Diltiazem and superoxide dismutase modulate hepatic acute phase response in gram-negative sepsis.
This study assessed the hepatic acute phase response and cellular Ca2+ regulation in septic animals and in hepatoma cell lines in vitro. Sepsis was induced in male Sprague-Dawley rats by implanting in their abdominal cavities fecal pellets impregnated with live Escherichia coli and Bacteroides fragilis. 8 h after implantations, rats were treated with diltiazem (1.2 mg/kg) or superoxide dismutase (SOD) (5 x 10(3) units/kg). After 24 h, plasma acute phase proteins (APP) were determined by immunoelectrophoresis, and hepatic APP-mRNAs by Northern blot hybridization. Effects of diltiazem, verapamil, or SOD on hepatic cells were determined in rat Reuber H-35 and human HepG2 hepatoma cells. Sepsis induced a significant increase in plasma APP and their hepatic mRNAs. Diltiazem and SOD reduced the sepsis-induced elevations in plasma lactate, the febrile response and mortality. APP expression in H-35 and HepG2 cells, stimulated by interleukin 1 (IL-1), IL-6, and dexamethasone, was inhibited by diltiazem or verapamil but not SOD. The results suggest that a heightened hepatic APP response in septic animals accompanies systemic/metabolic derangements and a significant animal mortality. Because diltiazem was previously shown to prevent sepsis-related disturbances in hepatic cellular Ca2+ regulation, its mediation of decrease in APP, systemic/metabolic response, and mortality may be effected through modifications in cellular Ca2+ regulation. The data from hepatoma cells show an attenuation of the AAP can result from direct effects of a calcium blocker. However, whether the blocker primarily modifies cellular Ca2+ regulation and secondarily effects APP gene expression, or directly effects gene expression remains unknown.
Rose
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Department of Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois 60153, USA.
Baumann
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Jahreis
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GP
Sayeed
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MM
D000209:Acute-Phase Proteins / Q000096:biosynthesis* / Q000235:genetics; D000210:Acute-Phase Reaction / Q000378:metabolism*; D000818:Animals; D001442:Bacteroides Infections / Q000188:drug therapy / Q000378:metabolism; D001441:Bacteroides fragilis; D001798:Blood Proteins / Q000032:analysis; D002118:Calcium / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D004110:Diltiazem / Q000494:pharmacology* / Q000627:therapeutic use; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008113:Liver Neoplasms / Q000473:pathology; D008297:Male; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D010538:Peritonitis / Q000188:drug therapy / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000188:drug therapy / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology / Q000627:therapeutic use
D000209:Acute-Phase Proteins; D001798:Blood Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D009363:Neoplasm Proteins; D014700:Verapamil; D013482:Superoxide Dismutase; D004110:Diltiazem; D002118:Calcium