Remote liver injury is attenuated by adenovirus-mediated gene transfer of heme oxygenase-1 during the systemic inflammatory response syndrome.
OBJECTIVE
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.
McCarter
Sarah D
SD
Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada.
Badhwar
Amit
A
Scott
Jeffrey R
JR
Akyea
Thelma G
TG
Bihari
Aurelia
A
Dungey
Alison A
AA
Harris
Kenneth A
KA
Potter
Richard F
RF
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D016923:Cell Death; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics* / Q000378:metabolism; D051547:Heme Oxygenase-1; D022781:Hepatocytes / Q000473:pathology; D008099:Liver / Q000098:blood supply / Q000201:enzymology* / Q000293:injuries* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000473:pathology; D018715:Microscopy, Video; D051381:Rats; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology / Q000628:therapy*
D008565:Membrane Proteins; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse