The purpose of this paper is to review the deleterious effects of complement activation during extracorporeal circulation on the lungs and to discuss the feasibility of FUT-175, a new synthetic protease inhibitor, as a com plement activation inhibitor. Complement activation causes leukocyte ag gregation and aggregated leukocytes behave as microemboli in the pulmonary vessels. Anaphylatoxins produced by complement activation have potent vaso active properties and many chemical mediators are also released from leuko cytes. FUT-175 might be effective to inhibit complement activation during car diopulmonary bypass (CPB). Although deleterious effects of CPB on the lungs are multifactorial, we hypothesize that complement activation may play a ma jor role in lung injury during CPB.
Kaplow, L.W. and J.A. Goffinet. "Profound Neutropenia during the Early Phase of Hemodialysis," J. Am. Med. Ass., 203:1135 (1968 ).
2.
Toren, M., J.A. Goffinet and L.S. Kaplow. "Pulmonary Bed Sequestration of Neutrophils during Hemodialysis ," Blood, 36:337 (1970).
3.
Craddock, P.R. , J. Fehr, A.P. Dalmasso, et al. "Hemodialysis Leukopenia, Pulmonary Vascular Leukostasis Resulting from Complement Activation by Dialyzer Cell Cellophane Membranes," J. Clin. Invest., 59:879 (1977).
4.
Jacob, H.S., P.R. Craddock, D.E. Hammerschmidt and C.F. Moldow. "Complement-Induced Granulocyte Aggregation," N Eng. J. Med., 302: 789 (1980).
5.
Chenoweth, D.E. , S.W. Cooper, T.E. Hugli, et al. "Complement Activation during Cardiopulmonary Bypass, Evidence for Generation of C3a and C5a Anaphylatoxins," N. Eng. J. Med., 304:497 (1981).
6.
Hammerschmidt, D.E., D.F. Stroncek, Bowerstk, et al. "Complement Activation and Neutropenia Occurring during Cardiopulmonary Bypass," J. Thorac. Cardiovasc Surg., 81:370 (1981).
7.
Gardinali, M. , M. Circardi, A. Agostini and T.E. Hugli. "Complement Activation in Extracorporeal Circulation, Physiological and Pathological Implications;' Pathol. Immunopathol. Res., 5:352 (1986).
8.
Brigham, K.L. and B. Meyrick. "Interactions of Granulocytes with the Lung," Cir. Res., 54:623 (1984).
9.
Goldstein, I.M. , C.L. Malmsten, B. Samuelsson and G. Weissman. "Prostaglandins, Thromboxanes and Polymorphonuclear Leukocytes," Inflammation, 2:309 (1977).
10.
Lundberg, C. , F. Marceau and T.E. Hugli. "C5a-Induced Hemodynamic and Hematologic Changes in the Rabbit. Role of Cyclo-Oxygenase Products, Histamine and PMNs ," Am. J. Path., 128:471 (1987).
11.
Wysocki, H. , A. Ponizynski, B. Wierusz-Wysocka, et al. "Cardiopulmonary Bypass-Induced Complement Activation Evidence for C5a Participation," Int. J. Artif. Organs, 5:305 (1982).
12.
Nagaki, K. and S. Inai. "Inactivator of the First Component of Human Complement (ClINA), Enhancement of ClINA Activity Against Cls by Acidic Mucopolysaccharides ;' Int. Arch. Allergy Appl. Immunol., 50:172 (1976).
13.
Boscoe, M., V. Yewdall, M. Thompson and J. Cameron. "Complement Activation during Cardiopulmonary Bypass, Quantitative Study of Effects of Methylprednisolone and Pulsatile Flow," Br. Med. J., 287:1747 (1983).
14.
Clark, R., R. Beauchamp, R. Magrath, et al. "Comparison of Bubble and Membrane Oxygenators in Short and Long Perfusions," J. Thorac. Cardiovasc. Surg., 78:655 (1979).
15.
Cavarocchi, N.C., J.R. Pluth, H.V. Schaff, et al. "Complement Activation during Cardiopulmonary Bypass, Comparison of Bubble and Membrane Oxygenators," J. Thorac. Cardiovasc. Surg., 91:252 (1986).
16.
Kinet, J.P. , D. Soyeur, N. Balland, et al. "Hemodynamic Study of Hypotension during Hemodialysis," Kidney Int., 21:868 (1982).
17.
Craddock, P.R. , J. Fehr, K.L. Brigham, et al. "Complement and Leukocyte-Mediated Pulmonary Dysfunction in Hemodialysis," N. Eng. J. Med., 296:769 (1977).
18.
Keshaviah, P. and F.L. Shapiro. "A Critical Examination of Dialysis-Induced Hypotension," Am. J. Kidney Dis., 2:290 (1982).
19.
Fountain, S.W. , B.A. Martin, C.E. Musclow and J.D. Cooper. "Pulmonary Leukostasis and Its Relationship to Pulmonary Dysfunction in Sheep and Rabbits;' Cir. Res. , 46:175 (1980).
20.
Wonders, T. , P. Huttemeier, D. Berry, et al. "Complement Depletion Prevents Pulmonary Hypertension and Leukopenia in Sheep Extracorporeal Membrane Oxygenation," Trans. Am. Soc. Artif. Intern. Organs, 29:210 (1983).
21.
Kirklin, J.K. , S. Westaby, E.H. Blackstone, et al. "Complement and the Damaging Effects of Cardiopulmonary Bypass," J. Thorac. Cardiovasc. Surg., 86:845 (1983).
22.
Fujii, S. and Y. Hitomi. "New Synthetic Inhibitors of Clr, Cl Esterase, Thrombin, Plasmin, Kallikrein and Trypsin," Biochimica et Biophysica Acta, 661:342 (1981).
23.
Hitomi, Y. and S. Fujii. "Inhibition of Various Immunological Reactions in vivo by a New Synthetic Complement Inhibitor," Int. Archs. Allergy Appl. Immun., 69:262 (1982).
24.
Ikari, N., Y. Sakai, Y. Hitomi and S. Fujii. "New Synthetic Inhibitor to the Alternative Complement Pathway," Immunology, 49:685 (1983).
25.
Aoyama, T., Y. Ino, M. Ozeki, et al. "Pharmacological Studies of FUT-175, Nafamstat Mesilate," Japan J. Pharmacol., 35:203 (1984).
26.
Ino, Y., Y. Sato, Y. Koshiyama, et al. "Effects of FUT-175, a Novel Synthetic Protease Inhibitor, on the Development of Adjuvant Arthritis in Rats and Some Biological Reactions Dependent of Complement Activation," Gen. Phamac., 18:513 (1987).
27.
Miyamoto, Y. , T.Z. Lajos, J.N. Bhayana, et al. "Physiologic Constraints in Autoperfused Heart-Lung Preservation;' J. Heart Transplant, 6:261 ( 1987).
28.
Naka, Y. "Experimental Study of Cardiopulmonary Preservation with Autoperfusing Heart-Lung Preparation, Prevention of Pulmonary Edema by FUT-175 and Leukocyte Depletion," Osaka Univ. Med. Magazine, 40: 215 (1988).
29.
Hitomi, Y., N. Ikari and S. Fujii. "Inhibitory Effect of a New Synthetic Protease Inhibitor (FUT-175) on the Coagulation System," Haemostasis, 15: 164 (1985).
30.
Skubitz, K.M. and P.R. Craddock. "Reversal of Hemodialysis Granulocytopenia and Pulmonary Leukostasis, a Clinical Manifestation of Selective Down-Regulation of Granulocyte Response to C5a," J. Clin. Invest., 67: 1383 (1981).
31.
Chenoweth, D.E., A.K. Cheung and L.W. Henderson. "Anaphylatoxin Formation during Hemodialysis, Effect of Different Dialyzer Membranes," Kidney Inter., 24:764 (1983).
32.
Jones, H.M. , N. Matthews, R.S. Vaughan and J.M. Stark. "Cardiopulmonary Bypass and Complement Activation Involvement of Classical and Alternative Pathways," Anaesthesia, 37:629 (1982).
33.
Collett, B. , A. Alhaq, N. Abdullah, et al. "Pathways to Complement Activation during Cardiopulmonary Bypass," Br. Med. J., 289:1251 (1984).
34.
Chu-Jeng Chiu, R. and R. Samson. "Complement (C3, C4) Consumption in Cardiopulmonary Bypass, Cardioplegia and Protamine Administration," Ann. Thorac. Surg., 37:229 (1984).
35.
Miyamoto, Y. , H. Hirose, H. Matsuda, et al. "Analysis of Complement Activation Profile during Cardiopulonary Bypass and Its Inhibition by FUT-175," Trans. Am. Soc. Artif. Intern. Organs, 31:508 (1985).
36.
Kitamura, H. , S. Inai and K. Nagaki. "A Simple Procedure for the Titration of Total Hemolytic Complement Activity, One Point Method," Jpn. J. Clin. Chem., 12:143 (1983).
