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. 1970 Jan 1;131(1):21–39. doi: 10.1084/jem.131.1.21

THE ROLE OF CHEMICAL MEDIATORS IN THE INFLAMMATORY RESPONSE INDUCED BY FOREIGN BODIES: COMPARISON WITH THE SCHISTOSOME EGG GRANULOMA

R W Kellermeyer 1, K S Warren 1
PMCID: PMC2138765  PMID: 5409947

Abstract

Both divinyl benzene copolymer (plastic) beads and schistosome eggs produce inflammatory reactions after intravenous deposition into the lung of a mouse. As reported previously, the schistosome egg granuloma is an immunologic reaction of the delayed hypersensitivity type; this inflammatory process is prevented by immunosuppressive measures, and characteristically demonstrates an anamnestic response. In contradistinction, the plastic bead granuloma appears to be characteristic of a foreign body reaction; it is unaffected by immunosuppressive measures and does not demonstrate an anamnestic response with repeated exposure. The data in this report suggest that the granuloma formation around plastic beads is a nonimmunologic reaction induced by chemical mediators of inflammation. This proposal is supported by the following findings: the plastic beads activate Hageman factor in normal human and mouse plasma; the plastic beads induce vascular permeability-enhancing activity as measured in guinea pig skin and kinin-like activity in normal human and mouse plasma that is dependent on Hageman factor; ellagic acid, an agent that activates Hageman factor in vivo and is reported to diminish kininogen by consumptive depletion, markedly depresses the plastic bead granuloma. These data are consistent with the idea that the plastic bead granuloma and perhaps other foreign body inflammatory reactions are in major part dependent on kinin formation. Ellagic acid also suppressed the schistosome egg granuloma, but not to the same degree as the plastic bead granuloma. The implications of this observation are discussed in the text. Silicosis and "blue velvet disease", pathologic processes associated with the deposition of silica and magnesium trisilicate, respectively, in the lung, and the induction of a foreign body reaction may also be dependent on the activation of chemical mediators of inflammation by the silica and magnesium trisilicate particles with immunologic mechanisms participating in only a minor way, if at all. The marked suppression of experimental silicosis and blue velvet disease in mice by ellagic acid supports this idea.

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Selected References

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  1. ARMSTRONG D., JEPSON J. B., KEELE C. A., STEWART J. W. Pain-producing substance in human inflammatory exudates and plasma. J Physiol. 1957 Feb 15;135(2):350–370. doi: 10.1113/jphysiol.1957.sp005715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. BECKER E. L., KAGEN L. THE PERMEABILITY GLOBULINS OF HUMAN SERUM AND THE BIOCHEMICAL MECHANISM OF HEREDITARY ANGIONEUROTIC EDEMA. Ann N Y Acad Sci. 1964 Aug 27;116:866–873. doi: 10.1111/j.1749-6632.1964.tb52552.x. [DOI] [PubMed] [Google Scholar]
  3. COKER C. M., LICHTENBERG F. A revised method for isolation of Schistosoma mansoni eggs for biological experimentation. Proc Soc Exp Biol Med. 1956 Aug-Sep;92(4):780–782. doi: 10.3181/00379727-92-22612. [DOI] [PubMed] [Google Scholar]
  4. Cohen S., Benacerraf B., McCluskey R. T., Ovary Z. Effect of anticoagulants on delayed hypersensitivity reactions. J Immunol. 1967 Feb;98(2):351–358. [PubMed] [Google Scholar]
  5. Dias Da Silva W., Lepow I. H. Complement as a mediator of inflammation. II. Biological properties of anaphylatoxin prepared with purified components of human complement. J Exp Med. 1967 May 1;125(5):921–946. doi: 10.1084/jem.125.5.921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Domingo E. O., Warren K. S. The inhibition of granuloma formation around Schistosoma mansoni eggs. 3. Heterologous antilymphocyte serum. Am J Pathol. 1968 Mar;52(3):613–631. [PMC free article] [PubMed] [Google Scholar]
  7. Domingo E. O., Warren K. S. The inhibition of granuloma formation around Schistosoma mansoni eggs. II. Thymectomy. Am J Pathol. 1967 Nov;51(5):757–767. [PMC free article] [PubMed] [Google Scholar]
  8. EPSTEIN W. L., SKAHEN J. R., KRASNOBROD H. THE ORGANIZED EPITHELIOID CELL GRANULOMA: DIFFERENTIATION OF ALLERGIC (ZIRCONIUM) FROM COLLOIDAL (SILICA) TYPES. Am J Pathol. 1963 Sep;43:391–405. [PMC free article] [PubMed] [Google Scholar]
  9. ERDOS E. G., JACKMAN V., BARNES W. C. Instrument for recording isotonic contractions of smooth muscles. J Appl Physiol. 1962 Mar;17:367–368. doi: 10.1152/jappl.1962.17.2.367. [DOI] [PubMed] [Google Scholar]
  10. Epstein W. L. Granulomatous hypersensitivity. Prog Allergy. 1967;11:36–88. [PubMed] [Google Scholar]
  11. Erdös E. G. Hypotensive peptides: bradykinin, kallidin, and eledoisin. Adv Pharmacol. 1966;4:1–90. doi: 10.1016/s1054-3589(08)60097-6. [DOI] [PubMed] [Google Scholar]
  12. Fallon J. T., Banting F. G. The Cellular Reaction to Silica. Can Med Assoc J. 1935 Oct;33(4):404–407. [PMC free article] [PubMed] [Google Scholar]
  13. Fallon J. T., Banting F. G. Tissue Reaction to Sericite. Can Med Assoc J. 1935 Oct;33(4):407–411. [PMC free article] [PubMed] [Google Scholar]
  14. GADDUM J. H., LEMBECK F. The assay of substances from the adrenal medulla. Br J Pharmacol Chemother. 1949 Dec;4(4):401–408. doi: 10.1111/j.1476-5381.1949.tb00566.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. GRAHAM R. C., Jr, EBERT R. H., RATNOFF O. D., MOSES J. M. PATHOGENESIS OF INFLAMMATION. II. IN VIVO OBSERVATIONS OF THE INFLAMMATORY EFFECTS OF ACTIVATED HAGEMAN FACTOR AND BRADYKININ. J Exp Med. 1965 May 1;121:807–818. doi: 10.1084/jem.121.5.807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gardner L. U., Cummings D. E. The Reaction to Fine and Medium Sized Quartz and Aluminum Oxide Particles. Silicotic Cirrhosis of the Liver. Am J Pathol. 1933;9(Suppl):751–764.5. [PMC free article] [PubMed] [Google Scholar]
  17. Gardner L. U. The Similarity of the Lesions Produced by Silica and by the Tubercle Bacillus. Am J Pathol. 1937 Jan;13(1):13–24.3. [PMC free article] [PubMed] [Google Scholar]
  18. Gautvik K. M., Rugstad H. E. Kinin formation and kininogen depletion in rats after intravenous injection of ellagic acid. Br J Pharmacol Chemother. 1967 Nov;31(3):390–400. doi: 10.1111/j.1476-5381.1967.tb00406.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. HILTON S. M., LEWIS G. P. Functional vasodilatation in the submandibular salivary gland. Br Med Bull. 1957 Sep;13(3):189–196. doi: 10.1093/oxfordjournals.bmb.a069612. [DOI] [PubMed] [Google Scholar]
  20. HOLDSTOCK D. J., MATHIAS A. P., SCHACHTER M. A comparative study of kinin, kallidin, and bradykinin. Br J Pharmacol Chemother. 1957 Jun;12(2):149–158. doi: 10.1111/j.1476-5381.1957.tb00113.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kellermeyer R. W., Graham R. C., Jr Kinins--possible physiologic and pathologic roles in man. N Engl J Med. 1968 Oct 17;279(16):859–concl. doi: 10.1056/NEJM196810172791605. [DOI] [PubMed] [Google Scholar]
  22. Kellermeyer W. F., Jr, Kellermeyer R. W. Hageman factor activation and kinin formation in human plasma induced by cellulose sulfate solutions. Proc Soc Exp Biol Med. 1969 Apr;130(4):1310–1314. doi: 10.3181/00379727-130-33780. [DOI] [PubMed] [Google Scholar]
  23. MARGOLIS J. The effect of colloidal silica on blood coagulation. Aust J Exp Biol Med Sci. 1961 Jun;39:249–258. doi: 10.1038/icb.1961.25. [DOI] [PubMed] [Google Scholar]
  24. MILES A. A. LARGE MOLECULAR SUBSTANCES AS MEDIATORS OF THE INFLAMMATORY REACTION. Ann N Y Acad Sci. 1964 Aug 27;116:855–865. doi: 10.1111/j.1749-6632.1964.tb52551.x. [DOI] [PubMed] [Google Scholar]
  25. MILES A. A., WILHELM D. L. Enzyme-like globulins from serum reproducing the vascular phenomena of inflammation. I. An activable permeability factor and its inhibitor in guinea-pig serum. Br J Exp Pathol. 1955 Feb;36(1):71–81. [PMC free article] [PubMed] [Google Scholar]
  26. Naff G. B., Ratnoff O. S. The enzymatic nature of C'1r. Conversion of C'1s to C'1 esterase and digestion of amino acid esters by C'1r. J Exp Med. 1968 Oct 1;128(4):571–593. doi: 10.1084/jem.128.4.571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Perrotto J. L., Warren K. S. Inhibition of granuloma formation around Schistosoma mansoni eggs. IV. X-irradiation. Am J Pathol. 1969 Aug;56(2):279–291. [PMC free article] [PubMed] [Google Scholar]
  28. Present D. H., Lindner A. E., Janowitz H. D. Granulomatous diseases of the gastrointestinal tract. Annu Rev Med. 1966;17:243–256. doi: 10.1146/annurev.me.17.020166.001331. [DOI] [PubMed] [Google Scholar]
  29. RATNOFF O. D., CRUM J. D. ACTIVATION OF HAGEMAN FACTOR BY SOLUTIONS OF ELLAGIC ACID. J Lab Clin Med. 1964 Mar;63:359–377. [PubMed] [Google Scholar]
  30. RATNOFF O. D., DAVIE E. W., MALLETT D. L. Studies on the action of Hageman factor: evidence that activated Hageman factor in turn activates plasma thromboplastin antecedent. J Clin Invest. 1961 May;40:803–819. doi: 10.1172/JCI104314. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. RATNOFF O. D., MILES A. A. THE INDUCTION OF PERMEABILITY-INCREASING ACTIVITY IN HUMAN PLASMA BY ACTIVATED HAGEMAN FACTOR. Br J Exp Pathol. 1964 Jun;45:328–345. [PMC free article] [PubMed] [Google Scholar]
  32. RATNOFF O. D., ROSENBLUM J. M. Role of Hageman factor in the initiation of clotting by glass; evidence that glass frees Hageman factor from inhibition. Am J Med. 1958 Aug;25(2):160–168. doi: 10.1016/0002-9343(58)90023-8. [DOI] [PubMed] [Google Scholar]
  33. ROCHA E SILVA M., BERALDO W. T., ROSENFELD G. Bradykinin, a hypotensive and smooth muscle stimulating factor released from plasma globulin by snake venoms and by trypsin. Am J Physiol. 1949 Feb;156(2):261–273. doi: 10.1152/ajplegacy.1949.156.2.261. [DOI] [PubMed] [Google Scholar]
  34. Ratnoff O. D. The biology and pathology of the initial stages of blood coagulation. Prog Hematol. 1966;5:204–245. [PubMed] [Google Scholar]
  35. Rothschild A. M., Castania A. Endotoxin shock in dogs pretreated with cellulose sulphate, an agent causing partial plasma kininogen depletion. J Pharm Pharmacol. 1968 Jan;20(1):77–78. doi: 10.1111/j.2042-7158.1968.tb09628.x. [DOI] [PubMed] [Google Scholar]
  36. SHELLEY W. B., HURLEY H. J. Experimental evidence for an allergic basis for granuloma formation in man. Nature. 1957 Nov 16;180(4594):1060–1061. doi: 10.1038/1801060a0. [DOI] [PubMed] [Google Scholar]
  37. SHELLEY W. B., HURLEY H. J. The pathogenesis of silica granulomas in man: a non-allergic collidial phenomenon. J Invest Dermatol. 1960 Feb;34:107–123. [PubMed] [Google Scholar]
  38. SPECTOR W. G., WILLOUGHBY D. A. THE EFFECT OF VASCULAR PERMEABILITY FACTORS ON THE EMIGRATION OF LEUCOCYTES. J Pathol Bacteriol. 1964 Apr;87:341–346. [PubMed] [Google Scholar]
  39. Schwartz H. J., Leskowitz S. The effect of carrageenan on delayed hypersensitivity reactions. J Immunol. 1969 Jul;103(1):87–91. [PubMed] [Google Scholar]
  40. Warren K. S., Domingo E. O., Cowan R. B. Granuloma formation around schistosome eggs as a manifestation of delayed hypersensitivity. Am J Pathol. 1967 Nov;51(5):735–756. [PMC free article] [PubMed] [Google Scholar]
  41. von LICHTENBERG Host response to eggs of S. mansoni. I. Granuloma formation in the unsensitized laboratory mouse. Am J Pathol. 1962 Dec;41:711–731. [PMC free article] [PubMed] [Google Scholar]

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