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MCP-1 production by macrophages is stimulated by neutrophil elastase and oxygen radicals generated by hypoxia, probably due to microthrombus formation after ischemia/reperfusion of the rat liver.

We investigated the role of hepatic macrophages in the inflammatory response following reperfusion injury by blocking Kupffer cell phagocytosis with gadolinium chloride (GdCl3). Liver ischemia was induced in rats by occluding the portal vein for 30 minutes. A bolus of GdCl3 (7 mg/kg) was injected intravenously 1 and 2 days before surgery. The serum levels of cytokine-induced neutrophil chemoattractant (CINC) in untreated rats increased following reperfusion, peaked after 6 hours, and then gradually decreased. GdCl3 or heparin alone significantly decreased the serum levels of CINC (P < .05). In addition, pretreatment with GdCl3/heparin further inhibited the rise in the serum levels of CINC following reperfusion compared with those in untreated animals (P < .01). The in vitro production of CINC by Kupffer cells, obtained from animals pretreated with heparin or GdCl3, was significantly lower than that of cells isolated from untreated animals. Pretreatment with GdCl3/heparin further decreased CINC production by Kupffer cells compared with that of cells from animals that were pretreated with heparin or GdCl3 alone. The expression of CINC transcripts in Kupffer cells or in liver tissue peaked 3 hours after reperfusion in untreated animals. Pretreatment with heparin, GdCl3, or both significantly decreased the levels of CINC messenger RNA (mRNA) transcripts. Pretreatment with heparin, GdCl3, or GdCl3/heparin significantly decreased the number of neutrophils that accumulated in the liver 24 hours following reperfusion, compared with those in untreated animals. These results suggest that Kupffer cells release CINC and may play an important role in early neutrophil infiltration into the liver following ischemia/reperfusion.

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...