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. 1996 Mar 1;97(5):1329–1334. doi: 10.1172/JCI118549

Molecular determinants of acute inflammatory responses to biomaterials.

L Tang 1, T P Ugarova 1, E F Plow 1, J W Eaton 1
PMCID: PMC507187  PMID: 8636446

Abstract

The frequent inflammatory responses to implanted medical devices are puzzling in view of the inert and nontoxic nature of most biomaterials. Because implant surfaces spontaneously adsorb host proteins, this proteinaceous film is probably important in the subsequent attraction of phagocytes. In fact, earlier we found that acute inflammatory responses to experimental polyethylene terephthalate implants in mice require the precedent adsorption of one particular host protein, fibrinogen. The present investigations were aimed at defining the molecular determinants of fibrinogen-mediated acute inflammatory responses to implanted biomaterials. We find: (a) plasmin degradation of purified fibrinogen into defined domains reveals that the proinflammatory activity resides within the D fragment, which contains neither the fibrin cross-linking sites nor RGD sequences; (b) the major (and, perhaps, exclusive) proinflammatory sequence appears to be fibrinogen gamma 190-202, previously shown to interact with CD11b/CD18 (Mac-1). The chemically synthesized peptide, cross-linked to albumin (which itself does not promote inflammatory responses), mimics the proinflammatory effect of adsorbed native fibrinogen; and (c) this sequence probably promotes inflammatory responses through interactions with Mac-1 because phagocyte accumulation on experimental implants is almost completely abrogated by administration of recombinant neutrophil inhibitory factor (which blocks CD11b-fibrin(ogen) interaction). We conclude that improved knowledge of such surface-protein-phagocyte interactions may permit the future development of more biocompatible implantable materials.

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Selected References

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

  1. Altieri D. C., Agbanyo F. R., Plescia J., Ginsberg M. H., Edgington T. S., Plow E. F. A unique recognition site mediates the interaction of fibrinogen with the leukocyte integrin Mac-1 (CD11b/CD18). J Biol Chem. 1990 Jul 25;265(21):12119–12122. [PubMed] [Google Scholar]
  2. Altieri D. C., Bader R., Mannucci P. M., Edgington T. S. Oligospecificity of the cellular adhesion receptor Mac-1 encompasses an inducible recognition specificity for fibrinogen. J Cell Biol. 1988 Nov;107(5):1893–1900. doi: 10.1083/jcb.107.5.1893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Altieri D. C., Plescia J., Plow E. F. The structural motif glycine 190-valine 202 of the fibrinogen gamma chain interacts with CD11b/CD18 integrin (alpha M beta 2, Mac-1) and promotes leukocyte adhesion. J Biol Chem. 1993 Jan 25;268(3):1847–1853. [PubMed] [Google Scholar]
  4. Andrade J. D., Hlady V. Plasma protein adsorption: the big twelve. Ann N Y Acad Sci. 1987;516:158–172. doi: 10.1111/j.1749-6632.1987.tb33038.x. [DOI] [PubMed] [Google Scholar]
  5. Brown E. J., Goodwin J. L. Fibronectin receptors of phagocytes. Characterization of the Arg-Gly-Asp binding proteins of human monocytes and polymorphonuclear leukocytes. J Exp Med. 1988 Mar 1;167(3):777–793. doi: 10.1084/jem.167.3.777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Diamond M. S., Springer T. A. A subpopulation of Mac-1 (CD11b/CD18) molecules mediates neutrophil adhesion to ICAM-1 and fibrinogen. J Cell Biol. 1993 Jan;120(2):545–556. doi: 10.1083/jcb.120.2.545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Domanskis E., Owsley J. Q., Jr Histological investigation of the etiology of capsule contracture following augmentation mammaplasty. Plast Reconstr Surg. 1976 Dec;58(6):689–693. doi: 10.1097/00006534-197612000-00006. [DOI] [PubMed] [Google Scholar]
  8. Doolittle R. F., Schubert D., Schwartz S. A. Amino acid sequence studies on artiodactyl fibrinopeptides. I. Dromedary camel, mule deer, and cape buffalo. Arch Biochem Biophys. 1967 Feb;118(2):456–467. doi: 10.1016/0003-9861(67)90374-8. [DOI] [PubMed] [Google Scholar]
  9. Geczy C. L., Farram E., Moon D. K., Meyer P. A., McKenzie I. F. Macrophage procoagulant activity as a measure of cell-mediated immunity in the mouse. J Immunol. 1983 Jun;130(6):2743–2749. [PubMed] [Google Scholar]
  10. Gordon M., Bullough P. G. Synovial and osseous inflammation in failed silicone-rubber prostheses. J Bone Joint Surg Am. 1982 Apr;64(4):574–580. [PubMed] [Google Scholar]
  11. Grabarek Z., Gergely J. Zero-length crosslinking procedure with the use of active esters. Anal Biochem. 1990 Feb 15;185(1):131–135. doi: 10.1016/0003-2697(90)90267-d. [DOI] [PubMed] [Google Scholar]
  12. Gresham H. D., Goodwin J. L., Allen P. M., Anderson D. C., Brown E. J. A novel member of the integrin receptor family mediates Arg-Gly-Asp-stimulated neutrophil phagocytosis. J Cell Biol. 1989 May;108(5):1935–1943. doi: 10.1083/jcb.108.5.1935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Guidoin R., Snyder R., Martin L., Botzko K., Marois M., Awad J., King M., Domurado D., Bedros M., Gosselin C. Albumin coating of a knitted polyester arterial prosthesis: an alternative to preclotting. Ann Thorac Surg. 1984 Jun;37(6):457–465. doi: 10.1016/s0003-4975(10)61131-9. [DOI] [PubMed] [Google Scholar]
  14. Haugen P. K., McCarthy J. B., Skubitz A. P., Furcht L. T., Letourneau P. C. Recognition of the A chain carboxy-terminal heparin binding region of fibronectin involves multiple sites: two contiguous sequences act independently to promote neural cell adhesion. J Cell Biol. 1990 Dec;111(6 Pt 1):2733–2745. doi: 10.1083/jcb.111.6.2733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Himmelhoch S. R., Evans W. H., Mage M. G., Peterson E. A. Purification of myeloperoxidases from the bone marrow of the guinea pig. Biochemistry. 1969 Mar;8(3):914–921. doi: 10.1021/bi00831a022. [DOI] [PubMed] [Google Scholar]
  16. Hogquist K. A., Unanue E. R., Chaplin D. D. Release of IL-1 from mononuclear phagocytes. J Immunol. 1991 Oct 1;147(7):2181–2186. [PubMed] [Google Scholar]
  17. Humphries M. J., Komoriya A., Akiyama S. K., Olden K., Yamada K. M. Identification of two distinct regions of the type III connecting segment of human plasma fibronectin that promote cell type-specific adhesion. J Biol Chem. 1987 May 15;262(14):6886–6892. [PubMed] [Google Scholar]
  18. Jasty M. Clinical reviews: particulate debris and failure of total hip replacements. J Appl Biomater. 1993 Fall;4(3):273–276. doi: 10.1002/jab.770040310. [DOI] [PubMed] [Google Scholar]
  19. Keogh J. R., Eaton J. W. Albumin binding surfaces for biomaterials. J Lab Clin Med. 1994 Oct;124(4):537–545. [PubMed] [Google Scholar]
  20. Kottke-Marchant K., Anderson J. M., Umemura Y., Marchant R. E. Effect of albumin coating on the in vitro blood compatibility of Dacron arterial prostheses. Biomaterials. 1989 Apr;10(3):147–155. doi: 10.1016/0142-9612(89)90017-3. [DOI] [PubMed] [Google Scholar]
  21. McCarthy J. B., Skubitz A. P., Qi Z., Yi X. Y., Mickelson D. J., Klein D. J., Furcht L. T. RGD-independent cell adhesion to the carboxy-terminal heparin-binding fragment of fibronectin involves heparin-dependent and -independent activities. J Cell Biol. 1990 Mar;110(3):777–787. doi: 10.1083/jcb.110.3.777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. McRitchie D. I., Girotti M. J., Glynn M. F., Goldberg J. M., Rotstein O. D. Effect of systemic fibrinogen depletion on intraabdominal abscess formation. J Lab Clin Med. 1991 Jul;118(1):48–55. [PubMed] [Google Scholar]
  23. Moyle M., Foster D. L., McGrath D. E., Brown S. M., Laroche Y., De Meutter J., Stanssens P., Bogowitz C. A., Fried V. A., Ely J. A. A hookworm glycoprotein that inhibits neutrophil function is a ligand of the integrin CD11b/CD18. J Biol Chem. 1994 Apr 1;269(13):10008–10015. [PubMed] [Google Scholar]
  24. Muchowski P. J., Zhang L., Chang E. R., Soule H. R., Plow E. F., Moyle M. Functional interaction between the integrin antagonist neutrophil inhibitory factor and the I domain of CD11b/CD18. J Biol Chem. 1994 Oct 21;269(42):26419–26423. [PubMed] [Google Scholar]
  25. Murray D. W., Rushton N. Macrophages stimulate bone resorption when they phagocytose particles. J Bone Joint Surg Br. 1990 Nov;72(6):988–992. doi: 10.1302/0301-620X.72B6.2246303. [DOI] [PubMed] [Google Scholar]
  26. Pankowsky D. A., Ziats N. P., Topham N. S., Ratnoff O. D., Anderson J. M. Morphologic characteristics of adsorbed human plasma proteins on vascular grafts and biomaterials. J Vasc Surg. 1990 Apr;11(4):599–606. [PubMed] [Google Scholar]
  27. Perez R. L., Roman J. Fibrin enhances the expression of IL-1 beta by human peripheral blood mononuclear cells. Implications in pulmonary inflammation. J Immunol. 1995 Feb 15;154(4):1879–1887. [PubMed] [Google Scholar]
  28. Picha G. J., Goldstein J. A., Stohr E. Natural-Y Même polyurethane versus smooth silicone: analysis of the soft-tissue interaction from 3 days to 1 year in the rat animal model. Plast Reconstr Surg. 1990 Jun;85(6):903–916. doi: 10.1097/00006534-199006000-00011. [DOI] [PubMed] [Google Scholar]
  29. Ratner B. D. New ideas in biomaterials science--a path to engineered biomaterials. J Biomed Mater Res. 1993 Jul;27(7):837–850. doi: 10.1002/jbm.820270702. [DOI] [PubMed] [Google Scholar]
  30. Rosen H., Gordon S. Monoclonal antibody to the murine type 3 complement receptor inhibits adhesion of myelomonocytic cells in vitro and inflammatory cell recruitment in vivo. J Exp Med. 1987 Dec 1;166(6):1685–1701. doi: 10.1084/jem.166.6.1685. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Ruoslahti E., Pierschbacher M. D. New perspectives in cell adhesion: RGD and integrins. Science. 1987 Oct 23;238(4826):491–497. doi: 10.1126/science.2821619. [DOI] [PubMed] [Google Scholar]
  32. Schlager S. I. Radioiodination of cell surface lipids and proteins for use in immunological studies. Methods Enzymol. 1980;70(A):252–265. doi: 10.1016/s0076-6879(80)70054-x. [DOI] [PubMed] [Google Scholar]
  33. Smahel J. Foreign material in the capsules around breast prostheses and the cellular reaction to it. Br J Plast Surg. 1979 Jan;32(1):35–42. doi: 10.1016/0007-1226(79)90058-4. [DOI] [PubMed] [Google Scholar]
  34. Stark G. B., Göbel M., Jaeger K. Intraluminal cyclosporine A reduces capsular thickness around silicone implants in rats. Ann Plast Surg. 1990 Feb;24(2):156–161. doi: 10.1097/00000637-199002000-00009. [DOI] [PubMed] [Google Scholar]
  35. Staros J. V., Wright R. W., Swingle D. M. Enhancement by N-hydroxysulfosuccinimide of water-soluble carbodiimide-mediated coupling reactions. Anal Biochem. 1986 Jul;156(1):220–222. doi: 10.1016/0003-2697(86)90176-4. [DOI] [PubMed] [Google Scholar]
  36. Sutherland K., Mahoney J. R., 2nd, Coury A. J., Eaton J. W. Degradation of biomaterials by phagocyte-derived oxidants. J Clin Invest. 1993 Nov;92(5):2360–2367. doi: 10.1172/JCI116841. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Tang L., Eaton J. W. Fibrin(ogen) mediates acute inflammatory responses to biomaterials. J Exp Med. 1993 Dec 1;178(6):2147–2156. doi: 10.1084/jem.178.6.2147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Tang L., Lucas A. H., Eaton J. W. Inflammatory responses to implanted polymeric biomaterials: role of surface-adsorbed immunoglobulin G. J Lab Clin Med. 1993 Sep;122(3):292–300. [PubMed] [Google Scholar]
  39. Torres J. L., Rush R. S., Main A. R. Physical and chemical characterization of a horse serum carboxylesterase. Arch Biochem Biophys. 1988 Nov 15;267(1):271–279. doi: 10.1016/0003-9861(88)90032-x. [DOI] [PubMed] [Google Scholar]
  40. Trezzini C., Jungi T. W., Kuhnert P., Peterhans E. Fibrinogen association with human monocytes: evidence for constitutive expression of fibrinogen receptors and for involvement of Mac-1 (CD18, CR3) in the binding. Biochem Biophys Res Commun. 1988 Oct 14;156(1):477–484. doi: 10.1016/s0006-291x(88)80866-0. [DOI] [PubMed] [Google Scholar]
  41. Ugarova T. P., Budzynski A. Z. Interaction between complementary polymerization sites in the structural D and E domains of human fibrin. J Biol Chem. 1992 Jul 5;267(19):13687–13693. [PubMed] [Google Scholar]
  42. Ugarova T. P., Budzynski A. Z., Shattil S. J., Ruggeri Z. M., Ginsberg M. H., Plow E. F. Conformational changes in fibrinogen elicited by its interaction with platelet membrane glycoprotein GPIIb-IIIa. J Biol Chem. 1993 Oct 5;268(28):21080–21087. [PubMed] [Google Scholar]
  43. Wachtfogel Y. T., Abrams W., Kucich U., Weinbaum G., Schapira M., Colman R. W. Fibronectin degradation products containing the cytoadhesive tetrapeptide stimulate human neutrophil degranulation. J Clin Invest. 1988 May;81(5):1310–1316. doi: 10.1172/JCI113456. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Watt K. W., Cottrell B. A., Strong D. D., Doolittle R. F. Amino acid sequence studies on the alpha chain of human fibrinogen. Overlapping sequences providing the complete sequence. Biochemistry. 1979 Nov 27;18(24):5410–5416. doi: 10.1021/bi00591a024. [DOI] [PubMed] [Google Scholar]
  45. Weitz J. I., Landman S. L., Crowley K. A., Birken S., Morgan F. J. Development of an assay for in vivo human neutrophil elastase activity. Increased elastase activity in patients with alpha 1-proteinase inhibitor deficiency. J Clin Invest. 1986 Jul;78(1):155–162. doi: 10.1172/JCI112545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Wu X., Helfrich M. H., Horton M. A., Feigen L. P., Lefkowith J. B. Fibrinogen mediates platelet-polymorphonuclear leukocyte cooperation during immune-complex glomerulonephritis in rats. J Clin Invest. 1994 Sep;94(3):928–936. doi: 10.1172/JCI117459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Yam L. T., Li C. Y., Crosby W. H. Cytochemical identification of monocytes and granulocytes. Am J Clin Pathol. 1971 Mar;55(3):283–290. doi: 10.1093/ajcp/55.3.283. [DOI] [PubMed] [Google Scholar]
  48. Zhao Q., Topham N., Anderson J. M., Hiltner A., Lodoen G., Payet C. R. Foreign-body giant cells and polyurethane biostability: in vivo correlation of cell adhesion and surface cracking. J Biomed Mater Res. 1991 Feb;25(2):177–183. doi: 10.1002/jbm.820250205. [DOI] [PubMed] [Google Scholar]

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