title: Role of heme oxygenase in the protection afforded skeletal muscle during ischemic tolerance.
abstract: OBJECTIVE
  Ischemic tolerance (IT) is known to improve resistance to ischemia/reperfusion (I/R)-induced injury; however, the mechanisms remain unknown. The authors hypothesized that induction of heme oxygenase (HO), a heat shock protein, would provide anti-inflammatory benefits during IT, thereby preventing leukocyte-derived I/R injury.
  
  
  METHODS
  Male Wistar rats were randomly assigned to sham (n = 4), I/R (n = 9), preconditioning (PC)+I/R (n = 7), chromium mesoporphyrin, to inhibit HO (CrMP; n = 4), or PC+I/R+CrMP (n = 6) groups. PC consisted of 5 cycles of I/R, each lasting 10 min, induced by tightening a tourniquet placed above the greater trochantor of the hindlimb. Twenty-four hours later, the hindlimb underwent 2 h of no-flow ischemia followed by intravital microscopy during 90 min reperfusion to assess capillary perfusion (#/mm), tissue injury (ratio of ethidium bromide to bisbenzimide labeled cells/100 microm2), leukocyte rolling (Lr, #/1000 microm2), and adhesion (La, #/1000 microm2) in postcapillary venules of the extensor digitorum longus (EDL) muscle.
  
  
  RESULTS
  In the I/R group, Lr was significantly increased (7.1 +/- 0.4) compared to sham (3.1 +/- 0.4). PC+I/R increased Lr (10.8 +/- 0.72), which was further exacerbated by the removal of HO (14.2 +/- 1.3). La (7.8 +/- 2.0) was significantly increased compared to sham (2.4 +/- 0.9), while PC returned La back to sham levels (1.9 +/- 0.7). Removal of HO activity, via CrMP, had no significant effect on La (3.9 +/- 0.7). However, CrMP removed the protection to microvascular perfusion (I/R = 9.4 +/- 1.1, PC = 16.6 +/- 1.8, sham = 20.5 +/- 2.8, PC+CrMP+I/R = 12.3 +/- 2.3) and prevented protection from ischemia-induced tissue injury.
  
  
  CONCLUSIONS
  The data suggest that HO is an important protective mechanism during IT in skeletal muscle, but such protection was by mechanisms other than altered leukocyte-endothelial cell interaction.
authors.affiliation: Centre for Critical Illness Research, Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Alison A
authors.initials: AA
authors.lastname: Dungey
authors.forename: Amit
authors.initials: A
authors.lastname: Badhwar
authors.forename: Aurelia
authors.initials: A
authors.lastname: Bihari
authors.forename: Peter R
authors.initials: PR
authors.lastname: Kvietys
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Harris
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Forbes
authors.forename: Richard F
authors.initials: RF
authors.lastname: Potter
mesh_terms: D000818:Animals; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D006614:Hindlimb / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D007249:Inflammation / Q000201:enzymology / Q000473:pathology; D019194:Ischemic Preconditioning; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000201:enzymology* / Q000473:pathology
chemical_list: D006360:Heat-Shock Proteins; D006419:Heme Oxygenase (Decyclizing)