|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
Blood, Vol. 95 No. 12 (June 15), 2000:
pp. 3781-3787
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
From the Department of Anesthesiology, Oita Medical University, and
the Department of Laboratory Medicine, Kumamoto University School of
Medicine, Kumamoto, Japan.
We examined whether activated protein C (APC) reduces
ischemia/reperfusion (I/R)-induced renal injury by inhibiting
leukocyte activation. In a rat model, intravenous administration of APC markedly reduced I/R-induced renal dysfunction and histological changes, whereas intravenous administration of dansyl
glutamylglycylarginyl chloromethyl ketone-treated factor Xa (DEGR-FXa;
active-site-blocked factor Xa), heparin or diisopropyl
fluorophosphate-treated APC (DIP-APC; inactive derivative of ARC) had
no effect. Furthermore, APC significantly inhibited the I/R-induced
decrease in renal tissue blood flow and the increase in the vascular
permeability, whereas neither DEGR-FXa, heparin, nor DIP-APC produced
such effects. Renal I/R-induced increases in plasma levels of fibrin
degradation products were significantly inhibited by APC, DEGR-FXa, and
heparin. These observations suggest that APC reduces I/R-induced renal injury independently of its anticoagulant effects but in a manner dependent on its serine protease activity. Renal levels of tumor necrosis factor-
Activated protein C (APC) is an important
physiologic anticoagulant that is generated from protein C by
the action of the thrombin-thrombomodulin complex on endothelial
cells.1 APC regulates the coagulation system by
inactivating factors Va and VIIIa.1,2 Although its precise
mechanisms of action have not been elucidated, APC was shown to reduce
the mortality rate of baboons challenged with lethal doses of
Escherichia coli not by inhibiting the coagulation abnormality
but by reducing organ damage.3,4 Because leukocytes have
been implicated in the organ damage induced by endotoxin,5
it is possible that APC reduces the organ damage by inhibiting
leukocyte activation. In vitro studies indicated that APC inhibits the
production of tumor necrosis factor Ischemia/reperfusion (I/R) is an important pathologic
mechanism leading to organ failure in shock.10 TNF- These findings suggest that APC may reduce I/R-induced renal
injury by inhibiting leukocyte activation as well as by attenuating the
coagulation abnormality. In this study, we examined whether APC reduces
I/R-induced renal injury in rats. To investigate the mechanism by which
APC diminishes renal injury, we analyzed the effects of APC, as well as
the effects of an inactive derivative of factor Xa that inhibits
thrombin generation selectively, heparin, and inactivated APC, on
I/R-induced renal injury in our rat model.
Protein C was purified from human plasma and activated by
thrombin as described previously.16 Nitrogen mustard (NM),
diisopropyl fluorophosphate (DIP), Evans blue dye, and myeloperoxidase
(MPO) were purchased from Sigma (St Louis, MO); dansyl
glutamylglycylarginyl chloromethyl ketone (DEGR) was from Calbiochem
(San Diego, CA); and heparin was from Novo Nordisk (Gentofte, Denmark).
All other reagents were of analytical grade.
Preparation of DEGR-treated factor Xa
Preparation of DIP-treated APC (DIP-APC)
Reduction in the number of circulating leukocytes by NM NM was used to produce leukocytopenia in rats. NM (1 mg/kg of body weight) or saline was administered intravenously to the animals 2 days before the experiment.21 On the day of the experiment, the number of circulating leukocytes was 10 722 ± 1041 in controls (n = 6) and 3100 ± 371 in NM-treated rats (n = 6; P < .01 compared with control value).Animal model of I/R-induced renal injury Specific pathogen-free male Wistar rats (Nihon SLC, Hamamatsu, Japan) weighing 180 to 220 g were used throughout the experiments. Animal care and handling were performed in accordance with the guidelines of the National Institutes of Health. The rats were given water but not food for 16 hours before the experiments. The renal I/R protocol was as follows.22 The rats were anesthetized by intraperitoneal injection of pentobarbital sodium (50 mg/kg; Abbott Laboratories, North Chicago, IL). In all rats, a midline incision was made, the left kidney was mobilized, the left renal vessels were ligated, and a left nephrectomy was performed. In the I/R groups, the right pedicle was clamped with a noncrushing microvascular clamp for 60 minutes. The presence of ischemia was visually confirmed by observing blanching of the kidney. During the period of renal ischemia, the rats were covered with plastic wrap to prevent evaporation. APC (100 µg/kg), DEGR-FXa (1 mg/kg), heparin (300 U/kg), DIP-APC (100 µg/kg), or saline was administered intravenously 30 minutes before reperfusion. After 60 minutes of ischemia, the clamps were removed, the wounds were closed with 3-0 silk, and the animals were returned to their cages. The rats in the sham-operation group underwent the same procedure except that clamping was not done. At specified times after reperfusion, animals were anesthetized by intraperitoneal administration of pentobarbital (50 mg/kg) and killed by exsanguination from the abdominal aorta. Blood was collected in tubes and centrifuged at 2000g for 10 minutes. Serum levels of blood urea nitrogen (BUN) and creatinine were measured with standard urease assays and picric acid reactions.11 Serum levels of fibrin degradation products [FDP(E)] were measured with a latex agglutination assay, as described previously.23Determination of renal microvascular permeability Renal vascular permeability was assessed by a dye method in which extravasated dye was measured as described previously.24 Briefly, Evans blue dye (25 µg/kg) was injected intravenously 10 minutes before the rats were killed by exsanguination from the abdominal aorta. The kidneys were removed, weighed, and put into tubes containing 5 mL of dimethylformamide (Wako, Osaka, Japan). After centrifugation (2000g for 10 minutes), the concentration of Evans blue dye extracted in the dimethylformamide was measured with a spectrophotometer (DU-54; Beckman, Irvine, CA) at a wavelength of 610 nm by comparison with results obtained with standards of known concentration. The Evans blue dye concentration for each sample was expressed in micrograms per gram of tissue.Measurement of blood flow in renal tissue The rats were anesthetized with pentobarbital sodium (50 mg/kg given intraperitoneally), laparotomy was performed, and the blood flow in renal tissue was measured by using a laser Doppler flowmeter (ALF21N; Advance, Tokyo, Japan), as described previously.25 The Doppler probe was directed toward the cortex. Renal tissue blood flow was measured from 30 minutes before ischemia until 3 hours after reperfusion. Electrical signals from the probe were digitized and recorded in real time by using a Macintosh Performa 6310 and MacLab software.26 Results were expressed as percentages of the preischemia levels.Histopathological studies of the kidneys The rats' kidneys were removed 24 hours after reperfusion, fixed in 10% formalin, embedded in paraffin, sectioned (5-µm thicknesses), and stained with hematoxylin and eosin. Histological changes were evaluated by assessments of neutrophil accumulation, tubular necrosis, and vascular congestion in the outer medulla, according to the methods described by Kelly et al11 and Chiao et al,13 with some modifications. Neutrophil accumulation was evaluated by counting the neutrophils in the outer medulla, whereas vascular congestion was assessed by counting the erythrocytes in the outer medulla. The cells were counted by using an eyepiece graticule (magnification ×400). Tubular necrosis was evaluated by determining the percentage of tubules in the outer medulla in which epithelial necrosis or necrotic debris was observed. Each variable was evaluated in 20 high-power fields. Samples were analyzed by a pathologist with no knowledge of the experiment group to which the rat belonged.Measurement of renal MPO activity Renal MPO activity was measured as described previously.21 The rats were killed at specified times after reperfusion. The kidneys were removed, weighed, and homogenized with a homogenizer (Physcotron; Nition, Tokyo, Japan) in 10% (wt/vol) homogenization buffer (50 mmol/L phosphate buffer [pH 6.0] containing 0.5% hexadecyltrimethylammonium bromide) and sonicated for 20 seconds. After centrifugation (4500g for 20 minutes at 4°C), 0.1 mL of supernatant was added to 0.55 mL of 0.1 mol/L phosphate buffer (pH 6.0) containing 1.25 mg/mL o-dianisidine and 0.05% hydrogen peroxide. After 5 minutes, the change in absorbance at 460 nm was measured with a spectrophotometer. Purified MPO was used as a standard. Results were expressed as units of MPO activity per gram of tissue.Measurement of renal levels of cytokines At specified times after reperfusion, the kidneys were removed, weighed, and homogenized with a homogenizer using 0.1 mol/L phosphate buffer (pH 7.4) containing 0.05% (wt/vol) of sodium azide at 4°C. Homogenates were then sonicated for 20 seconds and centrifuged (2000g for 10 minutes at 4°C). The supernatants were stored at 80°C until measurement of cytokines. Renal levels of TNF- and rat interleukin 8 (IL-8) were measured with use of a rat
TNF- enzyme-linked immunosorbent assay (ELISA) kit (Genzyme, Cambridge, MA) and a rat IL-8 ELISA kit (Amersham, Little Chalfont, UK), respectively. Results were expressed as picograms of the measured
cytokine per gram of tissue.
Statistical analysis Data are presented as mean ± SD values. Results were compared with an unpaired t test (single comparison) or analysis of variance followed by the Scheffe post hoc test (multiple comparisons). A level of P < .05 was considered significant.
Effects of APC, DEGR-FXa, heparin, DIP-APC, and leukocytopenia on I/R-induced renal dysfunction Serum levels of BUN and creatinine were significantly higher after reperfusion in rats that had I/R than in rats that had a sham operation and peaked at 24 hours after reperfusion (Figure 1). Intravenous administration of APC significantly inhibited the increases in serum levels of BUN and creatinine 24 hours after reperfusion, but neither DEGR-FXa, heparin, nor DIP-APC had any effect (Figure 2). The levels of BUN and creatinine 24 hours after reperfusion were significantly decreased in rats with leukocytopenia (Figure 2).
Histological changes Histological examinations of kidneys were performed 24 hours after reperfusion (Figure 3). Microscopical assessment of renal tissue revealed severe tubular necrosis, loss of brush border, necrosis and sloughing of tubular cells, and obstructing cast in the outer medulla (Figures 3B and 3I); such changes were not observed in rats in the sham-operation group (Figures 3A and 3H). Intravenous administration of APC markedly reduced these histological changes (Figures 3C and 3J), whereas neither DEGR-FXa (Figures 3D and 3K), heparin (Figures 3E and 3L), nor DIP-APC (Figures 3F and 3M) produced such an effect. The I/R-induced histological changes were also reduced by leukocytopenia (Figures 3G and 3N). Tubular necrosis was significantly diminished by APC administration and leukocytopenia but was not reduced in rats given either DEGR-FXa or heparin (Table 1). Administration of DIP-APC also did not attenuate this change (Table 1). Neutrophil accumulation in the vasa recta of the outer medulla and vascular congestion were also found after I/R of the kidney (Figures 3B and 3I). When analyzed quantitatively, renal neutrophil accumulation and the vascular congestion induced by renal I/R were significantly reduced in rats given APC and in those with leukocytopenia (Table 1). However, neither DEGR-FXa, heparin, nor DIP-APC affected the renal changes (Table 1). Fibrin deposition was not observed in kidneys from any group.
Effects of APC, DEGR-FXa, heparin, DIP-APC, and leukocytopenia on I/R-induced increases in serum FDP(E) levels Serum concentrations of FDP(E) were significantly higher after reperfusion in rats that had I/R than in rats that had a sham operation and peaked at 24 hours after reperfusion (Figure 4A). The increases in serum FDP(E) levels 24 hours after reperfusion were significantly inhibited by administration of APC, DEGR-FXa, or heparin but not by DIP-APC (Figure 4B). Leukocytopenia significantly inhibited the increase in serum FDP(E) levels in rats subjected to renal I/R (Figure 4B).
Effects of APC, DEGR-FXa, heparin, DIP-APC, and leukocytopenia on the changes in renal tissue blood flow in rats that had renal I/R Renal tissue blood flow decreased to approximately 40% of the preischemia level 3 hours after reperfusion (Figure 5). Intravenous administration of APC significantly inhibited the I/R-induced reduction in blood flow. No significant effect was observed in rats given DEGR-FXa, heparin, or DIP-APC (Figure 5). The reduction in blood flow was significantly decreased by leukocytopenia (Figure 5).
Effects of APC, DEGR-FXa, heparin, DIP-APC, and leukocytopenia on the increase in renal vascular permeability after renal I/R Renal vascular permeability as assessed by an increase in leakage of Evans blue dye was significantly higher after reperfusion in rats that had I/R than in rats that had a sham operation and peaked at 6 hours after reperfusion (Figure 6A). Both administration of APC and leukocytopenia significantly inhibited the increases in renal vascular permeability 6 hours after reperfusion, whereas neither DEGR-FXa, heparin, nor DIP-APC had any effect (Figure 6B).
Effects of APC, DEGR-FXa, heparin, DIP-APC, and leukocytopenia on
renal levels of TNF- and rat IL-8 in rats subjected to renal I/R
increased, reached their peaks at 3 hours after reperfusion, and
decreased gradually thereafter (Figures 7A
and 7B). Renal levels of MPO also increased after reperfusion
and peaked at 6 hours after reperfusion (Figure 7C). Administration of
APC significantly inhibited the I/R-induced increases in renal levels
of TNF- and rat IL-8 3 hours after reperfusion, whereas neither
DEGR-FXa, heparin, nor DIP-APC produced such effects (Figures 7D and
7E). Although APC inhibited the I/R-induced increases in renal levels of MPO 6 hours after reperfusion, neither DEGR-FXa, heparin, nor DIP-APC had any effect (Figure 7F). Renal tissue levels of TNF- and
rat IL-8 3 hours after reperfusion were significantly lower in rats
with leukocytopenia than in those given saline (Figures 7D and 7E). The
I/R-induced increases in renal levels of MPO 6 hours after reperfusion
were significantly inhibited in rats with leukocytopenia (Figure
7F).
In this study, we demonstrated that APC, a physiologic anticoagulant, reduced I/R-induced renal dysfunction and histological changes in rats. Although APC, DEGR-FXa (a selective inhibitor of thrombin generation), and heparin significantly inhibited the I/R-induced increases in serum levels of FDP(E), neither DEGR-FXa nor heparin diminished the I/R-induced renal dysfunction. These observations strongly suggest that the anticoagulant effect of APC may not have contributed to the reduction in I/R-induced renal injury. Because DIP-APC, an inactive derivative of APC, did not diminish the I/R renal injury, the serine protease activity of APC may be critical for its protective role.
Submitted September 13, 1999; accepted February 3, 2000.
Reprints: Kenji Okajima, Department of Laboratory Medicine, Kumamoto University School of Medicine, Honjo 1-1-1, Kumamoto 860-0811, Japan; e-mail: whynot{at}kaiju.medic.kumamoto-u.ac.jp.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
1. Walker FJ, Sexton PW, Esmon CT. The inhibition of blood coagulation by activated protein C through the selective inactivation of activated factor V. Biochim Biophys Acta. 1979;571:333[Medline] [Order article via Infotrieve].
2.
Esmon CT.
The protein C anticoagulant pathway.
Arterioscler Thromb.
1992;12:135 3. Taylor FB Jr, Chang A, Esmon CT, et al. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest. 1987;79:918.
4.
Taylor FB Jr, Chang AC, Peer GT, et al.
DEGR-factor Xa blocks disseminated intravascular coagulation initiated by Escherichia coli without preventing shock or organ damage.
Blood.
1991;78:364
5.
St John RC, Dorinsky PM.
Immunologic therapy for ARDS, septic shock and multiple organ failure.
Chest.
1993;103:932
6.
Grey S, Hau H, Salem HH, Hancock WW.
Selective effects of protein C on activation of human monocytes by lipopolysaccharide, interferon-
7.
Grey ST, Tsuchida A, Hau H, Orthner CL, Salem HH, Hancock WW.
Selective inhibitory effects of the anticoagulant activated protein C on the responses of human mononuclear phagocytes to LPS, IFN-
8.
Murakami K, Okajima K, Uchiba M, et al.
Activated protein C attenuates endotoxin-induced pulmonary vascular injury by inhibiting activated leukocytes in rats.
Blood.
1996;87:642
9.
Murakami K, Okajima K, Uchiba M, et al.
Activated protein C prevents LPS-induced pulmonary vascular injury by inhibiting cytokine production.
Am J Physiol.
1997;272:L197
10.
Thadhani R, Pascual M, Bonventre JV.
Acute renal failure.
N Engl J Med.
1996;334:1448 11. Kelly KJ, Williams WW Jr, Colvin RB, et al. Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury. J Clin Invest. 1996;97:1056[Medline] [Order article via Infotrieve]. 12. Bonventre JV. Mechanisms of acute renal failure. Kidney Int. 1993;43:1160[Medline] [Order article via Infotrieve].
13.
Chiao H, Kohda Y, McLeroy P, Craig L, Housini I, Star RA.
14. Losonczy G Jr. Early postischaemic renal fibrin deposition and reduction of glomerular filtration rate in the rat: effect of the defibrinating agent Arwin. Acta Physiol Hung. 1985;66:183[Medline] [Order article via Infotrieve]. 15. Druid H, Eneström S, Rammer L. Effect of anticoagulation upon nephron obstruction in experimental acute ischaemic renal failure: a morphological study. Int J Exp Pathol. 1998;79:55[Medline] [Order article via Infotrieve]. 16. Okajima K, Koga S, Kaji M, et al. Effect of protein C and activated protein C on coagulation and fibrinolysis in normal human subjects. Thromb Haemost. 1990;63:48[Medline] [Order article via Infotrieve].
17.
Nesheim ME, Kettner C, Shaw E, Mann KG.
Cofactor dependence of factor Xa incorporation into the prothrombinase complex.
J Biol Chem.
1981;256:6537 18. Bajaj SP, Rapaport SI, Prodanos CA. A simplified procedure for purification of human prothrombin, factor IX and factor X. Prep Biochem. 1981;11:397[Medline] [Order article via Infotrieve].
19.
Morita T, Jackson CM.
Localization of the structural difference between bovine blood coagulation factors X1 and X2 to tyrosine 18 in the activation peptide.
J Biol Chem.
1986;261:4008 20. Mann KG. Membrane-bound enzyme complexes in blood coagulation. In Spaet TH, ed. Progress in Hemostasis and Thrombosis. Vol 7. New York, NY: Grune & Stratton; 1984:1-24.
21.
Taoka Y, Okajima K, Uchiba M, et al.
Activated protein C reduces the severity of compression-induced spinal cord injury in rats by inhibiting activation of leukocytes.
J Neurosci.
1998;18:1393 22. Rabb H, Mendiola CC, Saba SR, et al. Antibodies to ICAM-1 protect kidneys in severe ischemic reperfusion injury. Biochem Biophys Res Commun. 1995;211:67[Medline] [Order article via Infotrieve]. 23. Okajima K, Ueyama H, Hashimoto Y, et al. Homozygous variant of antithrombin III that lacks affinity for heparin, AT III Kumamoto. Thromb Haemost. 1989;61:20[Medline] [Order article via Infotrieve]. 24. Plante GE, Bissonnette M, Sirois MG, Regoli D, Sirois P. Renal permeability alteration precedes hypertension and involves bradykinin in the spontaneously hypertensive rat. J Clin Invest. 1992;89:2030. 25. Hansell P, Nygren A, Ueda J. Influence of verapamil on regional blood flow: a study using multichannel laser-Doppler flowmetry. Acta Physiol Scand. 1990;139:15[Medline] [Order article via Infotrieve].
26.
Gurbanov K, Rubinstein I, Hoffman A, Abassi Z, Better OS, Winaver J.
Differential regulation of renal regional blood flow by endothelin-1.
Am J Physiol.
1996;271:F1166
27.
Kelly KJ, Williams WW Jr, Colvin RB, Bonventre JV.
Antibody to intercellular adhesion molecule 1 protects the kidney against ischemic injury.
Proc Natl Acad Sci U S A.
1994;91:812
28.
Inauen W, Granger DN, Meininger CJ, Schelling ME, Granger HJ, Kvietys PR.
An in vitro model of ischemia/reperfusion-induced microvascular injury.
Am J Physiol.
1990;259:G134 29. Bonventre JV, Colvin RB. Adhesion molecules in renal disease. Curr Opin Nephrol Hypertens. 1996;5:254[Medline] [Order article via Infotrieve]. 30. 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;132:432[Medline] [Order article via Infotrieve]. 31. Kawabata M, 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[Medline] [Order article via Infotrieve].
32.
Pober JS, Cotran RS.
Cytokines and endothelial cell biology.
Physiol Rev.
1990;70:427 33. Daemen MA, van de Ven MW, Heineman E, Buurman WA. Involvement of endogenous interleukin-10 and tumor necrosis factor-alpha in renal ischemia-reperfusion injury. Transplantation. 1999;27:792. 34. Remick DG, Villarete L. Regulation of cytokine gene expression by reactive oxygen and reactive nitrogen intermediates. J Leukoc Biol. 1996;59:471[Abstract]. 35. Okajima K, Imamura H, Koga S, Inoue M, Takatsuki K, Aoki N. Treatment of patients with disseminated intravascular coagulation by protein C. Am J Hematol 1990;33:277[Medline] [Order article via Infotrieve].
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  P. Raivio, R. Lassila, and J. Petaja Thrombin in myocardial ischemia-reperfusion during cardiac surgery. Ann. Thorac. Surg., July 1, 2009; 88(1): 318 - 325. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. T.B.G. Loubele, C. A. Spek, P. Leenders, R. van Oerle, H. L. Aberson, K. Hamulyak, G. Ferrell, C. T. Esmon, H. M.H. Spronk, and H. ten Cate Activated Protein C Protects Against Myocardial Ischemia/ Reperfusion Injury via Inhibition of Apoptosis and Inflammation Arterioscler Thromb Vasc Biol, July 1, 2009; 29(7): 1087 - 1092. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Sharfuddin, R. M. Sandoval, D. T. Berg, G. E. McDougal, S. B. Campos, C. L. Phillips, B. E. Jones, A. Gupta, B. W. Grinnell, and B. A. Molitoris Soluble Thrombomodulin Protects Ischemic Kidneys J. Am. Soc. Nephrol., March 1, 2009; 20(3): 524 - 534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Gupta, B. Gerlitz, M. A. Richardson, C. Bull, D. T. Berg, S. Syed, E. J. Galbreath, B. A. Swanson, B. E. Jones, and B. W. Grinnell Distinct Functions of Activated Protein C Differentially Attenuate Acute Kidney Injury J. Am. Soc. Nephrol., February 1, 2009; 20(2): 267 - 277. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. He, L. Lu, C. Altmann, T. S. Hoke, D. Ljubanovic, A. Jani, C. A. Dinarello, S. Faubel, and C. L. Edelstein Interleukin-18 binding protein transgenic mice are protected against ischemic acute kidney injury Am J Physiol Renal Physiol, November 1, 2008; 295(5): F1414 - F1421. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Mizutani, P. Enkhbaatar, A. Esechie, L. D. Traber, R. A. Cox, H. K. Hawkins, D. J. Deyo, K. Murakami, T. Noguchi, and D. L. Traber Pulmonary changes in a mouse model of combined burn and smoke inhalation-induced injury J Appl Physiol, August 1, 2008; 105(2): 678 - 684. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Yakut, H. Yasa, B. Bahriye Lafci, R. Ortac, E. Tulukoglu, M. Aksun, C. Ozbek, and A. Gurbuz The influence of levosimendan and iloprost on renal ischemia-reperfusion: an experimental study Interactive CardioVascular and Thoracic Surgery, April 1, 2008; 7(2): 235 - 239. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ozaki, C. Anas, S. Maruyama, T. Yamamoto, K. Yasuda, Y. Morita, Y. Ito, M. Gotoh, Y. Yuzawa, and S. Matsuo Intrarenal administration of recombinant human soluble thrombomodulin ameliorates ischaemic acute renal failure Nephrol. Dial. Transplant., January 1, 2008; 23(1): 110 - 119. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. T. Berg, A. Gupta, M. A. Richardson, L. A. O'Brien, D. Calnek, and B. W. Grinnell Negative Regulation of Inducible Nitric-oxide Synthase Expression Mediated through Transforming Growth Factor- -dependent Modulation of Transcription Factor TCF11 J. Biol. Chem., December 21, 2007; 282(51): 36837 - 36844. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Yang, J.-S. Bae, C. Manithody, and A. R. Rezaie Identification of a Specific Exosite on Activated Protein C for Interaction with Protease-activated Receptor 1 J. Biol. Chem., August 31, 2007; 282(35): 25493 - 25500. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Nitescu, E. Grimberg, S.-E. Ricksten, N. Marcussen, and G. Guron Thrombin inhibition with melagatran does not attenuate renal ischaemia-reperfusion injury in rats Nephrol. Dial. Transplant., August 1, 2007; 22(8): 2149 - 2155. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Gupta, G. J. Rhodes, D. T. Berg, B. Gerlitz, B. A. Molitoris, and B. W. Grinnell Activated protein C ameliorates LPS-induced acute kidney injury and downregulates renal INOS and angiotensin 2 Am J Physiol Renal Physiol, July 1, 2007; 293(1): F245 - F254. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. Jo, M. H. Rosner, and M. D. Okusa Pharmacologic Treatment of Acute Kidney Injury: Why Drugs Haven't Worked and What Is on the Horizon Clin. J. Am. Soc. Nephrol., March 1, 2007; 2(2): 356 - 365. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Raivio, J. A. Fernandez, A. Kuitunen, J. H. Griffin, R. Lassila, and J. Petaja Activation of protein C and hemodynamic recovery after coronary artery bypass surgery J. Thorac. Cardiovasc. Surg., January 1, 2007; 133(1): 44 - 51. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Alsfasser, A. L. Warshaw, S. P. Thayer, B. Antoniu, M. Laposata, K. B. Lewandrowski, and C. Fernandez-del Castillo Decreased Inflammation and Improved Survival With Recombinant Human Activated Protein C Treatment in Experimental Acute Pancreatitis Arch Surg, July 1, 2006; 141(7): 670 - 676. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Weijer, C. W. Wieland, S. Florquin, and T. van der Poll A thrombomodulin mutation that impairs activated protein C generation results in uncontrolled lung inflammation during murine tuberculosis Blood, October 15, 2005; 106(8): 2761 - 2768. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Uchiba, K. Okajima, Y. Oike, Y. Ito, K. Fukudome, H. Isobe, and T. Suda Activated Protein C Induces Endothelial Cell Proliferation by Mitogen-Activated Protein Kinase Activation In Vitro and Angiogenesis In Vivo Circ. Res., July 9, 2004; 95(1): 34 - 41. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Okajima, N. Harada, M. Uchiba, and H. Isobe Activation of Capsaicin-Sensitive Sensory Neurons by Carvedilol, a Nonselective {beta}-Blocker, in Spontaneous Hypertensive Rats J. Pharmacol. Exp. Ther., May 1, 2004; 309(2): 684 - 691. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. W. Rijneveld, S. Weijer, S. Florquin, C. T. Esmon, J. C. M. Meijers, P. Speelman, P. H. Reitsma, H. Ten Cate, and T. van der Poll Thrombomodulin mutant mice with a strongly reduced capacity to generate activated protein C have an unaltered pulmonary immune response to respiratory pathogens and lipopolysaccharide Blood, March 1, 2004; 103(5): 1702 - 1709. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Domotor, O. Benzakour, J. H. Griffin, D. Yule, K. Fukudome, and B. V. Zlokovic Activated protein C alters cytosolic calcium flux in human brain endothelium via binding to endothelial protein C receptor and activation of protease activated receptor-1 Blood, June 15, 2003; 101(12): 4797 - 4801. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Perkowski, J. Sun, S. Singhal, J. Santiago, G. D. Leikauf, and S. M. Albelda Gene Expression Profiling of the Early Pulmonary Response to Hyperoxia in Mice Am. J. Respir. Cell Mol. Biol., June 1, 2003; 28(6): 682 - 696. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Mizutani, K. Okajima, M. Uchiba, H. Isobe, N. Harada, S. Mizutani, and T. Noguchi Antithrombin reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation through promotion of prostacyclin production Blood, April 15, 2003; 101(8): 3029 - 3036. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Okajima, N. Harada, and M. Uchiba Ranitidine Reduces Ischemia/Reperfusion-Induced Liver Injury in Rats by Inhibiting Neutrophil Activation J. Pharmacol. Exp. Ther., June 1, 2002; 301(3): 1157 - 1165. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Furuichi, T. Wada, Y. Iwata, N. Sakai, K. Yoshimoto, K.-i. Kobayashi, N. Mukaida, K. Matsushima, and H. Yokoyama Administration of FR167653, a new anti-inflammatory compound, prevents renal ischaemia/reperfusion injury in mice Nephrol. Dial. Transplant., March 1, 2002; 17(3): 399 - 407. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Isobe, K. Okajima, M. Uchiba, A. Mizutani, N. Harada, A. Nagasaki, and K. Okabe Activated Protein C Prevents Endotoxin-Induced Hypotension in Rats by Inhibiting Excessive Production of Nitric Oxide Circulation, September 4, 2001; 104(10): 1171 - 1175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Weiler, V. Lindner, B. Kerlin, B. H. Isermann, S. B. Hendrickson, B. C. Cooley, D. A. Meh, M. W. Mosesson, N. W. Shworak, M. J. Post, et al. Characterization of a Mouse Model for Thrombomodulin Deficiency Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1531 - 1537. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Shibata, S. R. Kumar, A. Amar, J. A. Fernandez, F. Hofman, J. H. Griffin, and B. V. Zlokovic Anti-Inflammatory, Antithrombotic, and Neuroprotective Effects of Activated Protein C in a Murine Model of Focal Ischemic Stroke Circulation, April 3, 2001; 103(13): 1799 - 1805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. E. Joyce, L. Gelbert, A. Ciaccia, B. DeHoff, and B. W. Grinnell Gene Expression Profile of Antithrombotic Protein C Defines New Mechanisms Modulating Inflammation and Apoptosis J. Biol. Chem., March 30, 2001; 276(14): 11199 - 11203. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2000 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
(TNF-
P < .01 compared with the I/R
plus saline group.
, or PMA: modulation of effects on CD11b and CD14 but not CD25 or CD54 induction.
Transplant Proc.
1993;25:2913