TY - JOUR
T1 - Increased severity of alcoholic liver injury in female rats
T2 - Role of oxidative stress, endotoxin, and chemokines
AU - Nanji, Amin A.
AU - Jokelainen, Kalle
AU - Fotouhinia, Maryam
AU - Rahemtulla, Amir
AU - Thomas, Peter
AU - Tipoe, George L.
AU - Grace, L. S U
AU - Dannenberg, Andrew J.
PY - 2001
Y1 - 2001
N2 - 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- KB (NF- KB) activation, and mRNA levels of cyclooxygenase-1 (COX-1) and COX-2, tumor necrosis factor-α (TNF-α), 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- KB activation and upregulation of the chemokines MCP-1 and MIP-2. CYP2E1 activity and TNF-α 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- KB activation and chemokine production, enhancing liver injury. TNF-α and COX-2 upregulation are probably important in causing liver injury but do not explain gender-related differences.
AB - 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- KB (NF- KB) activation, and mRNA levels of cyclooxygenase-1 (COX-1) and COX-2, tumor necrosis factor-α (TNF-α), 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- KB activation and upregulation of the chemokines MCP-1 and MIP-2. CYP2E1 activity and TNF-α 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- KB activation and chemokine production, enhancing liver injury. TNF-α and COX-2 upregulation are probably important in causing liver injury but do not explain gender-related differences.
KW - Cyclooxygenase-2
KW - Cytokines
KW - Tumor necrosis factor-α
UR - http://www.scopus.com/inward/record.url?scp=0035665313&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035665313&partnerID=8YFLogxK
U2 - 10.1152/ajpgi.2001.281.6.g1348
DO - 10.1152/ajpgi.2001.281.6.g1348
M3 - Article
C2 - 11705739
AN - SCOPUS:0035665313
SN - 0193-1857
VL - 281
SP - G1348-G1356
JO - American Journal of Physiology - Gastrointestinal and Liver Physiology
JF - American Journal of Physiology - Gastrointestinal and Liver Physiology
IS - 6 44-6
ER -