Publications by authors named "Thelma G Akyea"

2 Publications

  • Page 1 of 1

Remote liver injury is attenuated by adenovirus-mediated gene transfer of heme oxygenase-1 during the systemic inflammatory response syndrome.

Microcirculation 2004 Oct-Nov;11(7):587-95

Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada.

Objectives: Adenovirus-mediated gene therapy is being investigated with increasing success for future treatment of autoimmune diseases. However, the use of adenoviruses is still limited by inflammatory and immune responses in the target organ. Previous work by the authors' laboratory established that the adenovirus encoding inducible heme oxygenase (Ad-HO-1) does not elicit the acute hepatic inflammation normally caused by adenoviruses, inviting further investigation in models of severe inflammation. Concurrently, there is increasing evidence for an endogenous protective role for heme oxygenase (HO) in the liver during the systemic inflammatory response syndrome (SIRS). Building on our previous results, this study investigated the effect of Ad-HO-1 pretreatment on remote liver injury during normotensive SIRS, induced by bilateral hind limb ischemia and reperfusion.

Methods: Microvascular perfusion and hepatocyte death were quantified using established intravital videomicroscopy techniques. Hepatocellular injury and liver function were assessed using blood-borne indicators.

Results: Microvascular perfusion deficits and increased hepatocyte death occurred following limb ischemia and 3 h of reperfusion in vehicle-pretreated animals; however, Ad-HO-1 pretreatment prevented these deficits. In contrast, the increase in serum alanine transaminase levels was unaffected by Ad-HO-1 pretreatment. Serum bilirubin levels were increased during systemic inflammation, predominantly in the conjugated form; and, this increase was prevented by administration of Ad-HO-1.

Conclusions: These data indicate that gene transfer of inducible HO is an effective method to protect the liver during SIRS, providing incentive for further investigation into gene therapy strategies exploiting this anti-inflammatory enzyme.
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http://dx.doi.org/10.1080/10739680490503384DOI Listing
March 2005

Endogenous heme oxygenase induction is a critical mechanism attenuating apoptosis and restoring microvascular perfusion following limb ischemia/reperfusion.

Surgery 2004 Jul;136(1):67-75

Department of Medical Biophysics, University of Western Ontario, and the London Health Science Centre and Lawson Health Research Institute, London, Ontario, Canada.

Background: A protective role for endogenous heme oxygenase (HO) in the initiation of remote liver injury after limb ischemia/reperfusion has been established. This study expands on our previous work by investigating the role of endogenous HO on hepatocellular injury, hepatocyte death (necrotic and apoptotic), and microvascular perfusion at protracted post-reperfusion times.

Methods: Remote liver injury was studied after 1 hour of bilateral hind limb ischemia and 3, 6, or 24 hours of reperfusion in male C57BL6 mice. Inhibition of HO was achieved with the use of chromium mesoporphrin (CrMP). Established intravital videomicroscopy techniques were used to evaluate microvascular perfusion and hepatocyte death. Hepatocellular injury was quantified by serum alanine transaminase. Apoptosis was measured by using DNA laddering, Cell Death ELISA, and caspase-3 activity.

Results: Although significant perfusion deficits and hepatocellular injury/death occurred after 3 hours, progression of hepatocellular death beyond 6 hours was not observed. A transient increase in apoptosis was observed at 6 hours. By 24 hours, microvascular perfusion was completely restored. This lack of progression correlated with increased HO activity, observed throughout the protocol. Administration of CrMP reduced HO activity to sham nonstressed levels, and caused increased microvascular perfusion deficits, hepatocellular injury, and hepatocyte death over 24 hours. The transient increase in apoptosis was increased in duration and magnitude in CrMP-treated animals.

Conclusions: These results suggest that endogenous HO activity prevents the progression of remote liver injury after limb ischemia/reperfusion.
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http://dx.doi.org/10.1016/j.surg.2003.11.002DOI Listing
July 2004
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