title: Proteasome Inhibition After Burn Injury.
abstract: The objective of this study was to assess the effects of proteasome inhibition on the development of burn-induced hypermetabolism. Rats underwent 30-40% total BSA scald burn or sham injury. The proteasome inhibitor bortezomib (0.1 mg/kg) or vehicle (n = 10) was administered i.p. 3× weekly starting at 2 hours (early bortezomib, n = 20) or 48 hours (late-bortezomib, n = 13) postburn. Body weights were determined weekly. Resting energy expenditures (REE) were measured at days 0 (baseline), 7, 14, 21, and 42 postburn. At day 42, blood and pectoral muscle were harvested. Routine blood chemistry parameters were analyzed. Proteasome content, proteasome peptidase activities, and ubiquitin-protein conjugates were measured in muscle extracts. As compared with sham-vehicle-treated animals, specific proteasome activities were increased after burn and vehicle treatment. Bortezomib treatment inhibited proteasome activities and increased ubiquitin-protein conjugates after sham and burn injury. Bortezomib treatment did not affect REE after sham procedure. REE significantly increased by 47% within 7 days and remained elevated until day 42 after burn and vehicle treatment. After early-bortezomib treatment, burn-induced increases in REE were delayed and significantly reduced by 42% at day 42, as compared with vehicle treatment. With late-bortezomib treatment, burn-induced increases in REE were also delayed but not attenuated at day 42. Mortality was 20% with vehicle, 65% (median survival time: 1.875 days) with early-bortezomib and 25% with late-bortezomib treatment after burns (P < .05 early-bortezomib vs vehicle and late-bortezomib). Proteasome inhibition delays development of burn-induced hypermetabolism. Although proteasome inhibition early after burn injury reduces the hypermetabolic response, it significantly increases early burn-associated mortality.
authors.affiliation: From the *Department of Surgery, Burn and Shock Trauma Research Institute, and †Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois.
authors.forename: P Geoff
authors.initials: PG
authors.lastname: Vana
authors.forename: Heather M
authors.initials: HM
authors.lastname: LaPorte
authors.forename: Yee M
authors.initials: YM
authors.lastname: Wong
authors.forename: Richard H
authors.initials: RH
authors.lastname: Kennedy
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gamelli
authors.forename: Matthias
authors.initials: M
authors.lastname: Majetschak
mesh_terms: D000818:Animals; D001481:Basal Metabolism; D001835:Body Weight; D000069286:Bortezomib / Q000008:administration & dosage*; D002056:Burns / Q000628:therapy*; D008297:Male; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D061988:Proteasome Inhibitors; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex