臨床検査52巻13号

2008年12月発行

今月の主題 凝固制御 総論

炎症と凝固のクロストーク―その分子機序と臨床治療への応用

著者： 岡嶋研二¹

所属機関： ¹名古屋市立大学大学院医学研究科 展開医科学分野

ページ範囲：P.1533 - P.1542

　凝固系の活性化は，侵害刺激を受けた宿主の生体防御反応の一つである．しかし，血管内皮細胞による生体防御反応の制御系が破綻すると，過剰な生体防御反応，すなわち炎症が惹起される．このような状況では凝固の活性化は炎症の増悪因子となる．アンチトロンビンなどの凝固制御物質の中のいくつかのものは抗凝固作用に加え，抗炎症作用や細胞再生促進作用を有し，重症敗血症などの炎症と血栓形成を伴う病態の治療に用いられる．

参考文献

1) Okajima K, Yang WP, Inoue M, et al：Role of leukocytes in the activation of intravascular coagulation in patients with septicemia. Am J Hematol　36：265-271, 1991

2) Okajima K：The role of leukocytes in disseminated intravascular coagulation associated with sepsis. Sepsis　3：135-142, 2000

3) Echtenacher B, Weigl K, Lehn N, et al：Tumor necrosis factor-dependent adhesions as a major protective mechanism early in septic peritonitis in mice. Infect Immun　69：3550-3555, 2001

4) Kao J, Fan YG, Haehnel I, et al：A peptide derived from the amino terminus of endothelial-monocyte-activating polypeptide II modulates mononuclear and polymorphonuclear leukocyte functions, defines an apparently novel cellular interaction site, and induces an acute inflammatory response. J Biol Chem　269：9774-9782, 1994

5) Okajima K, Harada N：Regulation of inflammatory responses by sensory neurons：molecular mechanism(s) and possible therapeutic applications. Curr Med Chem　13：2241-2251, 2006

6) Harada N, Okajima K, Kurihara H, et al：Stimulation of sensory neurons by capsaicin increases tissue levels of IGF-I, thereby reducing reperfusion-induced apoptosis in mice. Neuropharmacology　52：1303-1311, 2007

7) Carroll PV：Treatment with growth hormone and insulin-like growth factor-I in critical illness. Best Pract Res Clin Endocrinol Metab　15：435-451, 2001

8) Levi M, van der Poll T, ten Cate H, et al：The cytokine-mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia. Eur J Clin Invest　27：3-9, 1997

9) Bombeli T, Karsan A, Tait JF, et al：Apoptotic vascular endothelial cells become procoagulant. Blood　89：2429-2442, 1997

10) Niessen RW, Lamping RJ, Jansen PM, et al：Antithrombin acts as a negative acute phase protein as established with studies on HepG2 cells and in baboons. Thromb Haemost　78：1088-1092, 1997

11) Jansen PM, Boermeester MA, Fischer E, et al：Contribution of interleukin-1 to activation of coagulation and fibrinolysis, neutrophil degranulation, and the release of secretory-type phospholipase A2 in sepsis：studies in nonhuman primates after interleukin-1 alpha administration and during lethal bacteremia. Blood　86：1027-1034, 1995

12) Salat C, Boekstegers P, Holler E, et al：Hemostatic parameters in sepsis patients treated with anti-TNF alpha-monoclonal antibodies. Shock　6：233-237, 1996

13) Boermeester MA, van Leeuwen PA, Coyle SM, et al：Interleukin-1 blockade attenuates mediator release and dysregulation of the hemostatic mechanism during human sepsis. Arch Surg　130：739-748, 1995　　Iacoviello L, De Curtis A, D'Adamo MC,

14) Iacoviello L, De Curtis A, D'Adamo MC, et al：Prostacyclin is required for t-PA release after venous occlusion. Am J Physiol　266：H429-H434, 1994

15) Okajima K, Harada N, Uchiba M, et al：Neutrophil elastase contributes to the development of ischemia-reperfusion-induced liver injury by decreasing endothelial production of prostacyclin in rats. Am J Physiol Gastrointest Liver Physiol　287：G1116-G1123, 2004

16) Furie B, Furie BC：Leukocyte crosstalk at the vascular wall. Thromb Haemostas　78：306-309, 1997

17) Okajima K, Harada N, Uchiba M：Microthrombus formation enhances tumor necrosis factor production in the development of ischemia/reperfusion induced liver injury in rats. J Thromb Haemostas　1：1316-1317, 2003

18) Riewald M, Ruf W：Orchestration of coagulation protease signaling by tissue factor. Trends Cardiovascular Med　12：149-154, 2002

19) Taylor FB Jr, Chang A, Ruf W, et al：Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ Shock　33：127-134, 1991

20) Enkhbaatar P, Okajima K, Murakami K, et al：Recombinant tissue factor pathway inhibitor reduces lipopolysaccharide-induced pulmonary vascular injury by inhibiting leukocyte activation. Am J Respir Crit Care Med　162：1752-1759, 2000

21) Isobe H, Okajima K, Uchiba M, et al：Activated protein C prevents endotoxin-induced hypotension in rats by inhibiting excessive production of nitric oxide. Circulation　104：1171-1175, 2001

22) Pawlinski R, Pedersen B, Schabbauer G, et al：Role of tissue factor and protease-activated receptors in a mouse model of endotoxemia. Blood　103：1342-1347, 2004

23) Kahn ML, Nakanishi-Matsui M, Shapiro MJ, et al：Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J Clin Invest　103：879-887, 1999

24) Uchiba M, Okajima K, Murakami K, et al：Attenuation of endotoxin-induced pulmonary vascular injury by antithrombin III. Am J Physiol　270：L921-L930, 1996

25) Harada N, Okajima K, Kushimoto S, et al：Antithrombin reduces ischemia/reperfusion injury of rat liver by increasing the hepatic level of prostacyclin. Blood　93：157-164, 1999

26) Isobe H, Okajima K, Uchiba M, et al：Antithrombin prevents endotoxin-induced hypotension by inhibiting the induction of nitric oxide synthase in rats. Blood　99：1638-1645, 2002

27) Mizutani A, Okajima K, Uchiba M, et al：Antithrombin reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation through promotion of prostacyclin production. Blood　101：3029-3036, 2003

28) Uchiba M, Okajima K, Murakami K, et al：Effects of plasma kallikrein specific inhibitor and active-site blocked factor VIIa on the pulmonary vascular injury induced by endotoxin in rats. Thromb Haemostas　78：1209-1214, 1997

29) Okajima K：Regulation of inflammatory responses by natural anticoagulants. Immunol Rev　184：258-274, 2001

30) Oelschlager C, Romisch J, Staubitz A, et al：Antithrombin III inhibits nuclear factor kB activation in human monocytes and vascular endothelial cells. Blood　99：4015-4020, 2002

31) Komura H, Uchiba M, Mizuochi Y, et al：Antithrombin inhibits LPS-induced TNF production by monocytes in vitro through inhibition of Egr-1 expression. J Thromb Haemost　6：499-507, 2008

32) Uchiba M, Okajima K, Kaun C, et al：Inhibition of the endothelial cell activation by antithrombin in vitro. Thromb Haemost　92：1420-1427, 2004

33) Uchiba M, Okajima K：Antithrombin does not directly promote the endothelial production of prostacyclin in cultured endothelial cells. Thromb Haemost　86：722-723, 2001

34) Harada N, Okajima K, Uchiba M, et al：Antithrombin reduces reperfusion-induced liver injury in mice by enhancing sensory neuron activation. Thromb Haemost　95：788-795, 2006

35) Harada N, Okajima K, Isobe H, et al：Antithrombin reduces endotoxin-induced hypotension by enhancing pulmonary sensory neuron activation in rats. Thromb Haemost　95：1011-1018, 2006

36) Harada N, Okajima K, Kurihara H, et al：Antithrombin prevents reperfusion-induced hepatic apoptosis by enhancing insulin-like growth factor-I production in mice. Crit Care Med　36：971-974, 2008

37) Warren BL, Eid A, Singer P, et al：High dose antithrombin III in severe sepsis：A randomized controlled trial. JAMA　286：1869-1878, 2001

38) Yuksel M, Okajima K, Uchiba M, et al：Activated protein C inhibits lipopolysaccharide-induced tumor necrosis factor-a production by inhibiting activation of both nuclear factor-k B and activator protein-1 in human monocytes. Thromb Haemost　88：267-273, 2002

39) Okajima K：Regulation of inflammatory responses by activated protein C：The molecular mechanism(s)and therapeutic implications. Clin Chem Lab Med　42：132-141, 2004

40) Joyce DE, Gelbert L, Ciaccia A, et al：Gene expression profile of antithrombotic protein C defines new mechanisms modulating inflammation and apoptosis. J Biol Chem　276：11199-11203, 2001

41) Isobe H, Okajima K, Harada N, et al：Activated protein C reduces stress-induced gastric mucosal injury in rats by inhibiting the endothelial cell injury. J Thromb Haemost　2：313-320, 2004

42) Riewald M, Petrovan R, Donner A, et al：Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science　296：1880-1882, 2002

43) Uchiba M, Okajima K, Oike Y, et al：Activated protein C induces endothelial cell proliferation by mitogen-activated protein kinase activation in vitro and angiogenesis in vivo. Circ Res　95：34-41, 2004

44) Bernard GR, Vincent JL, Laterre PF, et al：Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344：699-709, 2001

45) Conway EM, Van de Wouwer M, Pollefeyt S, et al：The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor κB and mitogen-activated protein kinase pathways. J Exp Med　196：565-577, 2002

46) Enkhbaatar P, Okajima K, Uchiba M, et al：Recombinant tissue factor pathway inhibitor prevents lipopolysaccharide-induced systemic hypotension in rats by inhibiting excessive production of nitric oxide. Thromb Haemost　86：1573-1577, 2001

47) Enkhbaatar P, Okajima K, Murakami K, et al：Recombinant tissue factor pathway inhibitor reduces lipopolysaccharide-induced pulmonary vascular injury by inhibiting leukocyte activation. Am J Respir Crit Care Med　162：1752-1759, 2000

48) Abraham E, Reinhart K, Opal S, et al：Efficacy and safety of tifacogin(recombinant tissue factor pathway inhibitor)in severe sepsis：a randomized controlled trial. JAMA　290：238-247, 2003

49) Taoka Y, Okajima K, Uchiba M：Antithrombin reduces the compression-induced spinal cord injury in rats. J Neurotrauma　21：1818-1830, 2004