Proteasome Inhibition After Burn Injury

• Published in: Journal of burn care & research Vol. 37; no. 4; p. 207
• Main Authors: Vana, P Geoff, LaPorte, Heather M, Wong, Yee M, Kennedy, Richard H, Gamelli, Richard L, Majetschak, Matthias
• Format: Journal Article
• Language: English
• Published: England 01.07.2016
• Subjects: Animals; Basal Metabolism; Body Weight; Bortezomib - administration & dosage; Burns - therapy; Male; Proteasome Endopeptidase Complex; Proteasome Inhibitors - administration & dosage; Rats; Rats, Sprague-Dawley
• ISSN: 1559-0488
• DOI: 10.1097/BCR.0000000000000280

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.