Effects of Plasma Kallikrein Specific Inhibitor and Active-site Blocked Factor VIIa on the Pulmonary Vascular Injury Induced by Endotoxin in Rats

Summary

The acute respiratory distress syndrome (ARDS) is a serious complication of sepsis. To evaluate the role of the coagulation system in the pathogenesis of ARDS in sepsis, we examined the effects of the administration of a synthetic plasma kallikrein specific inhibitor (PKSI) and of active-site blocked factor VIIa (DEGR-VIIa) on the pulmonary vascular injury induced by E. coli endotoxin (ET) in rats. Administration of PKSI prevented the pulmonary vascular injury induced by ET as well as pulmonary histological changes in animals administered ET, but it did not affect the intravascular coagulation. The opposite effect was seen with DEGR-VIIa, which prevented the intravascular coagulation but not the pulmonary vascular injury. PKSI did not inhibit the activation of the complement system induced by ET leading to the activation of neutrophils.

Findings suggest that PKSI may prevent the pulmonary vascular injury induced by ET by inhibiting kallikrein, which activates the neutrophils. The intrinsic pathway of coagulation may be more important than the extrinsic pathway in the pulmonary vascular injury produced byET.

• References

• 1 Bone RC, Maunder R, Slotman G, Silverman H, Hyers TM, Kerstein MD, Ursprung JJ. early test of survival in patients with the adult respiratory distress syndrome. Chest 1989; 96: 849-51
• 2 Bone RC, Balk R, Slotman G, Maunder R, Silverman H, Hyers TM, Kerstein MD. Adult respiratory distress syndrome. Sequence and importance of development of multiple organ failure. Chest 1992; 101: 320-326
• 3 Hasegawa N, Husari AW, Hart WT, Kandra TG, Raffin TA. Role of the coagulation system in ARDS. Chest 1994; 105: 268-277
• 4 Murakami K, Okajima K, Uchiba M, Johno M, Nakagaki T, Okabe H, Takatsuki K. Activated protein C attenuates endotoxin-induced pulmonary vascular injury by inhibiting activated leukocytes in rats. Blood 1996; 87: 642-647
• 5 Jones A, Geczy CL. Thrombin and factor Xa enhance the production of interleukin-1. Immunology 1990; 71: 236-241
• 6 Okusawa S, Gelfand JA, Ikejima T, Connoly RJ, Dinarello CA. Interleukin 1 induces a shock-like state. J Clin Invest 1988; 81: 1162-1172
• 7 Wachtfogel YT, Kucich U, James HL, Scott CF, Schapira M, Zimmerman M, Cohen AB, Colman RW. Human plasma kallikrein release neutrophil elastase during blood coagulation. J Clin Invest 1983; 72: 1672-1677
• 8 Wachtfogel YT, Pixley RA, Kucich U, Abrams W, Weinbaum G, Schapira M, Colman RW. Purified plasma factor Xlla aggregates human neutrophils and causes degranulation. Blood 1986; 67: 1731-1737
• 9 Wanaka K, Okada Y, Tsuda Y, Okamoto U, Hijikata-Okunomiya A, Bohgaki M, Naito T, Horie N, Okada Y. Synthesis of trans 4-aminomethyl- cyclohexencarbonyl-L- and -D-phenylalanine 4-carboxymethylanilide and examination of their inhibitory activity against plasma kallikrein. Chem Pharm Bull 1992; 40: 1814-1817
• 10 Wanaka K, Okamoto S, Bohgaki M, Hijikata-Okunomiya A, Naito T, Okada Y. Effect of highly selective plasma-kallikrein synthetic inhibitor on contact activation relating to kinin generation, coagulation and fibrinolysis. Thromb Res 1990; 57: 889-895
• 11 Bregengaard C, Nordfang O, Wildgoose P, Diness V. Effect of two domain tissue factor pathway inhibitor (2D-TFPI) and inactivated factor Vila on endotoxin-induced DIC in rabbits. In: DIC: pathogenesis, diagnosis, and therapy of disseminated intravascular fibrin formation. Miiller-Berghaus G, Madlener K, Blombäck M, ten Cate JW. eds. Elsevier Science Publishers B.V.; Amsterdam, The Netherlands: 1993. pp 229-231
• 12 Uchiba M, Okajima K, Murakami K, Okabe H, Takatsuki K. Attenuation of endotoxin-induced pulmonary vascular injury by antithrombin III. Am J Physiol 1996; 270: L921-L930
• 13 Chang JC, Lesser M. Quantitation of leukocytes in bronchoalveolar lavage samples from rats after intravascular injection of endotoxin. Am Rev Respir Dis 1984; 129: 72-75
• 14 Osier AG, Strauss JH, Mayer MM. Diagnostic complement fixation. Am J Syph 1952; 36: 140-153
• 15 Kaplan AP, Kay AB, Austin KF. A prealbumin activator of prekallikrein III. Appearance of chemotactic activity for human neutrophils by the conversion of human prekallikrein to kallikrein. J Exp Med 1972; 135: 81-97
• 16 Abe H, Okajima K, Okabe H, Takatsuki K, Binder BR. Granulocyte proteases and hydrogen peroxide synergistically inactivate thrombomodulin of endothelial cells in vitro. J Lab Clin Med 1994; 123: 874-881
• 17 Cooper NR, Miles LA, Griffin JH. Effects of plasma kallikrein and plasmin on the first component of complement. J Immunol 1990 1980; 124: 1517-1523
• 18 Ghebrehiwet B, Silverberg M, Kaplan AP. Activation of the classical complement pathway by Hageman factor fragments. J Exp Med 1981; 153: 665-676
• 19 Moore Jr FD. Therapeutic regulation of the complement system in acute injury state,. Adv Immunol 1994; 56: 267-299
• 20 Jansen PM, Pixly RA, Brouwer M, de JongJW, Chang AC, Hack CE, Taylor FBJr, Colman RW. Inhibitation of factor XII in septic baboons attenuates the activation of complement and fibrinolytic systems and reduces the release of interleukin-6 and neutrophil elastase. Blood 1996; 87: 2337-2344
• 21 Katsu-ura Y, Okamoto S, Ohno N, Wanaka K. Effects of a highly selective synthetic inhibitor of plasma kallikrein on disseminated intravascular coagulation in rats. Thromb Res 1996; 82: 361-368
• 22 Taylor Jr FB, Chang ACK, Peer GT, Mather T, Blick K, Catlett R, Lockhart MS, Esmon CT. DEGR-factor Xa blocks disseminated intravascular coagulation initiated by Escherichia coli without preventing shock or organ damage. Blood 1991; 78: 364-368
• 23 Bone RC, Francis PB, Pierce AK. Intravascular coagulation associated with the adult respiratory distress syndrome. Am J Med 1976; 61: 585-589
• 24 Bachofen M, Weibel ER. Structural alterations of lung parenchyma in the adult respiratory distress syndrome. Clin Chest Med 1982; 3: 35-56
• 25 Pixley RA, La CadenaR, Page JD, Kaufman N, Wyshock EG, Chang A, Taylor FBJr, Colman RW. contact system contributes to hypotension but not disseminated intravascular coagulation in lethal bacteremia. In vivo use of a monoclonal antibody to block contact activation in baboons. J Clin Invest 1993; 91: 61-68
• 26 van DeventerSJH, Buller HR, ten CateJW, Aarden LA, Hack CE, Sturk A. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood 1990; 76: 2520-2526
• 27 Taylor FBJr, Chang A, Ruf W, Morrissey JH, Hinshaw L, Catlett R, Blick K, Edgington TS, Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ Shock 1991; 33: 127-134
• 28 Warr TA, Rao VM, Rapaport SI. Disseminated intravascular coagulation in rabbits induced by administration of endotoxin or tissue factor: effect of anti-tissue factor antibodies and measurement of plasma extrinsic pathway inhibitor activity. Blood 1990; 75: 1481-1489
• 29 Biemond BJ, Levi M, ten CateH, Soule HR, Morris LD, Foster DL, Bogwitz CA, der PollT, Büller HR, ten CateJW. Complete inhibition of endotoxin-induced coagulation activation in chimpanzees with monoclonal Fab fragment against factor Vll/VIIa. Thromb Haemost 1995; 73: 223-230
• 30 Carvalho AC, Demarins S, Scott CF, Silver LD, Schmaier AH, Colman RW. Activation of the contact system of plasma proteolysis in the adult respiratory distress syndrome. J Lab Clin Med 1988; 112: 270-277
• 31 Schapira M, Gardaz JP, Py P, Lew PD, Perrin LH, Suter PM. Prekallikrein activation in the adult respiratory distress syndrome. Bull Eur Physiopathol Respir 1985; 21: 237-241