Kidney and Liver Injuries After Major Burns in Rats Are Prevented by Resolvin D2.
OBJECTIVE
Innate immune dysfunction after major burn injuries increases the susceptibility to organ failure. Lipid mediators of inflammation resolution, e.g., resolvin D2, have been shown recently to restore neutrophil functionality and reduce mortality rate in a rat model of major burn injury. However, the physiological mechanisms responsible for the benefic activity of resolvin D2 are not well understood.


METHODS
Prospective randomized animal investigation.


METHODS
Academic research setting.


METHODS
Wistar male rats.


METHODS
Animals were subjected to a full-thickness burn of 30% total body surface area. Two hours after burn, 25 ng/kg resolvin D2 was administered IV and repeated every day, for 8 days. At day 10 post burn, 2 mg/kg of lipopolysaccharide was administered IV, and the presence of renal and hepatic injuries was evaluated at day 11 post burn by histology, immunohistochemistry, and relevant blood chemistry.


RESULTS
In untreated animals, we found significant tissue damage in the kidneys and liver, consistent with acute tubular necrosis and multifocal necrosis, and changes in blood chemistry, reflecting the deterioration of renal and hepatic functions. We detected less tissue damage and significantly lower values of blood urea nitrogen (26.4 ± 2.1 vs 36.0 ± 9.3 mg/dL; p ≤ 0.001), alanine aminotransferase (266.5 ± 295.2 vs 861.8 ± 813.7 U/L; p ≤ 0.01), and total bilirubin (0.13 ± 0.05 vs 0.30 ± 0.14 mg/dL; p ≤ 0.01) in resolvin D2-treated rats than in untreated animals. The mean blood pressure of all animals was above 65 mm Hg, indicating adequate tissue perfusion throughout the experiments. We measured significantly larger amounts of chromatin in the circulation of untreated than of resolvin D2-treated rats (575.1 ± 331.0 vs 264.1 ± 122.4 ng/mL; p ≤ 0.05) and identified neutrophil extracellular traps in kidney and liver tissues from untreated rats, consistent with the tissue damage.


CONCLUSIONS
Pathologic changes in kidney and liver tissues in a rat model of major burn and endotoxin insults are ameliorated by resolvin D2.
1Department of Surgery, Massachusetts General Hospital, Boston, MA. 2Shriners Hospital for Children, Boston, MA. 3Harvard Medical School, Boston, MA. 4Department of Pathology, Massachusetts General Hospital, Boston, MA. 5Nephrology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA. 6Department of Interventional Radiology, Massachusetts General Hospital, Boston, MA. 7Program in Membrane Biology, Division of Nephrology and Center for Systems Biology, Massachusetts General Hospital, Boston, MA. 8Department of Nuclear Medicine, Massachusetts General Hospital, Boston, MA. 9BioMEMS Resource Center, Massachusetts General Hospital, Boston, MA.
Yoshitaka
Y
Inoue
Yong-Ming
YM
Yu
Tomohiro
T
Kurihara
Aleksandr
A
Vasilyev
Amir
A
Ibrahim
Rahmi
R
Oklu
Gaofeng
G
Zhao
Anil V
AV
Nair
Dennis
D
Brown
Alan J
AJ
Fischman
Ronald G
RG
Tompkins
Daniel
D
Irimia
D000818:Animals; D001774:Blood Chemical Analysis; D001835:Body Weight; D002056:Burns / Q000150:complications*; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D006439:Hemodynamics; D048550:Hepatic Insufficiency / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D007249:Inflammation / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007677:Kidney Function Tests; D008070:Lipopolysaccharides / Q000494:pharmacology; D008111:Liver Function Tests; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000096:biosynthesis; D008297:Male; D011446:Prospective Studies; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D051437:Renal Insufficiency / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology
D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D026561:Low Density Lipoprotein Receptor-Related Protein-2; C545423:resolvin D2; D004281:Docosahexaenoic Acids