Pretreatment with activated protein C or active human urinary thrombomodulin attenuates the production of cytokine-induced neutrophil chemoattractant following ischemia/reperfusion in rat liver

Abstract

bance induced by microthrombotic occlusion following We investigated the role of anticoagulant in the isischemia/reperfusion. (HEPATOLOGY 1997;25:1136-1140.) chemia/reperfusion injury of the liver, using activated protein C (APC), active human urinary thrombomodulin (UTM), and factor Xa blocked at the active site Endothelial cells play an important regulatory role in the (DEGR-Xa). Liver ischemia was induced in male Wistar coagulation system. Protein C is a vitamin K-dependent rats by occlusion of the portal vein with a microvascuplasma glycoprotein that circulates as an inactive zymogen. lar clip for 30 minutes. Each anticoagulant was injectedAt the endothelial cell surface, thrombin in complex with intravenously 10 minutes before clamping the portal the integral membrane protein, thrombomodulin, converts vein. Serum concentrations of cytokine-induced neuprotein C to its active form by specific cleavage of an activatrophil chemoattractant (CINC) were determined by enzyme-linked immunosorbent assay. The serum levels tion peptide. [1][2][3] The active form of protein C has potent anticoof CINC increased significantly following reperfusion, agulant activity as a feedback regulator of thrombin generareaching a peak in 6 hours, and then decreasing gradu-tion, 4,5 and also has profibrinolytic, 6,7 anti-ischemic, 8 and ally to control levels by 24 hours. CINC levels in rats anti-inflammatory properties. 9 pretreated with APC (500 U/kg), UTM (3,000 TMU/kg), Neutrophil activation has been shown to play an important or DEGR-Xa (10 mg/kg) peaked 3 hours following reper-role in ischemia/reperfusion injury associated with the shock fusion and decreased rapidly to baseline level within process. 10,11 Recently, Jaeschke et al. 12 and Poggeti et al. 13 6 and 12 hours, respectively. These peak values were showed the importance of neutrophils in the development significantly lower than those observed in untreated of liver ischemia/reperfusion injury. When activated in the rats (P õ .01). Expression of CINC transcripts in liver microcirculation, neutrophils release a variety of inflammatissue of untreated rats was evaluated by Northern blot tory mediators capable of producing endothelial cell injury. 14 analysis and peaked 3 hours following reperfusion. Pre-Among these mediators, granulocyte proteases and hydrogen treatment with these anticoagulants significantly de-peroxide have been shown to induce inactivation of thrombocreased the expression of CINC messenger RNA tran-modulin synergistically, as well as damage to the endothelial scripts as compared with untreated animals. cell integrity. 15 Thus, it is likely that microthrombus can be Myeloperoxidase activity and the number of neutro-formed in ischemia/reperfusion as a result of activated leukophils accumulated into the liver 24 hours following cyte-induced endothelial cell injury, which may lead to tissue ischemia/reperfusion were also significantly decreased ischemia. Because production of interleukin (IL)-1 by monoin animals pretreated with these anticoagulants. In ad-cyte...

Soluble Thrombomodulin Protects Ischemic Kidneys

“…36 Ischemic liver injury has also been shown to be reduced by TM administration, along with anti-inflammatory effects. 37,38 Studies also support a prominent neuroprotective role for sTM by its blockade of PARs, and subsequent reduction in apoptosis. 39 Our data suggest that the anti-inflammatory effect of sTM in the PAC models is not due to APC generation and its ability to act as a cytoprotective factor via EPCR/PAR signaling.…”

Coagulation-Mediated Hypoxia and Neutrophil-Dependent Hepatic Injury in Rats Given Lipopolysaccharide and Ranitidine

“…For example, in the case of large, hepatotoxic doses of LPS, coagulation system activation is required for activation of PMNs and hepatotoxicity, but it is not important for up-regulation of the PMN chemokine, cytokine-induced neutrophil chemoattractant-1 (CINC-1) (Copple et al, 2003). In contrast, coagulation system activation is required for CINC-1 production and liver PMN accumulation in ischemia-reperfusion-induced liver damage (Yamaguchi et al, 1997). Accordingly, cross-talk between coagulation and PMNs can occur during liver injury.…”

The long-term effects of pre-treatment with activated protein C in a rat model of compression-induced spinal cord injury

“…In a rat model of liver ischemia and reperfusion, APC signi®cantly decreased neutrophil accumulation and cytokineinduced neutrophil chemoattractant. 28 Two mechanisms of APC's anti-in¯ammatory eect have been proposed. On the one hand, APC is thought to inhibit neutrophil recruitment and activation by down-regulating cytokine production by monocytes.…”

“…14 In the inclined-plane test, recovery from motor disturbance was assessed before, and again at 1,7,14,21,28,35,42,49, and 56 days after the compression. We recorded the maximum inclination of the plane on which the rats could maintain themselves for 5 s without falling.…”