Kidney and Liver Injuries After Major Burns in Rats Are... : Critical Care Medicine (original) (raw)

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Kidney and Liver Injuries After Major Burns in Rats Are Prevented by Resolvin D2

Inoue, Yoshitaka MD; Yu, Yong-Ming MD, PhD; Kurihara, Tomohiro MD; Vasilyev, Aleksandr MD, PhD; Ibrahim, Amir MD; Oklu, Rahmi MD, PhD; Zhao, Gaofeng MD, PhD; Nair, Anil V. PhD; Brown, Dennis PhD; Fischman, Alan J. MD, PhD; Tompkins, Ronald G. MD, ScD; Irimia, Daniel MD, PhD

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.

Current address for Dr. Vasilyev: Department of Biomedical Sciences, NYIT COM, Old Westbury, NY.

Current address for Dr. Ibrahim: Division of Plastic and Reconstructive Surgery, American University of Beirut Medical Center, Beirut-Lebanon, Lebanon.

Support for the Program in Membrane Biology Microscopy Core comes from the Boston Area Diabetes and Endocrinology Research Center (DK57521) and the MGH Center for the Study of Inflammatory Bowel Disease (DK43351).

Work was performed at Massachusetts General Hospital and Shriners Hospital for Children, Boston, MA.

This work was supported, in part, by funds from Shriners Hospital for Children and U.S. National Institutes of Health (NIH) grants DK082782 and DK097443 (Dr. Vasilyev), DK042956 (Dr. Brown), and GM-092804 (Dr. Irimia). Dr. Inoue received support for article research from the NIH, the Boston Area Diabetes and Endocrinology Research Center, and the Massachusetts General Hospital Center for the Study of Inflammatory Bowel Disease. He disclosed off-label product use (resolvin D2). Drs. Yu, Zhao, Nair, and Tompkins received support for article research from the NIH. Dr. Brown received support for article research from the NIH and received funding from Exosome Diagnostics. The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: [email protected]

Abstract

Objectives:

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.

Design:

Prospective randomized animal investigation.

Setting:

Academic research setting.

Subjects:

Wistar male rats.

Interventions:

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.

Measurements and Main 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.