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Originally published online as doi:10.1189/jlb.0508288 on February 24, 2009

Published online before print February 24, 2009
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(Journal of Leukocyte Biology. 2009;85:1015-1026.)
© 2009 by Society for Leukocyte Biology

Mechanism of hepatoprotection in proestrus female rats following trauma-hemorrhage: heme oxygenase-1-derived normalization of hepatic inflammatory responses

Shaolong Yang1, Shunhua Hu1, Jianguo Chen, Mashkoor A. Choudhry, Loring W. Rue, III, Kirby I. Bland and Irshad H. Chaudry2

Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA

2 Correspondence: Center for Surgical Research, The University of Alabama at Birmingham, 1670 University Blvd., G094 Volker Hall, Birmingham, AL 35294-0019, USA. E-mail: irshad.chaudry{at}ccc.uab.edu

ABSTRACT

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 17β-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-I{kappa}B-{alpha}, and NF-{kappa}B expression increased in OVX and CrMP-, ZnPP-, and Wort-PE rats; liver myeloperoxidase, NF-{kappa}B 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 -β 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.

Key Words: estrus cycle • ovariectomy • liver damage • HO-1 inhibitor • PI3K/Akt inhibitor