Increased severity of alcoholic liver injury in female rats: role of oxidative stress, endotoxin, and chemokines.
Alcoholic liver injury is more severe and rapidly developing in women than men. To evaluate the reason(s) for these gender-related differences, we determined whether pathogenic mechanisms important in alcoholic liver injury in male rats were further upregulated in female rats. Male and age-matched female rats (7/group) were fed ethanol and a diet containing fish oil for 4 wk by intragastric infusion. Dextrose isocalorically replaced ethanol in control rats. We analyzed liver histopathology, lipid peroxidation, cytochrome P-450 (CYP)2E1 activity, nonheme iron, endotoxin, nuclear factor-kappa B (NF-kappa B) activation, and mRNA levels of cyclooxygenase-1 (COX-1) and COX-2, tumor necrosis factor-alpha (TNF-alpha), monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2). Alcohol-induced liver injury was more severe in female vs. male rats. Female rats had higher endotoxin, lipid peroxidation, and nonheme iron levels and increased NF-kappa B activation and upregulation of the chemokines MCP-1 and MIP-2. CYP2E1 activity and TNF-alpha and COX-2 levels were similar in male and female rats. Remarkably, female rats fed fish oil and dextrose also showed necrosis and inflammation. Our findings in ethanol-fed rats suggest that increased endotoxemia and lipid peroxidation in females stimulate NF-kappa B activation and chemokine production, enhancing liver injury. TNF-alpha and COX-2 upregulation are probably important in causing liver injury but do not explain gender-related differences.
Nanji
A A
AA
Department of Pathology, The University of Hong Kong and Queen Mary Hospital, Hong Kong. ananji@pathology.hku.hk
Jokelainen
K
K
Fotouhinia
M
M
Rahemtulla
A
A
Thomas
P
P
Tipoe
G L
GL
Su
G L
GL
Dannenberg
A J
AJ
D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics; D054426:Chemokine CXCL2; D018925:Chemokines / Q000235:genetics / Q000502:physiology*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004042:Dietary Fats, Unsaturated / Q000008:administration & dosage; D019446:Endotoxemia / Q000503:physiopathology; D004731:Endotoxins / Q000502:physiology*; D000431:Ethanol / Q000008:administration & dosage; D005260:Female; D005395:Fish Oils / Q000008:administration & dosage; D007501:Iron / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics; D015227:Lipid Peroxidation; D008099:Liver / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008565:Membrane Proteins; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D012727:Sex Characteristics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015430:Weight Gain
D018932:Chemokine CCL2; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D004042:Dietary Fats, Unsaturated; D004731:Endotoxins; D005395:Fish Oils; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D007501:Iron; D019392:Cytochrome P-450 CYP2E1; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat