Proteolysis-Induced Pathomechanisms in Acute Inflammation and Related Therapeutic Approaches

  • M. Jochum
  • W. Machleidt
  • H. Fritz
Conference paper
Part of the Colloquium der Gesellschaft für Biologische Chemie 11.–13. April 1991 in Mosbach/Baden book series (MOSBACH, volume 42)


Proteolysis-induced pathomechanisms seem to play a major role in the primary response of the organism to inflammatory stimuli such as tissue destruction due to multiple trauma and major surgery or invasive microbes and endotoxins in sepsis. Physiologically, the inflammation response is directed towards inactivating and eliminating the deleterious agents and to initiate the process of repair and healing. Yet, the activation of the complex interacting cellular and humoral defence mechanisms necessary for this purpose carries with it also the risk of damaging healthy tissue, thus perpetuating the inflammatory process. In this respect, the lysosomal serine proteinase elastase and the cysteine proteinase cathepsin B of the primary inflammatory cells, polymorphonuclear (PMN) granulocytes, and monocytes/macrophages are supposed to be potent effectors of proteolytic tissue damage if they are discharged extracellularly in high amounts during activation of the phagocytes. Moreover, proteinases of humoral origin (plasma kallikrein, thrombin, plasmin, complement esterases) and protein split products generated by their proteolytic action (fibrinopeptides and fibrin monomers, fibronectin peptides, complement-derived factors such as C3a, C4a, and C5a, etc.) have been proven to be of major importance as strong stimulators of the primary defence cells.


Acute Respiratory Distress Syndrome Adult Respiratory Distress Syndrome Lysosomal Proteinase Split Product Fibrin Monomer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  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 - indicator for the release of lysosomal cysteine proteinases in severe trauma and inflammation. Biol Chem Hoppe-Seyler 37l(Suppl):211–222Google Scholar
  2. Billing A, Fröhlich D, Jochum M, Kortmann H (1988) Impaired phagocytosis in peritonitis exudate secondary to complement consumption. Surg Res Comm 3:335–345Google Scholar
  3. Billing A, Fröhlich D, Jochum M, Kortmann H (1990) Deficient phagocytosis in abdominal sepsis: the influence of intraperitoneal substitution of opsonins - first results. Surg Res Comm 9:297–302Google Scholar
  4. Billing A, Fröhlich D, Assfalg-Machleidt I, Machleidt W, Jochum M (1991) Proteolysis of defensive proteins in peritonitis exudate: pathobiochemic aspects and therapeutic approach. Biomed Biochim Acta 50 (in press)Google Scholar
  5. Blauhut B, Kramer H, Vinazzer H, Bergmann H (1985) Substitution of antithrombin III in shock and DIC. A randomized study. Thromb Res 39:81–89PubMedCrossRefGoogle Scholar
  6. Duswald K-H, Jochum M, Schramm W, Fritz H (1985) Released granulocytic elastase: an indicator of pathobiochemical alterations in septicemia after abdominal surgery. Surgery 98:892–898PubMedGoogle Scholar
  7. 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):27–33CrossRefGoogle Scholar
  8. Fritz H, Collins J, Jochum M (1991) Proteinase inhibitor candidates for therapy of enzyme-inhibitor imbalances. In: Grassi C, Travis J, Casali L, Luisetti M (eds) Current concepts in the biochemistry of pulmonary emphysema. Springer, Berlin Heidelberg New York, Bi & Gi, Verona Publishers, London (in press)Google Scholar
  9. Gippner-Steppert C (1991) Entwicklung eines spezifischen Testsystems für den Nachweis der Bildung eines proteolytischen Spaltproduktes des Fibrinogens durch lysosomale PMN-Elastase sowie Untersuchungen am Miniplasminogen, einem Elastase-spezifischen Spaltprodukt des Plasminogens. Dissertation, Fakultät für Chemie, Biologie und Geowissenschaften der Technischen Universität MünchenGoogle Scholar
  10. 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 142:782–788PubMedGoogle Scholar
  11. Idell S, Kucich U, Fein A, Kueppers F, James HL, Walsch PN, Weinbaum G, Colman RW, Cohen AB (1985) Neutrophil elastase-releasing factors in bronchoalveolar lavage from patients with adult respiratory distress syndrome. Am Rev Respir Dis 132:1098–1105PubMedGoogle Scholar
  12. Inthorn D, Jochum M (1988) Auswirkungen chirurgischer Infektionen auf die Stimulierbarkeit zur Chemilumineszenz von Granulozyten und die Freisetzung granulozytärer Elastase. In: Häring R (Hrsg) Risiko in der Chirurgie. Analyse und Kalkulation. Walter de Gruyter, Berlin, pp 219–224Google Scholar
  13. Jochum M (1988) Lysosomale Faktoren aus polymorphkernigen Granulozyten: Pathobiochemische, diagnostische und therapeutische Aspekte. Habilitationsschrift an der Medizinischen Fakultät der Ludwig-Maximilians-Universität MünchenGoogle Scholar
  14. Jochum M (1991) Specific proteins of inflammatory cells and α1-proteinase inhibitor in alveolar epithelial lining fluid of polytraumatized patients: do they indicate posttraumatic lung failure? In: Sturm JA (ed) Posttraumatic acute respiratory distress syndrome. Springer, Berlin Heidelberg New York, pp 193–211Google Scholar
  15. Jochum M, Fritz H (1989) Pathobiochemical mechanisms in inflammation. In: Faist E, Nürnemann JL, Green DR (eds) Immune consequences of trauma, shock and sepsis. Springer, Berlin Heidelberg New York, pp 165–172Google Scholar
  16. Jochum M, Fritz H (1990) Elastase and its inhibitors in intensive care medicine. Biomed Prog 3:55–59Google Scholar
  17. Jochum M, Lander S, Heimburger N, Fritz H (1981) Effect of human granulocytic elastase on isolated human antithrombin III Hoppe Seyler’s Z Physiol Chem 362:103–112CrossRefGoogle Scholar
  18. Jochum M, Welter HF, Siebeck M, Fritz H (1987) Proteinase 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 proteolysis. Academic Press, Orlando, pp 85–90Google Scholar
  19. Jochum M, Assfalg-Machleidt I, Inthorn D, Nast-Kolb D, Waydhas Ch, Fritz H (1990) Leukozytäre Proteinasen und Hämostasestörung bei der Sepsis. In: Matthias R, Tilsner V (Hrsg) XXXH. Hamburger Symposium über Blutgerinnung: Infektion, Entzündung und Blutgerinnung. Editiones Roche, Basel, pp 241–254Google Scholar
  20. 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 (Hrsg) Blut, Blutkomponenten und Blutersatzstoffe in der Intensivmedizin. Bericht über das 10. Bremer Interdisziplinäre Intensivtherapie-Colloquium. W. Zuckschwerdt-Verlag, München pp 46–58Google Scholar
  21. 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): 19–22CrossRefGoogle Scholar
  22. Machleidt W, Assfalg-Machleidt I, Billing A, Fröhlich D, Joka Th, Nast-Kolb D (1991) The role of lysosomal cysteine proteinases as markers of macrophage activation and as non-specific mediators of inflammation. In: Proc 2nd Int. Congr on the Immune consequences of trauma, shock, and sepsis. Springer, Berlin Heidelberg New York (in press)Google Scholar
  23. Nast-Kolb D, Waydhas Ch, Jochum M, Spannagl M, Duswald KH, Schweiberer L (1990) Günstigster Zeitpunkt für die Versorgung von Femurschaftfrakturen beim Polytrauma? Chirurg 61:259–265PubMedGoogle Scholar
  24. Neumann S, Jochum M (1984) Elastase-α1-proteinase inhibitor complex. In: Bergmeyer HU, Bergmeyer J, Graßl M (eds) Methods of enzymatic analysis, 3rd edn, vol 5. Verlag Chemie, Weinheim, pp 184–195Google Scholar
  25. Obertacke U, Joka Th, Reuter M, Schmit-Neuerburg KP (1991) Bronchoalveolar lavage. In: Sturm, JA (ed) Adult respiratory distress syndrome. Springer, Berlin Heidelberg New York, pp 17–21Google Scholar
  26. Schraufstatter I, Revak SD, Cochrane CG (1984) Biochemical factors in pulmonary inflammatory disease. Fed Proc 43:2807–2810PubMedGoogle Scholar
  27. Siebeck M, Hoffmann H, Jochum M, Fritz H (1989a) Inhibition of proteinases with recombinant eglin c during experimental Escherichia coli septicemia in the pig. Eur Surg Res 21:11–17PubMedCrossRefGoogle Scholar
  28. Siebeck M, Hoffmann H, Weipert J, Spannagl M (1989b) Therapeutic effects of the combination of two proteinase inhibitors in endotoxin shock of the pig. In: Schlag G, Redl H (eds) Progress in clinical and biological research, vol 308. Second Vienna Shock Forum. Alan R. Liss, New York, pp 937–943Google Scholar
  29. Spannagl M, Hoffmann H, Siebeck M, Weipert J, Schwartz HP, Schramm W (1991) A purified antithrombin III-heparin complex as a potent inhibitor of thrombin in porcine endotoxin shock. Thromb Res 61:1–10PubMedCrossRefGoogle Scholar
  30. Sturm JA (ed) (1991) Adult respiratory distress syndrome. An aspect of multiple organ failure. Results of a prospective clinical study. Springer, Berlin Heidelberg New YorkGoogle Scholar
  31. Vinazzer H (1987) Clinical use of antithrombin III concentrates. Vox Sang 53:193–198PubMedCrossRefGoogle Scholar
  32. 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 72:1672–1677PubMedCrossRefGoogle Scholar
  33. Wachtfogel YT, Pixley RA, Kucich U, Abrams W, Weinbaum G, Schapira M, Colman RW (1985) Purified plasma factor XIIa aggregates human neutrophils and releases elastase. Circulation 70(Suppl. II):352Google Scholar
  34. Waydhas Ch, Nast-Kolb D, Jochum M, Trupka A, Lenk S, Fritz H, Duswald KH, Schweiberer L (1991) Inflammatory mediators, infection, sepsis, and multiorgan failure after severe trauma. Arch Surg (in press)Google Scholar
  35. Weitz JI, Landmann SL, Crowley KA, Birken S, Morgan FJ (1986) Development of an assay for in vivo human neutrophil elastase activity. J Clin Invest 78:155–162PubMedCrossRefGoogle Scholar
  36. Wewers MD, Herzyk DJ, Gadek JE (1988) Alveolar fluid neutrophil elastase activity in the adult respiratory distress syndrome is complexed to alpha-2-macroglobulin. J Clin Invest 82:1260–1264PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1991

Authors and Affiliations

  • M. Jochum
    • 1
  • W. Machleidt
    • 2
  • H. Fritz
    • 1
  1. 1.Department of Clinical Chemistry and Clinical BiochemistrySurgical Clinic City of the University of MunichMunich 2Germany
  2. 2.Institute of Physiological ChemistryPhysical Biochemistry and Cell Biology of the University of MunichMunich 2Germany

Personalised recommendations