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. 1995 Jun;221(6):625–634. doi: 10.1097/00000658-199506000-00002

Decreased mortality of severe acute pancreatitis after proximal cytokine blockade.

J G Norman 1, M G Franz 1, G S Fink 1, J Messina 1, P J Fabri 1, W R Gower 1, L C Carey 1
PMCID: PMC1234684  PMID: 7794067

Abstract

OBJECTIVE: This study determined the ability of interleukin-1 receptor antagonist (IL-1ra) to decrease the mortality of experimental acute pancreatitis. The response of the inflammatory cytokine cascade and its subsequent effects on pancreatic morphology were measured to determine the role of these peptides in mediating pancreatic injury. SUMMARY BACKGROUND DATA: Previous studies have shown that proinflammatory cytokines are produced in large amounts during acute pancreatitis and that blockade at the level of the IL-1 receptor significantly decreases intrinsic pancreatic damage. The subsequent effect on survival is not known. METHODS: A lethal form of acute hemorrhagic necrotizing pancreatitis was induced in young female mice by feeding a choline-deficient, ethionine supplemented (CDE) diet for 72 hours. For determination of mortality, the animals were divided into 3 groups of 45 animals each: control subjects received 100/microL normal saline intraperitoneally every 6 hours for 5 days; IL-1ra early mice received recombinant interleukin-1 receptor antagonist 15 mg/kg intraperitoneally every 6 hours for 5 days beginning at time 0; IL-1ra late mice received IL-1ra 15 mg/kg intraperitoneally every 6 hours for 3.5 days beginning 1.5 days after introduction of the CDE diet. A parallel experiment was conducted simultaneously with a minimum of 29 animals per group, which were sacrificed daily for comparisons of serum amylase, lipase, IL-1, IL-6, tumor necrosis factor-alpha, IL-1ra, pancreatic wet weight, and blind histopathologic grading. RESULTS: The 10-day mortality in the untreated control group was 73%. Early and late IL-1ra administration resulted in decreases of mortality to 44% and 51%, respectively (both p < 0.001). Interleukin-1 antagonism also was associated with a significant attenuation in the rise in pancreatic wet weight and serum amylase and lipase in both early and late IL-1ra groups (all p < 0.05). All control animals developed a rapid elevation of the inflammatory cytokines, with maximal levels reached on day 3. The IL-1ra-treated animals, however, demonstrated a blunted rise of these mediators (all p < 0.05). Blind histologic grading revealed an overall decrease in the severity of pancreatitis in those animals receiving the antagonist. CONCLUSIONS: Early or late blockade of the cytokine cascade at the level of the IL-1 receptor significantly decreases the mortality of severe acute pancreatitis. The mechanism by which this is accomplished appears to include attenuation of systemic inflammatory cytokines and decreased pancreatic destruction.

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Selected References

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

  1. Aiura K., Gelfand J. A., Burke J. F., Thompson R. C., Dinarello C. A. Interleukin-1 (IL-1) receptor antagonist prevents Staphylococcus epidermidis-induced hypotension and reduces circulating levels of tumor necrosis factor and IL-1 beta in rabbits. Infect Immun. 1993 Aug;61(8):3342–3350. doi: 10.1128/iai.61.8.3342-3350.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arend W. P., Welgus H. G., Thompson R. C., Eisenberg S. P. Biological properties of recombinant human monocyte-derived interleukin 1 receptor antagonist. J Clin Invest. 1990 May;85(5):1694–1697. doi: 10.1172/JCI114622. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Carter D. B., Deibel M. R., Jr, Dunn C. J., Tomich C. S., Laborde A. L., Slightom J. L., Berger A. E., Bienkowski M. J., Sun F. F., McEwan R. N. Purification, cloning, expression and biological characterization of an interleukin-1 receptor antagonist protein. Nature. 1990 Apr 12;344(6267):633–638. doi: 10.1038/344633a0. [DOI] [PubMed] [Google Scholar]
  4. Cioffi W. G., Burleson D. G., Pruitt B. A., Jr Leukocyte responses to injury. Arch Surg. 1993 Nov;128(11):1260–1267. doi: 10.1001/archsurg.1993.01420230088014. [DOI] [PubMed] [Google Scholar]
  5. Dinarello C. A. Biology of interleukin 1. FASEB J. 1988 Feb;2(2):108–115. [PubMed] [Google Scholar]
  6. Fischer E., Marano M. A., Barber A. E., Hudson A., Lee K., Rock C. S., Hawes A. S., Thompson R. C., Hayes T. J., Anderson T. D. Comparison between effects of interleukin-1 alpha administration and sublethal endotoxemia in primates. Am J Physiol. 1991 Aug;261(2 Pt 2):R442–R452. doi: 10.1152/ajpregu.1991.261.2.R442. [DOI] [PubMed] [Google Scholar]
  7. Granowitz E. V., Clark B. D., Vannier E., Callahan M. V., Dinarello C. A. Effect of interleukin-1 (IL-1) blockade on cytokine synthesis: I. IL-1 receptor antagonist inhibits IL-1-induced cytokine synthesis and blocks the binding of IL-1 to its type II receptor on human monocytes. Blood. 1992 May 1;79(9):2356–2363. [PubMed] [Google Scholar]
  8. Granowitz E. V., Porat R., Mier J. W., Pribble J. P., Stiles D. M., Bloedow D. C., Catalano M. A., Wolff S. M., Dinarello C. A. Pharmacokinetics, safety and immunomodulatory effects of human recombinant interleukin-1 receptor antagonist in healthy humans. Cytokine. 1992 Sep;4(5):353–360. doi: 10.1016/1043-4666(92)90078-6. [DOI] [PubMed] [Google Scholar]
  9. Grewal H. P., Kotb M., el Din A. M., Ohman M., Salem A., Gaber L., Gaber A. O. Induction of tumor necrosis factor in severe acute pancreatitis and its subsequent reduction after hepatic passage. Surgery. 1994 Feb;115(2):213–221. [PubMed] [Google Scholar]
  10. Grewal H. P., Mohey el Din A., Gaber L., Kotb M., Gaber A. O. Amelioration of the physiologic and biochemical changes of acute pancreatitis using an anti-TNF-alpha polyclonal antibody. Am J Surg. 1994 Jan;167(1):214–219. doi: 10.1016/0002-9610(94)90076-0. [DOI] [PubMed] [Google Scholar]
  11. Guice K. S., Oldham K. T., Remick D. G., Kunkel S. L., Ward P. A. Anti-tumor necrosis factor antibody augments edema formation in caerulein-induced acute pancreatitis. J Surg Res. 1991 Dec;51(6):495–499. doi: 10.1016/0022-4804(91)90171-h. [DOI] [PubMed] [Google Scholar]
  12. Heath D. I., Cruickshank A., Gudgeon M., Jehanli A., Shenkin A., Imrie C. W. Role of interleukin-6 in mediating the acute phase protein response and potential as an early means of severity assessment in acute pancreatitis. Gut. 1993 Jan;34(1):41–45. doi: 10.1136/gut.34.1.41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Lombardi B., Estes L. W., Longnecker D. S. Acute hemorrhagic pancreatitis (massive necrosis) with fat necrosis induced in mice by DL-ethionine fed with a choline-deficient diet. Am J Pathol. 1975 Jun;79(3):465–480. [PMC free article] [PubMed] [Google Scholar]
  14. Lowry S. F. Cytokine mediators of immunity and inflammation. Arch Surg. 1993 Nov;128(11):1235–1241. doi: 10.1001/archsurg.1993.01420230063010. [DOI] [PubMed] [Google Scholar]
  15. Neta R., Oppenheim J. J. Why should internists be interested in interleukin-1? Ann Intern Med. 1988 Jul 1;109(1):1–3. doi: 10.7326/0003-4819-109-1-1. [DOI] [PubMed] [Google Scholar]
  16. Niederau C., Liddle R. A., Ferrell L. D., Grendell J. H. Beneficial effects of cholecystokinin-receptor blockade and inhibition of proteolytic enzyme activity in experimental acute hemorrhagic pancreatitis in mice. Evidence for cholecystokinin as a major factor in the development of acute pancreatitis. J Clin Invest. 1986 Oct;78(4):1056–1063. doi: 10.1172/JCI112661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Niederau C., Niederau M., Borchard F., Ude K., Lüthen R., Strohmeyer G., Ferrell L. D., Grendell J. H. Effects of antioxidants and free radical scavengers in three different models of acute pancreatitis. Pancreas. 1992;7(4):486–496. doi: 10.1097/00006676-199207000-00011. [DOI] [PubMed] [Google Scholar]
  18. Norman J., Franz M., Messina J., Riker A., Fabri P. J., Rosemurgy A. S., Gower W. R., Jr Interleukin-1 receptor antagonist decreases severity of experimental acute pancreatitis. Surgery. 1995 Jun;117(6):648–655. doi: 10.1016/s0039-6060(95)80008-5. [DOI] [PubMed] [Google Scholar]
  19. Okusawa S., Gelfand J. A., Ikejima T., Connolly R. J., Dinarello C. A. Interleukin 1 induces a shock-like state in rabbits. Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition. J Clin Invest. 1988 Apr;81(4):1162–1172. doi: 10.1172/JCI113431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Tani S., Otsuki M., Itoh H., Fujii M., Nakamura T., Oka T., Baba S. Histologic and biochemical alterations in experimental acute pancreatitis induced by supramaximal caerulein stimulation. Int J Pancreatol. 1987 Oct-Dec;2(5-6):337–348. doi: 10.1007/BF02788433. [DOI] [PubMed] [Google Scholar]
  21. Waage A., Espevik T. Interleukin 1 potentiates the lethal effect of tumor necrosis factor alpha/cachectin in mice. J Exp Med. 1988 Jun 1;167(6):1987–1992. doi: 10.1084/jem.167.6.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. di Giovine F. S., Duff G. W. Interleukin 1: the first interleukin. Immunol Today. 1990 Jan;11(1):13–20. doi: 10.1016/0167-5699(90)90005-t. [DOI] [PubMed] [Google Scholar]

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