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

Abstract

Background Innate immune dysfunction after major burn injuries increases the susceptibility to organ failure. Lipid mediators of inflammation resolution, e.g. Resolvin D2 (RvD2), 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 RvD2 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 skin burn of 30% total body surface area. Two hours after burn, 25 ng/kg RvD2 was administered i.v. and repeated every day, for 8 days. At day 10 post burn (pb), 2 mg/kg of lipopolysaccharide (LPS) was administered i.v., and the presence of renal and hepatic injuries was evaluated at day 11 pb by immunohistochemistry and relevant blood chemistry. Measurements and Main Results In untreated animals, we found significant tissue damage in the kidney and liver, consistent with acute tubular necrosis and multifocal necrosis, and changes in blood chemistry, reflecting the deterioration of renal and hepatic functions. In RvD2 treated rats, we detected less tissue damage and significantly lower values of blood urea nitrogen (BUN) (26.4±2.1 vs. 36.0±9.3 mg/dl, p≤0.001), alanine aminotransferase (ALT) (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), compared to untreated animals. The mean blood pressure of all animals was above 65 mmHg, indicating adequate tissue perfusion throughout the experiments. We measured significantly larger amounts of chromatin in the circulation of untreated compared to RvD2 treated rats (575.1±331.0 vs. 264.1±122.4 ng/ml, p≤0.05) and identified neutrophil extracellular traps (NETs) in kidney and liver tissues from untreated rats, consistent with the tissue damage. Conclusions Pathological changes in kidney and liver tissues in a rat model of major burn and endotoxin insults are ameliorated by RvD2.

Novel Resolvin D2 Receptor Axis in Infectious Inflammation

“…RvD2 is a potent immunoresolvent that stereoselectively reduces excessive PMN trafficking in peritonitis and improves survival in sepsis (19). RvD2’s potent nanogram actions are also protective in disease models where RvD2 prevents inflammatory bowel disease such as colitis (22), alleviates inflammatory and fibromyalgia-induced pain (23, 24), increases survival following burn wound and reduces kidney and liver injuries in mice (25, 26), periodontitis (27) as well as nerve injuries as seen in Parkinson’s disease (28). …”

Extracellular DNA traps released by acute promyelocytic leukemia cells through autophagy

“…9, 10, 11 NET formation is involved in inflammatory responses, such as thrombosis and tissue injury. 12, 13, 14, 15 Although eosinophils, mast cells, monocyte and chronic myelocytic leukemia cell-derived neutrophils have been reported to release ETs, 16, 17, 18, 19, 20, 21 it remains unclear whether immature granulocytes like APL cells undergo ETosis. Recent reports showed that differentiation of HL-60 cells, a human promyelocytic leukemia cell line, into mature neutrophils with calcium ionophore, ATRA, or dimethyl sulfoxide or exposure to the glycosyltransferase inhibitor tunicamycin (TM) resulted in the formation of NET-like structures.…”

Capillary plexuses are vulnerable to neutrophil extracellular traps

“…17 This chain of events could explain the association between major burn injury and subsequent acute tubular necrosis and liver injury. 18 In other conditions, the trapping of NETs in capillaries may have a beneficial effect. For example, chromatin released during inflammation in a tissue is likely to be transported to the lung, where it is mechanically trapped by the dense capillary network of the alveolae.…”