Hypertonic preconditioning prevents hepatocellular injury following ischemia/reperfusion in mice: A role for interleukin 10

Abstract

Ischemia/reperfusion (I/R) of the liver occurs in many clinical scenarios including trauma, elective surgery, and transplantation. Events initiated by this process can lead to inflammation in the liver, culminating in local injury as well as distant organ dysfunction. Recent studies have suggested that hypertonic saline exerts anti-inflammatory effects, which may be beneficial in preventing organ injury. In the present study, we examine the effect of hypertonic saline on the development of liver inflammation following I/R in both rat and mouse models. Hypertonic pretreatment was shown to prevent liver enzyme release concomitant with a reduction in liver neutrophil sequestration. Hypertonic saline appeared to exert this effect by inhibiting liver tumor necrosis factor ␣ (TNF-␣) generation, an effect that culminated in reduced liver adhesion molecule expression. Hypertonic saline pretreatment was shown to augment liver interleukin 10 (IL-10) expression following I/R, as a potential mechanism underlying its anti-inflammatory effect. To examine the role of IL-10 in the protective effect of hypertonic saline on liver I/R injury, we used a murine model of I/R. In wild type mice, hypertonic pretreatment similarly prevented liver injury induced by I/R. However, in IL-10 knockout animals, hypertonic pretreatment was unable to prevent the liver enzyme release, TNF-␣ generation, or neutrophil sequestration induced by I/R. In conclusion, these findings define a novel mechanism responsible for the anti-inflammatory effects of hypertonic saline and also suggest a potential clinical role for hyperosmolar solutions in the prevention of liver injury associated with I/R. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). (HEPATOLOGY 2004;40:211-220.)

Molecular Physiology of Preconditioning-Induced Brain Tolerance to Ischemia

“…Endotoxin preconditioning enhanced IL-10 renal expression in rats, and this change correlated with ischemic tolerance (140). In the liver of wild-type mice, hypertonic preconditioning increased IL-10 expression and prevented ischemia/reperfusion injury; ischemic tolerance was suppressed in IL-10 knockout mice (296). In cultured microglia and astrocytes, the expression of IL-10 mRNA as well as the production of IL-10 protein was enhanced by innate activation with LPS (52, 254).…”

Physiology of Cell Volume Regulation in Vertebrates

“…In addition to playing a role in control of volume recovery in at least some cell types, this reorganization may exert protective roles, e.g., by cortical reinforcement, and contribute to volume-dependent regulation of gene transcription. Demonstrating the importance of these phenomena, several (patho)physiological effects of volume perturbations have been shown to be mediated by the cytoskeleton, including shrinkage-induced inhibition of neutrophil function (852) and stimulation of glucose transport (307, 308), the protective effect of hypertonic preconditioning prior to ischemia (750), and the swelling-induced inhibition of autophagic proteolysis (1048,1051). Below, we discuss pertinent aspects of the current knowledge on the role of the cytoskeleton in volume-dependent signaling events.…”

Ischemic preconditioning of the liver: A few perspectives from the bench to bedside translation

“…The merits of this composite endpoint were discussed in the Severity of Ischemia and RP Injury section, subsection Liver Transplantation. Remote preconditioning via limb ischemia 81,82 (1) Applicable to DCD donors; (2) Inexpensive Hypertonic saline dextran 83,84 (1) Volume enhancement, especially in donors and applicable to DCD donors; (2) Inexpensive Anesthetic preconditioning (volatile anesthetics, nitric oxide) 3,4,85 (1) May not be feasible in all donor hospitals; (2) Nitric oxide is expensive Pharmacologic preconditioning (nitrites, adenosine, interleukin-10) 2,6,7 (1) More expensive; (2) Potential side effects of agents NOTE: In contradistinction to ischemic preconditioning, all listed modalities are applicable in both liver donors and recipients. They share avoidance of direct organ ischemia and, when used in deceased donors, have the potential to benefit recipients of many organs.…”