and A2MG for neutrophil elastase, the ratio of A2MG to A1AT in the fluid (0.57%) coincided with the ratio of the A2MG- to A1AT-complexed elastase (0.36%). These findings suggest that the net lung protease-antiprotease balance in ARDS is shifted largely in favor of the antiproteases (chiefly A1AT), and that the antiproteases, A1AT and A2MG, have similar affinities for neutrophil elastase in vivo.

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Selected References

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  • Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet. 1967 Aug 12;2(7511):319–323. [PubMed]
  • Rinaldo JE, Rogers RM. Adult respiratory-distress syndrome: changing concepts of lung injury and repair. N Engl J Med. 1982 Apr 15;306(15):900–909. [PubMed]
  • Bone RC, Francis PB, Pierce AK. Intravascular coagulation associated with the adult respiratory distress syndrome. Am J Med. 1976 Nov;61(5):585–589. [PubMed]
  • Lee CT, Fein AM, Lippmann M, Holtzman H, Kimbel P, Weinbaum G. Elastolytic activity in pulmonary lavage fluid from patients with adult respiratory-distress syndrome. N Engl J Med. 1981 Jan 22;304(4):192–196. [PubMed]
  • McGuire WW, Spragg RG, Cohen AB, Cochrane CG. Studies on the pathogenesis of the adult respiratory distress syndrome. J Clin Invest. 1982 Mar;69(3):543–553. [PMC free article] [PubMed]
  • Idell S, Kucich U, Fein A, Kueppers F, James HL, Walsh PN, Weinbaum G, Colman RW, Cohen AB. Neutrophil elastase-releasing factors in bronchoalveolar lavage from patients with adult respiratory distress syndrome. Am Rev Respir Dis. 1985 Nov;132(5):1098–1105. [PubMed]
  • Weiland JE, Davis WB, Holter JF, Mohammed JR, Dorinsky PM, Gadek JE. Lung neutrophils in the adult respiratory distress syndrome. Clinical and pathophysiologic significance. Am Rev Respir Dis. 1986 Feb;133(2):218–225. [PubMed]
  • Holter JF, Weiland JE, Pacht ER, Gadek JE, Davis WB. Protein permeability in the adult respiratory distress syndrome. Loss of size selectivity of the alveolar epithelium. J Clin Invest. 1986 Dec;78(6):1513–1522. [PMC free article] [PubMed]
  • Wewers MD, Casolaro MA, Crystal RG. 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. 1987 Mar;135(3):539–543. [PubMed]
  • Gadek JE, Fells GA, Zimmerman RL, Rennard SI, Crystal RG. Antielastases of the human alveolar structures. Implications for the protease-antiprotease theory of emphysema. J Clin Invest. 1981 Oct;68(4):889–898. [PMC free article] [PubMed]
  • Harpel PC, Mosesson MW. Degradation of human fibrinogen by plasms alpha2-macroglobulin-enzyme complexes. J Clin Invest. 1973 Sep;52(9):2175–2184. [PMC free article] [PubMed]
  • Salvesen G, Virca GD, Travis J. Interaction of alpha 2-macroglobulin with neutrophil and plasma proteinases. Ann N Y Acad Sci. 1983;421:316–326. [PubMed]
  • Hunninghake GW, Gadek JE, Kawanami O, Ferrans VJ, Crystal RG. 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. [PubMed]
  • Powers JC, Boone R, Carroll DL, Gupton BF, Kam CM, Nishino N, Sakamoto M, Tuhy PM. Reaction of azapeptides with human leukocyte elastase and porcine pancreatic elastase. New inhibitors and active site titrants. J Biol Chem. 1984 Apr 10;259(7):4288–4294. [PubMed]
  • Castillo MJ, Nakajima K, Zimmerman M, Powers JC. Sensitive substrates for human leukocyte and porcine pancreatic elastase: a study of the merits of various chromophoric and fluorogenic leaving groups in assays for serine proteases. Anal Biochem. 1979 Oct 15;99(1):53–64. [PubMed]
  • Banda MJ, Werb Z. Mouse macrophage elastase. Purification and characterization as a metalloproteinase. Biochem J. 1981 Feb 1;193(2):589–605. [PubMed]
  • Jeppsson JO, Laurell CB, Fagerhol M. Properties of isolated human alpha1-antitrypsins of Pi types M, S and Z. Eur J Biochem. 1978 Feb 1;83(1):143–153. [PubMed]
  • Pannell R, Johnson D, Travis J. Isolation and properties of human plasma alpha-1-proteinase inhibitor. Biochemistry. 1974 Dec 17;13(26):5439–5445. [PubMed]
  • Meyer JF, Bieth J, Metais P. On the inhibition of elastase by serum. Some distinguishing properties of alpha1-antitrypsin and alpha2-macroglobulin. Clin Chim Acta. 1975 Jul 9;62(1):43–53. [PubMed]
  • Beatty K, Bieth J, Travis J. Kinetics of association of serine proteinases with native and oxidized alpha-1-proteinase inhibitor and alpha-1-antichymotrypsin. J Biol Chem. 1980 May 10;255(9):3931–3934. [PubMed]
  • Kaplan J, Keogh EA. Studies on the physiology of macrophage receptors for alpha-macroglobulin X protease complexes. Ann N Y Acad Sci. 1983;421:442–456. [PubMed]
  • Stone PJ, Calore JD, Snider GL, Franzblau C. Role of alpha-macroglobulin-elastase complexes in the pathogenesis of elastase-induced emphysema in hamsters. J Clin Invest. 1982 Apr;69(4):920–931. [PMC free article] [PubMed]
  • Galdston M, Levytska V, Liener IE, Twumasi DY. Degradation of tropoelastin and elastin substrates by human neutrophil elastase, free and bound to alpha2-macroglobulin in serum of the M and Z (Pi) phenotypes for alpha1-antitrypsin. Am Rev Respir Dis. 1979 Mar;119(3):435–441. [PubMed]
  • Travis J, Salvesen GS. Human plasma proteinase inhibitors. Annu Rev Biochem. 1983;52:655–709. [PubMed]
  • Reilly CF, Schechter NB, Travis J. Inactivation of bradykinin and kallidin by cathepsin G and mast cell chymase. Biochem Biophys Res Commun. 1985 Mar 15;127(2):443–449. [PubMed]
  • Reilly CF, Tewksbury DA, Schechter NM, Travis J. Rapid conversion of angiotensin I to angiotensin II by neutrophil and mast cell proteinases. J Biol Chem. 1982 Aug 10;257(15):8619–8622. [PubMed]
  • Wintroub BU, Klickstein LB, Watt KW. A human neutrophil-dependent pathway for generation of angiotensin II. Purification of the product and identification as angiotensin II. J Clin Invest. 1981 Aug;68(2):484–490. [PMC free article] [PubMed]

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