Recombinant Tissue Factor Pathway Inhibitor Prevents Lipopolysaccharide-induced Systemic Hypotension in Rats by Inhibiting Excessive Production of Nitric Oxide

Perenlei Enkhbaatar; Kenji Okajima; Mitsuhiro Uchiba; Hirotaka Isobe; Hiroaki Okabe

doi:10.1055/s-0037-1616764

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2001; 86(06): 1573-1577
DOI: 10.1055/s-0037-1616764

Review Article

Schattauer GmbH

Recombinant Tissue Factor Pathway Inhibitor Prevents Lipopolysaccharide-induced Systemic Hypotension in Rats by Inhibiting Excessive Production of Nitric Oxide

Perenlei Enkhbaatar

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

,

Kenji Okajima

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

,

Mitsuhiro Uchiba

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

,

Hirotaka Isobe

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

,

Hiroaki Okabe

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

› Author Affiliations

Abstract

Summary

Excessive production of nitric oxide (NO) by the inducible form of NO synthase (iNOS) plays a key role in the development of endotoxin shock. Tumor necrosis factor-α (TNF-α) induces iNOS, thereby contributing to the development of shock. We recently reported that recombinant tissue factor pathway inhibitor (r-TFPI), an important inhibitor of the extrinsic pathway of the coagulation system, inhibits TNF-α production by monocytes. In this study, we investigated whether r-TFPI could ameliorate hypotension by inhibiting excessive production of NO in rats given lipopolysaccharide (LPS). Pretreatment of animals with r-TFPI prevented LPS-induced hypotension. Recombinant TFPI significantly inhibited the increases in both the plasma levels of NO₂ ^-/NO₃ ^- and lung iNOS activity 3 h after LPS administration. Expression of iNOS mRNA in the lung was also inhibited by intravenous administration of r-TFPI. However, neither DX-9065a, a selective inhibitor of factor Xa, nor an inactive derivative of factor VIIa (DEGR-F.VIIa) that selectively inhibits factor VIIa activity, had any effect on LPS-induced hypotension despite their potent anticoagulant effects. Moreover, neither the plasma levels of NO₂ ^-/NO₃ ^- nor lung iNOS activity were affected by administration of DX-9065a and DEGR-F.VIIa. These results suggested that r-TFPI ameliorates LPS-induced hypotension by reducing excessive production of NO in rats given LPS and this effect was not attributable to its anticoagulant effects, but to the inhibition of TNF-α production.

Keywords

Recombinant tissue factor pathway inhibitor - nitric oxide - tumor necrosis factor-α - hypotension - inducible nitric oxide synthase

Full Text

References

References
1 Bone RC. The pathogenesis of sepsis. Ann Int Med 1991; 115: 457-69.
2 Nathan C, Xie Q. Nitric oxide synthases: roles, tolls, and controls. Cell 1994; 78: 915-8.
3 Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol 1991; 43: 109-42.
4 Geller DA, Nussler AK, Di Silvio M, Lowenstein CJ, Shapiro RA, Wang SC, Simmons RL, Billiar TR. Cytokines, endotoxin, and glucocorticoids regulate the expression of inducible nitric oxide synthase in hepatocytes. Proc Natl Acad Sci USA 1993; 90: 522-6.
5 Thiemermann C. The role of the L-arginine: nitric oxide pathway in circulatory shock. Adv Pharmacol 1994; 28: 45-79.
6 Szabó C, Mitchell JA, Thiemermann C, Vane JR. Nitric oxide-mediated hyporeactivity to noradrenaline precedes the induction of nitric oxide synthase in endotoxin shock. Br J Pharmacol 1993; 108: 786-92.
7 Julou-Schaeffer G, Gray GA, Fleming I, Schott C, Parratt JR, Stoclet JC. Loss of vascular responsiveness induced by endotoxin involves L-arginine pathway. Am J Physiol 1990; 259: H1038-43.
8 Girard TJ, Warren LA, Novotny WF, Likert KM, Brown SG, Miletich JP, Broze Jr GJ. Functional significance of the Kunitz-type inhibitory domains of lipoprotein-associated coagulation inhibitor. Nature 1989; 338: 518-20.
9 Sandset PM, Warn-Cramer BJ, Rao LV, Maki SL, Rapaport SI. Depletion of extrinsic pathway inhibitor (EPI) sensitizes rabbits to disseminated intravascular coagulation induced with tissue factor: evidence supporting a physiologic role for EPI as a natural anticoagulant. Proc Natl Acad Sci USA 1991; 88: 708-12.
10 Sandset PM, Warn-Cramer BJ, Maki SL, Rappaport SI. Immunodepletion of extrinsic pathway inhibitor sensitizes rabbits to endotoxin-induced intravascular coagulation and the generalized Shwartzman reaction. Blood 1991; 78: 1496-502.
11 Carr C, Bild GS, Chang ACK, Peer GT, Palmier MO, Frazier RB, Gustafson ME, Wun T-C, Creasey AA, Hinshaw LB, Taylor Jr FB, Galluppi GR. Recombinant E. coli-derived tissue factor pathway inhibitor reduces coagulopathic and lethal effects in the baboon gram-negative model of septic shock. Circ Shock 1994; 44: 126-37.
12 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 Res Crit Care Med 2000; 162: 1752-9.
13 Wizemann TM, Gardner CR, Laskin JD, Quinones S, Durham SK, Goller NL, Ohnishi ST, Laskin DL. Production of nitric oxide and peroxynitrite in the lung during acute endotoxemia. J Leuk Biol 1994; 56: 759-68.
14 Enjyoji K, Meaty T, Kamikubo Y, Kato H. Effect of heparin on the inhibition of factor Xa by tissue factor pathway inhibitor: a segment, Gly212-Phe243, of the third Kunitz domain is a heparin-binding site. Biochemistry 1995; 34: 5725-35.
15 Kamei S, Kamikubo Y, Hamuro T, Fujimoto H, Ishihara M, Yonemura H, Miyamoto S, Funatsu A, Enjyoji K, Abumiya T, Miyata T, Kato H. Amino acid sequence and inhibitory activity of rhesus monkey tissue factor pathway inhibitor (TFPI): comparison with human TFPI. J Biochem 1994; 115: 708-14.
16 Hara T, Yokoyama A, Ishihara H, Yokoyama Y, Nagahara T, Iwamoto M. DX-9065a, a new synthetic, potent anticoagulant and selective inhibitor for factor Xa. Thromb Haemost 1994; 71: 314-31.
17 Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem 1982; 126: 131-8.
18 Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987; 162: 156-9.
19 Nunokawa Y, Ishida N, Tanaka S. Cloning of inducible nitric oxide synthase in rat vascular smooth muscle cells. Biochem Biophys Res Commun 1993; 191: 89-94.
20 Wang D, Wei J, Hsu K, Jau J, Lieu MW, Chao TJ, Chen HI. Effects of nitric oxide synthase inhibitors on systemic hypotension, cytokines and inducible nitric oxide synthase expression and lung injury following endotoxin administration in rats. J Biomed Sci 1999; 6: 28-35.
21 Beutler B, Cerami A. Cachectin and tumor necrosis factor as two sides of the same biological coin. Nature 1986; 320: 584-8.
22 Tiemermann C, Wu CC, Szabo C, Perretti M, Vane JR. Role of tumor necrosis factor in the induction of nitric oxide synthase in rat model of endotoxin shock. Br J Pharmacol 1993; 110: 177-82.
23 Taylor Jr FB, Chang ACK, Peer G, Li A, Ezban M, Hedner U. Active site inhibited factor VIIa (DEGR VIIa) attenuates the coagulant and interleukin-6 and -8, but not tumor necrosis factor, responses of the baboon to LD100 Escherichia coli . Blood 1998; 91: 1609-15.
24 Park CT, Creasey A, Wright SD. Tissue factor pathway inhibitor blocks cellular effects of endotoxin by binding to endotoxin and interfering with transfer of CD14. Blood 1997; 89: 4268-74.
25 Taylor Jr FB, 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: 127-34.
26 Taylor Jr FB, Chang AC, 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: 364-8.
27 Nemerson Y. Tissue factor and hemostasis. Blood 1984; 71: 1-8.
28 Papapetropoulos A, Piccardoni P, Cirino G, Bucci M, Sorrentino R, Cicala C, Johnson K, Zachariou V, Sessa WC, Altieri DC. Hypotension and inflammatory cytokine gene expression triggered by factor Xa-nitric oxide signaling. Proc Natl Acad Sci USA 1998; 96: 4738-42.
29 Opal SM, Palardy JE, Pajero NA, Creasey AA. The activity of tissue factor pathway inhibitor in experimental models of superantigen-induced shock and polymicrobial intra-abdominal sepsis. Crit Care Med 2001; 29: 13-7.
30 de Jonge E, Dekkers PE, Creasey AA, Hack CE, Paulson SK, Karim A, Kesecioglu J, Levi M, van Deventer SJ, van der Poll T. Tissue factor pathway inhibitor dose-dependently inhibits coagulation activation without influencing the fibrinolytic and cytokine response during human endotoxemia. Blood 2000; 95: 1124-9.