Proteolytic Enzyme Systems

  • M. Jochum
  • W. Machleidt
  • H. Fritz

Abstract

Sepsis has traditionally been defined as a systemic inflammatory reaction of the organism to gramnegative bacterial leading to septic shock and even tually to (septic) multi-organ failure. Interestingly, it has become evident that the final common pathways of multi-organ failure initiated by trauma or by infection are very similar involving basically the same humoral and cell-dependent effectors and mediators. Amongst these, proteolytic enzyme systems have been suggested to play an equally im portant role in the course of sepsis-like syndrome and trauma-induced inflammatory response. As outlined in the chapter by Jochum et al. (pp 46–60), the lysosomal serine proteinase elastase and the cysteine proteinases cathepsins B and L of the primary inflammatory cells, polymorpho nuclear (PMN) granulocytes and monocytes/ macrophages, respectively, are thought to be par ticularly potent effectors of proteolytic tissue damage if they are discharged extracellularly in high amounts during activation and disintegration of the phagocytes due to multiple trauma or sepsis. The initial mechanisms of stimulation in these in flammatory processes, however, are significantly different. Bacterial endotoxin and other bacterial products, e.g., exotoxins, N-formylated peptides, and bacterial proteinases but also antigen-antibody complexes have been identified as potent stimula tors of the inflammatory response to infection.

Keywords

Placebo Superoxide Cysteine Heparin Histamine 

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References

  1. Assfalg-Machleidt I, Jochum M, Nast-Kolb D, Siebeck M, Billing A, Joka Th, Rothe G, Valet G, Zauner R, Scheuber HP, Machleidt W (1990) Cathepsin B — in dicator for the release of lysosomal cysteine pro teinases in severe trauma and inflammation. Biol Chem Hoppe Seyler 371[Suppl]:211–222.PubMedGoogle Scholar
  2. Bichler J, Fritz H (1991) Hirudin, a new therapeutic tool? Ann Hematol 63:67–76.PubMedCrossRefGoogle Scholar
  3. Billing A (1992) Untersuchungen zur intraabdominalen Abwehrfunktion bei der menschlichen Peritonitis und ihre therapeutische Beeinflußbarkeit. Habilitations schrift, Med. Faculty of the LM-University of Munich.Google Scholar
  4. Billing A, Fröhlich D, Jochum M, Kortmann H (1988a) Impaired phagocytosis in peritonitis exudate second ary to complement consumption. Surg Res Commun 3:335–345.Google Scholar
  5. Billing A, Fröhlich D, Jochum M, Kortmann H (1988b) Deficient phagocytosis secondary to proteolytic breakdown of opsonins in peritonitis exudate. Adv Exp Med Biol 240:441–448.PubMedGoogle Scholar
  6. Billing A, Kortmann H, Fröhlich D, Jochum M (1989) Breakdown of C3 complement and IgG in peritonitis exudate — pathophysiological aspects and therapeu tical approach. Prog Biol Res 308:527–533.Google Scholar
  7. Billing A, Fröhlich D, Assfalg-Machleidt I, Machleidt W, Jochum M (1991) Proteolysis of defensive proteins in peritonitis exudate: pathobiochemic aspects and ther apeutic approach. Biomed Biochim Acta 50:399–402.PubMedGoogle Scholar
  8. Blauhut B, Kramer H, Vinazzer H, Bergmann H (1985) Substitution of antithrombin III in shock and DIC. A randomized study. Thromb Res 39:81–89.PubMedCrossRefGoogle Scholar
  9. Braun NJ, Schnebli HP (1986) A brief review of the bio chemistry and pharmacology of eglin c, an elastase inhibitor. Eur J Respir Dis 146[Suppl]:541–547.Google Scholar
  10. Duswald K-H, Jochum M, Schramm W, Fritz H (1985) Released granulocytic elastase: an indicator of pathobiochemical alterations in septicemia after ab dominal surgery. Surgery 98:892–898.PubMedGoogle Scholar
  11. Egbring R, Havemann K (1978) Possible role of polymorphonuclear granulocyte proteases in blood coagulation. In: Havemann K, Janoff A (eds) Neutral proteases of human polymorphonuclear leukocytes. Urban and Schwarzenberg, Baltimore, pp 442–455.Google Scholar
  12. Egbring R, Seitz R, Blanke H, Leititis J, Kesper HJ, Burghard R, Fuchs G, Lerch L (1986) The proteinase inhibitor complexes (antithrombin Ill-thrombin, a2-antiplasmin-plasmin and α1-antitrypsin-elastase) in septicemia, fulminant hepatic failure and cardiac shock: Value for diagnosis and therapy control in DIC/F syndrome. Behring Inst Mitt 79:87–103.PubMedGoogle Scholar
  13. Emerson TE, Fournel MA, Redens TB, Taylor FB (1989) Efficacy of antithrombin III supplementation in animal models of fulminant Escherichia coli endotoxemia or bacteremia. Am J Med 87[Suppl 3B]:27–33.CrossRefGoogle Scholar
  14. Fink MP, Heard SO (1990) Laboratory models of sepsis and septic shock. J Surg Res 49:186–196.PubMedCrossRefGoogle Scholar
  15. Fink PC, Suin de Boutemard C, Gaitzsch A (1988) Determination of endotoxemia and leukocyte elastase in patients with septicemia. GIT Labor-Medizin 7-8:409–415.Google Scholar
  16. Fink PC, Erdmann R, Schöndube F, Baca I (1989) Leukocytes, neutrophilia, and elastase-α1-proteinase inhibitor-complex: marker of different validity for monitoring the perioperative infection risk. Prog Clin Biol Res 308:695–700.PubMedGoogle Scholar
  17. Fritz H, Collins J, Jochum M (1992) Proteinase inhibitor candidates for therapy of enzyme-inhibitor im balances. In: Grassi C, Travis J, Casali L, Luisetti M (eds) Current concepts in the biochemistry of pul monary emphysema. Springer, Berlin Heidelberg New York/Bi and Gi, Verona Publishers, pp 101–112.Google Scholar
  18. Frommherz KJ, Faller B, Bieth JG (1991) Heparin strongly decreases the rate of inhibition of neutrophil elastase by α1-proteinase inhibitor. J Biol Chem 266:15356–15362.PubMedGoogle Scholar
  19. Geiger R, Sokal S, Siebeck M, Hoffmann H, Trefz G (1988) Determination of leukocyte elastase-inhibitor complexes and leukocyte neutral proteinase inhibitor by enzyme immunoassays. J Clin Chem Clin Biochem 26:605–609.PubMedGoogle Scholar
  20. Gippner-Steppert C (1991) Entwicklung eines spezifischen Testsystems für den Nachweis der Bildung eines pro teolytischen Spaltproduktes des Fibrinogens durch lysosomale PMN-Elastase sowie Untersuchungen am Miniplasminogen, einem Elastase-spezifischen Spalt produkt des Plasminogens. Dissertation, Chem. Facul ty of the Technical University of Munich.Google Scholar
  21. Glauser MP, Zanetti G, Baumgartner JD, Cohen J (1991) Septic shock: pathogenesis. Lancet 338:732–735.PubMedCrossRefGoogle Scholar
  22. Hoffmann H, Siebeck M, Spannagl M, Weipert J, Geiger R, Jochum M, Fritz H (1990) Effect of recombinant hirudin, a specific inhibitor of thrombin, on endotoxin-induced intravascular coagulation and acute lung injury in pigs. Am Rev Respir Dis 142:782–788.PubMedGoogle Scholar
  23. Inthorn D, Jochum M (1988) Auswirkungen chirurgi scher Infektionen auf die Stimulierbarkeit zur Chemilumineszenz von Granulozyten und die Freisetzung granulozytärer Elastase. In: Häring R (ed) Risiko in der Chirurgie. Analyse und Kalkulation. De Gruyter, Berlin, pp 219–224.Google Scholar
  24. Jochum M (1988) Lysosomale Faktoren aus polymorph kernigen Granulozyten: pathobiochemische, diagnosti sche und therapeutische Aspekte. Habilitationsschrift, Med. Faculty of the LM-University of Munich.Google Scholar
  25. Jochum M, Fritz H (1990) Elastase and its inhibitors in intensive care medicine. Biomed Prog 3:55–59.Google Scholar
  26. Jochum M, Lander S, Heimburger N, Fritz H (1981) Ef fect of human granulocytic elastase on isolated human antithrombin III. Hoppe Seyler’s Z Physiol Chem 362:103–112.PubMedCrossRefGoogle Scholar
  27. Jochum M, Welter HF, Siebeck M, Fritz H (1987) Pro teinase inhibitor therapy of severe inflammation in pigs. First results with eglin, a potent inhibitor of granulocyte elastase and cathepsin G. In: Taylor JC, Mittmann C (eds) Pulmonary emphysema and pro teolysis. Academic, Orlando, pp 85–90.Google Scholar
  28. Jochum M, Assfalg-Machleidt I, Inthorn D, Nast-Kolb D, Waydhas C, Fritz H (1990) Leukozytäre Pro teinasen und Hämostasestörung bei der Sepsis. In: Tilsner V, Matthias R (eds) XXXIIth Hamburger Symposion über Blutgerinnung: Infektion, Entzün dung und Blutgerinnung. Editiones Roche, Basel, pp 241–254.Google Scholar
  29. Jochum M, Inthorn D, Nast-Kolb D, Fritz H (1991) AT III — ein neues therapeutisches Konzept bei der Behandlung der Sepsis und beim Organversagen? In: Henschel WF (ed) Blut, Blutkomponenten und Blutersatzstoffe in der Intensivmedizin. Bericht über das 10. Bremer Interdisziplinäre IntensivtherapieColloquium. Zuckschwerdt, Munich, pp 46-58.Google Scholar
  30. Jordan RE, Nelson RM, Kilpatrick J, Newgren JO, Esmon PC, Fournel MA (1989) Antithrombin inactivation by neutrophil elastase requires heparin. Am J Med 87[Suppl 3B]:19–22.CrossRefGoogle Scholar
  31. Lo SK, Lai L, Cooper JA, Malik AB (1988) Thrombininduced generation of neutrophil activating factors in blood. Am J Pathol 130:22–32.PubMedGoogle Scholar
  32. Machleidt W, Assfalg-Machleidt I, Billing A, Fröhlich D, Jochum M, Joka T, Nast-Kolb D (1993) The role of lysosomal cysteine proteinases as markers of macro phage activation and as non-specific mediators of in flammation. In: Faist E, Meakins J, Schildberg FW (eds) Host Defence Dysfunction in Trauma, Shock and Sepsis. Springer, Berlin Heidelberg, pp 459–463.Google Scholar
  33. Markwardt F (guest ed) (1991) Hirudin. Semin Thromb Hemost 17 (2).Google Scholar
  34. Neugebauer E, Lorenz W (1988) Causality in circulatory shock: strategies for integrating mediators, mecha nisms and therapies. Prog Clin Biol Res 264:295–305.PubMedGoogle Scholar
  35. Neugebauer E, Lorenz W, Maroske D, Barthlen W, Ennis M (1987) The role of mediators in septic/endotoxic shock. A meta-analysis evaluating the current status of histamine. Theor Surg 2:1–28.Google Scholar
  36. Pacher R, Redl H, Frass M, Petzl DH, Schuster E, Wolosczuk W (1989) Relationship between neopterin and granulocyte elastase plasma levels and the severi ty of multiple organ failure. Crit Care Med 17: 221–226.PubMedCrossRefGoogle Scholar
  37. Parrillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cunnion RE, Ognibene FP (1990) Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and ther apy. Ann Intern Med 113:227–242.PubMedGoogle Scholar
  38. Redl H, Schlag G, Bahrami S, Schade U, Ceska M, Stütz P (1991) Plasma neutrophil-activating peptide-1/interleukin-8 and neutrophil elastase in a primate bac teremia model. J Infect Dis 164:383–388.PubMedCrossRefGoogle Scholar
  39. Schöffel U, Kopp KH, Lausen M, Ruf G, Farthmann EH (1989a) Monitoring of postoperative intraabdominal septic complications following major abdominal surgery. Surg Res Commun 5:49–53.Google Scholar
  40. Schöffel U, Zeller T, Lausen M, Ruf G, Farthmann EH (1989b) Monitoring of the inflammatory response in early peritonitis. Am J Surg 157:567–572.PubMedCrossRefGoogle Scholar
  41. Schwartz RS, Bauer KA, Rosenberg RD, Kavanaugh EJ, Davies DC, Bogdanoff DA (1989) Clinical experience with antithrombin III concentrate in treatment of congenital and acquired deficiency of antithrombin. Am J Med 87[Suppl 3B]:53–60.CrossRefGoogle Scholar
  42. Seitz R, Wolf M, Egbring R, Radtke KP, Liesenfeld A, Pittner P, Havemann K (1987) Participation and in teractions of neutrophil elastase in haemostatic disorders of patients with severe infections. Eur J Haematol 38:231–240.PubMedCrossRefGoogle Scholar
  43. Seitz R, Wolf M, Egbring R, Havemann K (1989) The disturbance of hemostasis in septic shock: role of neutrophil elastase and thrombin, effects of anti thrombin III and plasma substitution. Eur J Haema tol 43:22–28.CrossRefGoogle Scholar
  44. Shimanuki K, Sakurabayashi I, Kanazawa K (1989) Perioperative fluctuation in plasma levels of granulocyte elastase and alpha-1-antitrypsin: the in fluence of the severity of surgical intervention and their effect on the respiratory index. Jpn J Surg 19:410–417.PubMedCrossRefGoogle Scholar
  45. Siebeck M, Hoffmann H, Geiger R, Schweiberer L (1989a) Leukocyte neutral proteinase inhibitor of the pig: Modification by eglin c and superoxide dismutase of the response to shock. Prog Clin Biol Res 308:945–951.PubMedGoogle Scholar
  46. Siebeck M, Hoffmann H, Jochum M, Fritz H (1989b) Inhibition of proteinases with recombinant eglin c during experimental Escherichia coli septicemia in the pig. Eur Surg Res 21:11–17.PubMedCrossRefGoogle Scholar
  47. Siebeck M, Hoffmann H, Weipert J, Spannagl M (1989c) Therapeutic effects of the combination of two pro teinase inhibitors in endotoxin shock of the pig. Prog Clin Biol Res 308:937–943.PubMedGoogle Scholar
  48. Siebeck M, Weipert J, Keser C, Kohl J, Spannagl M, Machleidt W, Schweiberer L (1991) A triazolodiazepine platelet activating factor receptor antagonist (WEB 2086) reduces pulmonary dysfunction during endotoxin shock in swine. J Trauma 31:942–949.PubMedCrossRefGoogle Scholar
  49. Spannagl M, Hoffmann H, Siebeck M, Weipert J, Schwartz HP, Schramm W (1991) A purified an tithrombin Ill-heparin complex as a potent inhibitor of thrombin in porcine endotoxin shock. Thromb Res 61:1–10.PubMedCrossRefGoogle Scholar
  50. Speer CP, Tegtmeyer F (1989) Elastase-α1-proteinase in hibitor in neonatal infections, hyaline membrane dis ease and meconium aspiration. In: Cosmi EV, di Renzo GC (eds) Proceedings of the XIth European con gress of perinatal medicine. Harwood, Chur, pp 852–858.Google Scholar
  51. Tanaka H, Sugimoto H, Yoshioka T, Sugimoto T (1991) Role of granulocyte elastase in tissue injury in pa tients with septic shock complicated by multiple organ failure. Ann Surg 213:81–85.PubMedCrossRefGoogle Scholar
  52. Tsaka T, Herkner KR (1990) Polymorphonuclear elastase in neonatal sepsis. Clin Chim Acta 193:103–112.PubMedCrossRefGoogle Scholar
  53. Vinazzer H (1987) Clinical use of antithrombin III con centrates. Vox Sang 53:193–198.PubMedCrossRefGoogle Scholar
  54. Wachtfogel YT, Kucich U, James HL, Scott CF, Schapira M, Zimmerman M, Cohen A, Colman RW (1983) Human plasma kallikrein releases neutrophil elastase during blood coagulation. J Clin Invest 72: 1672–1677.PubMedCrossRefGoogle Scholar
  55. Wachtfogel YT, Pixley RA, Kucich U, Abrams W, Weinbaum G, Schapira M, Colman RW (1985) Purified plasma factor Xlla aggregates human neutrophils and releases elastase. Circulation 70 [Suppl II]:352.Google Scholar
  56. Waydhas C, Nast-Kolb D, Jochum M, Trupka A, Lenk S, Fritz H, Duswald K-H, Schweiberer L (1992) Inflam matory mediators, infection, sepsis, and multiorgan failure after severe trauma. Arch Surg 127:460–467.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • M. Jochum
    • 1
  • W. Machleidt
    • 2
  • H. Fritz
    • 1
  1. 1.Department of Clinical Chemistry and Clinical Biochemistry in the Department of Surgery, Klinikum InnenstadtUniversity of MunichMunich 2Germany
  2. 2.Institute of Physiological Chemistry, Physical Biochemistry and Cell BiologyUniversity of MunichMunich 2Germany

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