Increased O-linked beta-N-acetylglucosamine levels on proteins improves survival, reduces inflammation and organ damage 24 hours after trauma-hemorrhage in rats.

Abstract

OBJECTIVE:

To evaluate the effects of O-linked beta-N-acetylglucosamine (O-GlcNAc) levels on survival, inflammation, and organ damage 24 hrs after trauma-hemorrhage. We have previously shown that increasing protein O-GlcNAc levels by different mechanisms reduced inflammatory responses and improved organ function 2 hrs after trauma-hemorrhage.

DESIGN:

Prospective, randomized, controlled study.

SETTING:

Animal research laboratory.

SUBJECTS:

Male, adult Sprague-Dawley rats.

INTERVENTIONS:

Overnight fasted animals were subjected to either sham surgery or trauma-hemorrhage and during the resuscitation phase received glucosamine (270 mg/kg) to increase O-GlcNAc synthesis or O-(2-acetamido-2-deoxy-D-glucopyranosylidene) amino N-phenyl carbamate (PUGNAc, 7 mg/kg) to inhibit O-GlcNAc removal, or mannitol as control.

MEASUREMENTS AND MAIN RESULTS:

Survival was followed up for 24 hrs. Surviving rats were euthanized and inflammatory responses, and end organ injuries were assessed. Both glucosamine and PUGNAc increased 24-hr survival compared with controls (control: 53%, GN: 85%, PUGNAc: 86%, log-rank test, p < .05). PUGNAc attenuated the trauma-hemorrhage-induced increase in serum interleukin-6 (sham surgery: 8 +/- 6, control: 181 +/- 36, PUGNAc: 42 +/- 22 pg/mL, p < .05), alanine transaminase (sham surgery: 95 +/- 14, control: 297 +/- 56, PUGNAc: 126 +/- 21 IU, p < .05), aspartate transaminase (sham surgery: 536 +/- 110, control: 1661 +/- 215, PUGNAc: 897 +/- 155 IU, p < .05), and lactate dehydrogenase (sham surgery: 160 +/- 18, control: 1499 +/- 311, PUGNAc: 357 +/- 99 IU, p < .05); however, glucosamine had no effect on these serum parameters. Furthermore, PUGNAc but not glucosamine maintained O-GlcNAc levels in liver and lung and significantly attenuated the NF-kappaB DNA activation in the liver. In the liver and heart, increased inducible nitric oxide synthase expression was also attenuated in the PUGNAc-treated group.

CONCLUSIONS:

These results demonstrate that increasing O-GlcNAc with either glucosamine or PUGNAc improved 24-hr survival after trauma-hemorrhage. However, only PUGNAc treatment attenuated significantly the subsequent tissue injury and inflammatory responses, suggesting that inhibition of O-GlcNAc removal may represent a new therapeutic approach for the treatment of hypovolemic shock.

• Authors: Laszlo G Nöt, Charlye A Brocks, Laszlo Vámhidy, Richard B Marchase, John C Chatham
• Journal: Critical care medicine (Crit Care Med) Vol. 38 Issue 2 Pg. 562-71 (Feb 2010) ISSN: 1530-0293 [Electronic] United States
• PMID: 20016375 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Blood Glucose
• Blood Proteins
• Cytokines
• NF-kappa B
• Peroxidase
• Acetylglucosamine

Topics

• Acetylglucosamine (blood)
• Animals
• Apoptosis
• Blood Gas Analysis
• Blood Glucose (analysis)
• Blood Proteins (metabolism)
• Cytokines (blood)
• Disease Models, Animal
• Hyperglycemia (metabolism)
• Immunoblotting
• Inflammation (blood, metabolism, physiopathology)
• Male
• NF-kappa B (blood)
• Peroxidase (blood)
• Phosphorylation
• Rats
• Rats, Sprague-Dawley
• Shock, Hemorrhagic (blood, metabolism, physiopathology)