Mechanism of hepatoprotection in proestrus female rats following trauma-hemorrhage: heme oxygenase-1-derived normalization of hepatic inflammatory responses.
Hepatic damage occurs in males and ovariectomized (OVX), not in proestrus (PE), females following trauma-hemorrhage (T-H). The mechanism responsible for hepatoprotection remains unknown. We hypothesized protection in PE is a result of enhanced heme oxygenase-1 (HO-1)-derived down-regulation of liver inflammatory responses. PE and OVX rats underwent T-H (midline laparotomy, 60% blood loss). PE rats received vehicle (Veh; saline), HO-1 inhibitor chromium mesoporphyrin IX chloride (CrMP; 2.5 mg/kg), zinc protoporphyrin IX (ZnPP; 25 mg/kg), or Akt/PI-3K inhibitor Wortmannin (Wort; 1 mg/kg) 30 min prior to resuscitation or sham operation i.p. OVX rats received Veh or 17beta-estradiol (E2; 1 mg/kg) 30 min before hemorrhage. Rats were killed 2 h thereafter. Following T-H, left ventricular performance was maintained in PE and E2 OVX rats but was depressed in OVX and CrMP-, ZnPP-, and Wort-treated PE rats; liver damage was not evident in PE rats, and CrMP, ZnPP, and Wort abrogated protection; liver HO-1, p38 MAPK, Akt/PI3K, and Bcl-2 expression increased in PE and E2 OVX rats, which was abrogated by CrMP, ZnPP, and Wort, and liver ICAM-1, caspase-3, phospho-IkappaB-alpha, and NF-kappaB expression increased in OVX and CrMP-, ZnPP-, and Wort-PE rats; liver myeloperoxidase, NF-kappaB DNA-binding activity, TNF-alpha, IL-6, plasma proinflammatory cytokines, and cytokine-induced neutrophil chemoattractants increased in OVX and CrMP-, ZnPP-, and Wort-PE rats; and plasma estradiol levels and hepatic estrogen receptor-alpha and -beta expression decreased in OVX but were unaltered by CrMP, ZnPP, and Wort. Thus, enhanced HO-1 in PE and E2 OVX females modulates inflammatory responses and protects liver following T-H.
Yang
Shaolong
S
The University of Alabama at Birmingham, 1670 University Blvd., G094 Volker Hall, Birmingham, AL 35294-0019, USA.
Hu
Shunhua
S
Chen
Jianguo
J
Choudhry
Mashkoor A
MA
Rue
Loring W
LW
Bland
Kirby I
KI
Chaudry
Irshad H
IH
D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004247:DNA / Q000378:metabolism; D004958:Estradiol / Q000097:blood; D005260:Female; D005982:Glutathione Transferase / Q000097:blood; D006352:Heart Ventricles / Q000503:physiopathology; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006439:Hemodynamics; D006470:Hemorrhage / Q000139:chemically induced / Q000150:complications / Q000473:pathology*; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000201:enzymology* / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011359:Proestrus / Q000502:physiology*; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism; D014947:Wounds and Injuries / Q000139:chemically induced / Q000150:complications / Q000473:pathology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D011960:Receptors, Estrogen; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D004958:Estradiol; D004247:DNA; D009195:Peroxidase; D051547:Heme Oxygenase-1; D005982:Glutathione Transferase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3