title: c-Jun terminal kinase-2 gene deleted mice overexpress hemeoxygenase-1 and are protected from hepatic ischemia reperfusion injury.
abstract: BACKGROUND
  Targeted deletion of c-jun amino terminal kinase-2 (jnk-2) upregulates the activator protein-1 transcription factor system. We hypothesized that this would lead to induction of hemeoxygenase-1 (HO-1) and confer protection from hepatic ischemia reperfusion injury.
  
  
  METHODS
  Wild-type and jnk-2 -/- animals were subjected to hepatic ischemia reperfusion insults in two models: a total hepatic ischemia model involving timed Pringle maneuver, and a partial hepatic ischemia model involving selective occlusion of the portal pedicle supplying the left hepatic lobe. Optimal durations of injury were calibrated for each model. After 24 hr, animals were killed, and blood and tissues were collected for alanine aminotransferase, histologic injury scoring, and other analyses. Before total or partial hepatic ischemia reperfusion insults, some animals were subject to HO-1 inhibition with chromium mesoporphyrin IX or Kupffer cell depletion with liposomal clodronate. Bone marrow-derived monocytes were grown from hemopoietic progenitors taken from wild-type and jnk-2 -/- mice before stimulation with lipopolysaccharide and measurement of tumour necrosis factor-alpha production.
  
  
  RESULTS
  Jnk-2 -/- animals were protected from hepatic ischemia reperfusion injury. HO-1 expression and activity was elevated in jnk-2 -/- animals (2.2-fold; P=0.006). Most HO-1 was expressed in Kupffer cells. Inhibition of HO-1 in jnk-2 -/- animals led to the loss of protection from ischemia. Depletion of Kupffer cells using liposomal clodronate led to loss of hepatic HO-1 expression and much more severe injury in wild-type and jnk-2 -/- animals. In vitro studies of cultured macrophages demonstrated reduced tumour necrosis factor-alpha secretion after lipopolysaccharide stimulus, an effect lost after HO-1 inhibition.
authors: Centre for Inflammation Research, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom. luke@devey.net
authors: Luke
authors: L
authors: Devey
authors: Elodie
authors: E
authors: Mohr
authors: Christopher
authors: C
authors: Bellamy
authors: Kenneth
authors: K
authors: Simpson
authors: Neil
authors: N
authors: Henderson
authors: Ewen M
authors: EM
authors: Harrison
authors: James A
authors: JA
authors: Ross
authors: Stephen J
authors: SJ
authors: Wigmore
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D002478:Cells, Cultured; D004002:Clodronic Acid / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006412:Hematopoietic Stem Cells / Q000201:enzymology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007511:Ischemia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D007728:Kupffer Cells / Q000201:enzymology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008652:Mesoporphyrins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048056:Mitogen-Activated Protein Kinase 9 / Q000172:deficiency* / Q000235:genetics; D009000:Monocytes / Q000201:enzymology; D015427:Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D012720:Severity of Illness Index; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D008652:Mesoporphyrins; D014409:Tumor Necrosis Factor-alpha; C427471:chromium mesoporphyrin; D004002:Clodronic Acid; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D000410:Alanine Transaminase; D048056:Mitogen-Activated Protein Kinase 9