Skip to main content
PMC home page
Thorax logoLink to Thorax
. 2001 Jan;56(1):53–58. doi: 10.1136/thorax.56.1.53

Association of α1-antichymotrypsin deficiency with milder lung disease in patients with cystic fibrosis

R Mahadeva 1, L Sharples 1, R Ross-Russell 1, A Webb 1, D Bilton 1, D Lomas 1
PMCID: PMC1745909  PMID: 11120905

Abstract

BACKGROUND—Cystic fibrosis (CF) is characterised by an excess of free proteinases that destroy lung tissue. Despite this, previous studies have shown that patients with CF with a mild deficiency variant of the proteinase inhibitor α1-antitrypsin have less, rather than more, severe pulmonary disease. Alpha1-antichymotrypsin is another important serine proteinase inhibitor that protects the lung against proteolytic attack, and point mutations in the α1-antichymotrypsin gene that result in plasma deficiency are associated with chronic obstructive pulmonary disease.
METHODS—The effect of α1-antichymotrypsin deficiency and the -15 α1-antichymotrypsin signal peptide genotype on lung function was assessed in patients with CF.
RESULTS—One hundred and fifty seven patients with CF were screened and 10 were identified with a plasma deficiency of α1-antichymotrypsin (plasma concentration <0.2 g/l). In a multivariate analysis these individuals had significantly less severe lung disease than those who had normal or raised levels of α1-antichymotrypsin: forced expiratory volume in one second (FEV1) 69.9% predicted versus 53.2% predicted (p=0.04) and chest radiographic score of 7.2 versus 9.7 (p=0.03) for those with and without α1-antichymotrypsin deficiency, respectively. The -15 signal peptide genotype did not affect plasma levels, but the -15 Ala/Ala signal peptide genotype was over-represented in individuals with CF compared with healthy blood donor controls.
CONCLUSION—These data indicate that deficiency of α1-antichymotrypsin is associated with less severe pulmonary disease in patients with CF, and support our previous observations that mild genetic deficiency of a proteinase inhibitor is associated with an improved outcome.



Full Text

The Full Text of this article is available as a PDF (176.6 KB).

Selected References

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

  1. Abraham C. R., Selkoe D. J., Potter H. Immunochemical identification of the serine protease inhibitor alpha 1-antichymotrypsin in the brain amyloid deposits of Alzheimer's disease. Cell. 1988 Feb 26;52(4):487–501. doi: 10.1016/0092-8674(88)90462-x. [DOI] [PubMed] [Google Scholar]
  2. Aronsen K. F., Ekelund G., Kindmark C. O., Laurell C. B. Sequential changes of plasma proteins after surgical trauma. Scand J Clin Lab Invest Suppl. 1972;124:127–136. doi: 10.3109/00365517209102760. [DOI] [PubMed] [Google Scholar]
  3. Bank U., Küpper B., Reinhold D., Hoffmann T., Ansorge S. Evidence for a crucial role of neutrophil-derived serine proteases in the inactivation of interleukin-6 at sites of inflammation. FEBS Lett. 1999 Nov 19;461(3):235–240. doi: 10.1016/s0014-5793(99)01466-0. [DOI] [PubMed] [Google Scholar]
  4. Boudier C., Godeau G., Hornebeck W., Robert L., Bieth J. G. The elastolytic activity of cathepsin G: an ex vivo study with dermal elastin. Am J Respir Cell Mol Biol. 1991 Jun;4(6):497–503. doi: 10.1165/ajrcmb/4.6.497. [DOI] [PubMed] [Google Scholar]
  5. Burnett D., McGillivray D. H., Stockley R. A. Evidence that alveolar macrophages can synthesize and secrete alpha 1-antichymotrypsin. Am Rev Respir Dis. 1984 Mar;129(3):473–476. doi: 10.1164/arrd.1984.129.3.473. [DOI] [PubMed] [Google Scholar]
  6. Calvin J., Neale G., Fotherby K. J., Price C. P. The relative merits of acute phase proteins in the recognition of inflammatory conditions. Ann Clin Biochem. 1988 Jan;25(Pt 1):60–66. doi: 10.1177/000456328802500108. [DOI] [PubMed] [Google Scholar]
  7. Conway S. P., Pond M. N., Bowler I., Smith D. L., Simmonds E. J., Joanes D. N., Hambleton G., Hiller E. J., Stableforth D. E., Weller P. The chest radiograph in cystic fibrosis: a new scoring system compared with the Chrispin-Norman and Brasfield scores. Thorax. 1994 Sep;49(9):860–862. doi: 10.1136/thx.49.9.860. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Döring G., Goldstein W., Botzenhart K., Kharazmi A., Schiøtz P. O., Høiby N., Dasgupta M. Elastase from polymorphonuclear leucocytes: a regulatory enzyme in immune complex disease. Clin Exp Immunol. 1986 Jun;64(3):597–605. [PMC free article] [PubMed] [Google Scholar]
  9. Döring G., Krogh-Johansen H., Weidinger S., Høiby N. Allotypes of alpha 1-antitrypsin in patients with cystic fibrosis, homozygous and heterozygous for deltaF508. Pediatr Pulmonol. 1994 Jul;18(1):3–7. doi: 10.1002/ppul.1950180104. [DOI] [PubMed] [Google Scholar]
  10. Eriksson S., Lindmark B., Lilja H. Familial alpha 1-antichymotrypsin deficiency. Acta Med Scand. 1986;220(5):447–453. [PubMed] [Google Scholar]
  11. Faber J. P., Poller W., Olek K., Baumann U., Carlson J., Lindmark B., Eriksson S. The molecular basis of alpha 1-antichymotrypsin deficiency in a heterozygote with liver and lung disease. J Hepatol. 1993 Jul;18(3):313–321. doi: 10.1016/s0168-8278(05)80275-2. [DOI] [PubMed] [Google Scholar]
  12. Goldstein W., Döring G. Lysosomal enzymes from polymorphonuclear leukocytes and proteinase inhibitors in patients with cystic fibrosis. Am Rev Respir Dis. 1986 Jul;134(1):49–56. doi: 10.1164/arrd.1986.134.1.49. [DOI] [PubMed] [Google Scholar]
  13. Hudig D., Haverty T., Fulcher C., Redelman D., Mendelsohn J. Inhibition of human natural cytotoxicity by macromolecular antiproteases. J Immunol. 1981 Apr;126(4):1569–1574. [PubMed] [Google Scholar]
  14. Kamboh M. I., Sanghera D. K., Ferrell R. E., DeKosky S. T. APOE*4-associated Alzheimer's disease risk is modified by alpha 1-antichymotrypsin polymorphism. Nat Genet. 1995 Aug;10(4):486–488. doi: 10.1038/ng0895-486. [DOI] [PubMed] [Google Scholar]
  15. Knight J. C., Udalova I., Hill A. V., Greenwood B. M., Peshu N., Marsh K., Kwiatkowski D. A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria. Nat Genet. 1999 Jun;22(2):145–150. doi: 10.1038/9649. [DOI] [PubMed] [Google Scholar]
  16. Kurdowska A., Travis J. Acute phase protein stimulation by alpha 1-antichymotrypsin-cathepsin G complexes. Evidence for the involvement of interleukin-6. J Biol Chem. 1990 Dec 5;265(34):21023–21026. [PubMed] [Google Scholar]
  17. Lindmark B. E., Arborelius M., Jr, Eriksson S. G. Pulmonary function in middle-aged women with heterozygous deficiency of the serine protease inhibitor alpha 1-antichymotrypsin. Am Rev Respir Dis. 1990 Apr;141(4 Pt 1):884–888. doi: 10.1164/ajrccm/141.4_Pt_1.884. [DOI] [PubMed] [Google Scholar]
  18. Lindmark B., Eriksson S. Partial deficiency of alpha 1-antichymotrypsin is associated with chronic cryptogenic liver disease. Scand J Gastroenterol. 1991 May;26(5):508–512. doi: 10.3109/00365529108998574. [DOI] [PubMed] [Google Scholar]
  19. Lomas D. A., Stone S. R., Llewellyn-Jones C., Keogan M. T., Wang Z. M., Rubin H., Carrell R. W., Stockley R. A. The control of neutrophil chemotaxis by inhibitors of cathepsin G and chymotrypsin. J Biol Chem. 1995 Oct 6;270(40):23437–23443. doi: 10.1074/jbc.270.40.23437. [DOI] [PubMed] [Google Scholar]
  20. Lucey E. C., Stone P. J., Breuer R., Christensen T. G., Calore J. D., Catanese A., Franzblau C., Snider G. L. Effect of combined human neutrophil cathepsin G and elastase on induction of secretory cell metaplasia and emphysema in hamsters, with in vitro observations on elastolysis by these enzymes. Am Rev Respir Dis. 1985 Aug;132(2):362–366. doi: 10.1164/arrd.1985.132.2.362. [DOI] [PubMed] [Google Scholar]
  21. Mahadeva R., Stewart S., Bilton D., Lomas D. A. Alpha-1 antitrypsin deficiency alleles and severe cystic fibrosis lung disease. Thorax. 1998 Dec;53(12):1022–1024. doi: 10.1136/thx.53.12.1022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Mahadeva R., Westerbeek R. C., Perry D. J., Lovegrove J. U., Whitehouse D. B., Carroll N. R., Ross-Russell R. I., Webb A. K., Bilton D., Lomas D. A. Alpha1-antitrypsin deficiency alleles and the Taq-I G-->A allele in cystic fibrosis lung disease. Eur Respir J. 1998 Apr;11(4):873–879. doi: 10.1183/09031936.98.11040873. [DOI] [PubMed] [Google Scholar]
  23. Matsumoto M., Tsuda M., Kusumi T., Takada S., Shimamura T., Katsunuma T. Enhancement by alpha-1-antichymotrypsin of antibody response in vivo. Biochem Biophys Res Commun. 1981 May 15;100(1):478–482. doi: 10.1016/s0006-291x(81)80121-0. [DOI] [PubMed] [Google Scholar]
  24. Pasternack J. M., Abraham C. R., Van Dyke B. J., Potter H., Younkin S. G. Astrocytes in Alzheimer's disease gray matter express alpha 1-antichymotrypsin mRNA. Am J Pathol. 1989 Nov;135(5):827–834. [PMC free article] [PubMed] [Google Scholar]
  25. Poller W., Faber J. P., Weidinger S., Tief K., Scholz S., Fischer M., Olek K., Kirchgesser M., Heidtmann H. H. A leucine-to-proline substitution causes a defective alpha 1-antichymotrypsin allele associated with familial obstructive lung disease. Genomics. 1993 Sep;17(3):740–743. doi: 10.1006/geno.1993.1396. [DOI] [PubMed] [Google Scholar]
  26. Potempa J., Fedak D., Dubin A., Mast A., Travis J. Proteolytic inactivation of alpha-1-anti-chymotrypsin. Sites of cleavage and generation of chemotactic activity. J Biol Chem. 1991 Nov 15;266(32):21482–21487. [PubMed] [Google Scholar]
  27. Santis G., Osborne L., Knight R. A., Hodson M. E. Independent genetic determinants of pancreatic and pulmonary status in cystic fibrosis. Lancet. 1990 Nov 3;336(8723):1081–1084. doi: 10.1016/0140-6736(90)92566-z. [DOI] [PubMed] [Google Scholar]
  28. Sommerhoff C. P., Nadel J. A., Basbaum C. B., Caughey G. H. Neutrophil elastase and cathepsin G stimulate secretion from cultured bovine airway gland serous cells. J Clin Invest. 1990 Mar;85(3):682–689. doi: 10.1172/JCI114492. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Spitznagel J. K. Antibiotic proteins of human neutrophils. J Clin Invest. 1990 Nov;86(5):1381–1386. doi: 10.1172/JCI114851. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Suter S., Schaad U. B., Tegner H., Ohlsson K., Desgrandchamps D., Waldvogel F. A. Levels of free granulocyte elastase in bronchial secretions from patients with cystic fibrosis: effect of antimicrobial treatment against Pseudomonas aeruginosa. J Infect Dis. 1986 May;153(5):902–909. doi: 10.1093/infdis/153.5.902. [DOI] [PubMed] [Google Scholar]
  31. Travis J., Bowen J., Baugh R. Human alpha-1-antichymotrypsin: interaction with chymotrypsin-like proteinases. Biochemistry. 1978 Dec 26;17(26):5651–5656. doi: 10.1021/bi00619a011. [DOI] [PubMed] [Google Scholar]
  32. Travis J. Structure, function, and control of neutrophil proteinases. Am J Med. 1988 Jun 24;84(6A):37–42. doi: 10.1016/0002-9343(88)90156-8. [DOI] [PubMed] [Google Scholar]

Articles from Thorax are provided here courtesy of BMJ Publishing Group

RESOURCES