Role of Microthrombus Formation in the Development of Ischemia/Reperfusion-induced Liver Injury in Rats

Kenji Okajima; Naoaki Harada; Shigeki Kushimoto; Mitsuhiro Uchiba

doi:10.1055/s-0037-1613240

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2002; 88(03): 473-480
DOI: 10.1055/s-0037-1613240

Review Article

Schattauer GmbH

Role of Microthrombus Formation in the Development of Ischemia/Reperfusion-induced Liver Injury in Rats

Kenji Okajima

¹Department of Laboratory Medicine, Kumamoto University School of Medicine, Kumamoto, Japan

,

Naoaki Harada

¹Department of Laboratory Medicine, Kumamoto University School of Medicine, Kumamoto, Japan

,

Shigeki Kushimoto

¹Department of Laboratory Medicine, Kumamoto University School of Medicine, Kumamoto, Japan

,

Mitsuhiro Uchiba

¹Department of Laboratory Medicine, Kumamoto University School of Medicine, Kumamoto, Japan

› Institutsangaben

Abstract

Summary

Although tumor necrosis factor-α (TNF-α) has been shown to play a critical role in the pathologic process leading to ischemia/reperfusion (I/R)-induced liver injury in rats by activating neutrophils, it is not clear whether or not microthrombus formation induced by TNF-α contributes to the liver injury. In the present study, we investigated the role of microthrombus formation in I/R-induced liver injury in rats. Hepatic tissue levels of TNF-α were significantly increased after reperfusion, and these were higher in animals subjected to 120 min-hepatic I/R than in those subjected to 60 min-hepatic I/R. Fibrin deposition was observed histologically in the hepatic sinusoidal space only in animals subjected to 120 min-hepatic I/R. Both the decrease in hepatic tissue blood flow and the extent of liver injury in animals subjected to 60 minand 120 min-hepatic I/R were significantly inhibited by pretreatment with anti-rat TNF-α antibody. Although neutrophil elastase inhibitors inhibited the decrease in hepatic tissue blood flow and reduced liver injury in animals subjected to 60 min-hepatic I/R, anticoagulants did not show any effects. Both anticoagulants and neutrophil elastase inhibitors inhibited the decrease in hepatic tissue blood flow and reduced liver injury in animals subjected to 120 min-hepatic I/R. Therapeutic effects of anti-rat TNF-α antibody on the120 min-I/R-induced liver injury were more marked than those of each anticoagulant or each neutrophil elastase inhibitor, and were comparable to those of combined use of anticoagulants and neutrophil elastase inhibitors. These observations strongly suggest that TNF-α induces I/R-induced liver injury primarily by activating neutrophils, and it exacerbates liver injury by inducing microthrombus formation when the production of TNF-α is further increased.

Keywords

Ischemia/reperfusion-induced liver injury - tumor necrosis factor-α - microthrombus - neutrophil elastase - endothelial cell injury

Volltext

Referenzen

References
1 Hasselgren PO. Prevention and treatment of ischemia of the liver. Surg Gynecol Obstet 1987; 164: 187-96.
2 Keller GA, West MA, Cerra FB, Simmons RL. Macrophage-mediated modulation of hepatic function in multi-system failure. J Surg Res 1985; 39: 555-63.
3 Jaeschke H, Farhood A, Smith CW. Neutrophils contribute to ischemia/ reperfusion injury in rat liver in vivo. FASEB J 1990; 04: 3355-9.
4 Ishii T, Kim YI, Tatsuma T, Kawano K, Kai T, Kobayashi M. Immunodepressants ameliorate normothermic ischemia injury to the rat liver by down-regulating tumor necrosis factor, not by alleviation of lipid peroxidase injury. Transpl Int 1994; 07 (Suppl. 01) S507-11.
5 Vollmar B, Glasz J, Menger MD, Messmer K. Leukocytes contribute to hepatic ischemia/reperfusion injury via intercellular adhesion molecule-1mediated venular adherence. Surgery 1995; 117: 195-200.
6 Farhood A, McGuire GM, Manning AM, Miyasaka M, Smith CW, Jaeschke H. Intercellular adhesion molecule 1 (ICAM-1) expression and its role in neutrophil-induced ischemia-reperfusion injury in rat liver. J Leukoc Biol 1995; 57: 368-74.
7 Klebanoff SJ, Vadas MA, Harlan JM, Sparks LH, Gamble JR, Agosti JM, Waltersdorph AM. Stimulation of neutrophils by tumor necrosis factor. J Immunol 1986; 136: 4220-5.
8 Colletti LM, Burtch GD, Remick DG, Kunkel SL, Strieter RM, Guice KS, Oldham KT, Campbell Jr DA. The production of tumor necrosis factor alpha and the development of a pulmonary capillary injury following hepatic ischemia/reperfusion. Transplantation 1990; 49: 268-72.
9 Kushimoto S, Okajima K, Uchiba M, Murakami K, Harada N, Okabe H, Takatsuki K. Role of granulocyte elastase in ischemia/reperfusion injury of rat liver. Crit Care Med 1996; 24: 1908-12.
10 Naworth PP, Stern DM. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med 1986; 163: 740-5.
11 Moore KL, Esmon CT, Esmon NL. Tumor necrosis factor leads to the internalization and degradation of thrombomodulin from the surface of bovine aortic endothelial cells in culture. Blood 1989; 73: 159-65.
12 Kobayashi M, Shimada K, Ozawa T. Human recombinant interleukin-1beta- and tumor necrosis factor-alpha-mediated suppression of heparinlike compounds on cultured porcine aortic endothelial cells. J Cell Physiol 1990; 144: 383-90.
13 Schleef RR, Bevilacua MP, Sawdey M, Gimborne Jr. MA, Loskutoff DJ. Cytokine activation of vascular endothelium. J Biol Chem 1988; 263: 5797-803.
14 Hashikura Y, Kawasaki S, Okumura N, Ishikawa S, Matsunami H, Ikegami T, Nakazawa Y, Makuuchi M. Prevention of hepatic artery thrombosis in pediatric liver transplantation. Transplantation 1995; 60: 1109-12.
15 Suzuki S, Toledo-Pereyra LH. Interleukin 1 and tumor necrosis factor production as the initial stimulants of liver ischemia and reperfusion injury. J Surg Res 1994; 57: 253-8.
16 Zimmermann BJ, Granger DN. Reperfusion-induced leukocyte infiltration: role of elastase. Am J Physiol 1990; 259: H390-4.
17 Kawabata K, Suzuki M, Sugitani M, Imaki K, Toda M, Miyamoto T. ONO-5046, a novel inhibitor of human neutrophil elastase. Biochem Biophys Res Commun 1991; 177: 814-20.
18 NeSheim ME, Kettner C, Shaw E, Mann KG. Cofactor dependence of factor Xa incorporation into the prothrombinase complex. J Biol Chem 1981; 256: 6537-40.
19 Harada N, Okajima K, Kushimoto S, Isobe H, Tanaka K. Antithrombin reduces ischemia/reperfusion injury of rat liver by increasing the hepatic level of prostacyclin. Blood 1999; 93: 157-64.
20 Isobe H, Okajima K, Uchiba M, Mizutani A, Harada N, Nagasaki A, Okabe K. Activated protein C prevents endotoxin-induced hypotension in rats by inhibiting excessive production of nitric oxide. Circulation 2001; 104: 1171-5.
21 Enkhbaatar P, Okajima K, Murakami K, Uchiba M, Okabe H, Okabe K, Yamaguchi Y. Recombinant tissue factor pathway inhibitor reduces lipopolysaccharide-induced pulmonary vascular injury by inhibiting leukocyte activation. Am J Respir Crit Care Med 2000; 162: 1752-9.
22 Liu W, Okajima K, Murakami K, Harada N, Isobe H, Irie T. Role of neutrophil elastase in stress-induced gastric mucosal injury in rats. J Lab Clin Med 1998; 93: 157-64.
23 Shito M, Wakabayashi G, Ueda M, Shimazu M, Shirasugi N, Endo M, Mukai M, Kitajima M. Interleukin 1 receptor blockade reduces tumor necrosis factor production, tissue injury, and mortality after hepatic ischemia-reperfusion in the rat. Transplantation 1997; 63: 143-8.
24 Watanabe K, Konishi K, Fujioka M, Kinoshita S, Nakagawa H. The neutrophil chemoattractant produced by the rat kidney epitheloid cell line NRK-52E is a protein related to the KC/gro protein. J Biol Chem 1989; 264: 19559-63.
25 Harada N, Okajima K, Kushimoto S. Gabexate mesilate, a synthetic protease inhibitor, reduces ischemia/reperfusion injury of rat liver by inhibiting leukocyte activation. Crit Care Med 1999; 27: 1958-64.
26 Puchtler H, Waldrop FS, Meloan SN. On the mechanism of Mallory’s phosphotungstic acid-haematoxylin stain. J Microsc 1980; 119: 383-90.
27 Clauss A. Rapid physiological coagulation method for the determination of fibrinogen. Acta Haematol 1957; 17: 237-46.
28 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: 642-7.
29 Chmielewska J, Wiman B. Determination of tissue plasminogen activator and its “fast” inhibitor in plasma. Clin Chem 1986; 32: 482-5.
30 Bzeizi KI, Jalan R, MacGregor I, Drummund O, Lee A, Hayes PC. Neutrophil elastase: A determinant of endothelial damage and reperfusion injury after liver transplantation?. Transplantation 1996; 62: 916-20.
31 Okajima K. Regulation of inflammatory responses by natural anticoagulants. Immunol Rev 2001; 184: 258-74.
32 Isobe H, Okajima K, Uchiba M, Harada N, Okabe H. Antithrombin prevents endotoxin-induced hypotension by inhibiting the induction of nitric oxide synthase in rats. Blood 2002; 99: 1638-45.
33 Inthorn D, Hoffmann JN, Hartl WH, Muhlbayer D, Jochum M. Antithrombin III supplementation in severe sepsis: beneficial effects on organ dysfunction. Shock 1997; 05: 328-34.