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Balazs Toth, MD; Yukihiro Yokoyama, MD, PhD; Joachim F. Kuebler, MD; Martin G. Schwacha, PhD; Loring W. Rue III, MD; Kirby I. Bland, MD; Irshad H. Chaudry, PhD

Arch Surg. 2003;138:1375-1382.

Hypothesis  Sex differentially influences heme oxygenase (HO) expression following trauma and hemorrhagic shock.

Design  Prospective controlled animal study.

Setting  A university laboratory.

Interventions  Female Sprague-Dawley rats in the proestrus stage of their estrus cycle and male rats underwent a 5-cm midline laparotomy (ie, induction of soft tissue trauma) and were bled to a mean arterial blood pressure of 35 mm Hg for approximately 90 minutes, after which they were resuscitated with Ringer lactate solution (4 x the shed blood volume). In another group of animals, tin protoporphyrin IX was used to block HO activity.

Main Outcome Measures  Liver samples were collected for analysis of HO expression and activity, plasma samples were collected, and alanine transaminase levels were determined 5 hours after resuscitation. Portal pressure and bile production were measured in vivo 5 hours after resuscitation.

Results  Trauma and hemorrhage induced a 2-fold increase in hepatic HO1 expression (the inducible form of HO) in proestrus females compared with males. Hepatic expression of HO2 (a constitutive isoform of HO) was unaffected by sex or trauma and hemorrhage. Blockade of HO in vivo with tin protoporphyrin IX abolished the sex differences caused by diverse HO1 expression. Treatment with tin protoporphyrin IX also elevated the portal pressure, decreased bile production, and increased alanine transaminase to similar levels in proestrus females and males following trauma and hemorrhage.

Conclusions  Sex influences the hepatic expression of HO1 following trauma and hemorrhage. The enhanced induction of HO1 expression and activity in females after trauma and hemorrhage may attenuate hepatocellular dysfunction and injury by maintaining microcirculation via the increased production of carbon monoxide.

From the Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham.

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