Isoflurane Preconditioning at Clinically Relevant Doses Induce Protective Effects of Heme Oxygenase-1 on Hepatic Ischemia Reperfusion in Rats

Abstract

BackgroundActivation of heme oxygenase-1 (HO-1) has been proved to reduce damages to the liver in ischemia reperfusion injury. The objective of present study was to determine whether clinic relevant doses of isoflurane treatment could be sufficient to activate HO-1 inducing, which confers protective effect against hepatic ischemia-reperfusion injury.MethodsThe hepatic artery and portal vein to the left and the median liver lobes of forty male Sprague-Dawley rats were occluded for 60 minutes. Reperfusion was allowed for 4 hours before the animal subjects were sacrificed. Six groups (n = 12) were included in the study. A negative control group received sham operation and positive control group a standard ischemia-reperfusion regimen. The third group was pretreated with isoflurane prior to the ischemia-reperfusion. The fourth group received an HO-1 inhibitor zinc protoporphyrin (Znpp) prior to the isoflurane pretreatment and the ischemia-reperfusion. The fifth group received Znpp alone before ischemia-reperfusion procedure, and the sixth group was administrated with a HO-1 inducer hemin prior to IR. HO-1 in the liver was measured using an enzymatic activity assay, a Western blot analysis, as well as immunohistochemical method. Extent of liver damage was estimated by determination of the serum transaminases, liver lipid peroxidation and hepatic histology. Infiltration of the liver by neutrophils was measured using a myeloperoxidase activity assay. TNFα mRNA in the liver was measured using RT-PCR.ResultsIsoflurane pretreatment significantly attenuated the hepatic injuries and inflammatory responses caused by the ischemia reperfusion. Selectively inhibiting HO-1 with ZnPP completed blocked the protective effects of isoflurane. Inducing HO-1 with hemin alone produced protective effects similar in magnitude to that of isoflurane.ConclusionsClinic relevant doses of isoflurane attenuate ischemia reperfusion injury in rats by increasing the HO-1 expression and activity.

Volatile Anesthetics and AKI

“…28 Subsequent studies discovered the protective effects of volatile anesthetic pretreatment before prolonged ischemia in other organs (e.g., liver, brain) and this phenomenon was termed anesthetic preconditioning. 29,30 Furthermore, volatile anesthetics also protect several organs, including the kidney and heart, when administered after completion of ischemic insult and this phenomenon was termed anesthetic postconditioning. 31 These studies establish volatile anesthetics as new potential therapeutic agents to protect against organ inflammation and ischemia.…”

Isoflurane Preconditioning Increases Survival of Rat Skin Random-Pattern Flaps by Induction of HIF-1a Expression

“…Animals were exposed to isoflurane as described previously [18]. Briefly, a homemade tilt transparent plastic chamber with in- and out-flow at the opposite long ends was used.…”

“…We and others have demonstrated that isoflurane was able to modulate expression of several genes related to cell survival, including HIF-1α [11,12,13,14,15]. Tissue preconditioning properties of isoflurane have been well described in the literature and are established in clinical practice [14,16,17,18,19]. Therefore, we hypothesized that isoflurane preconditioning might be beneficial in reducing necrosis in ischemic skin flaps through up-regulation of HIF-1α and its downstream genes.…”

Redox therapeutics in hepatic ischemia reperfusion injury

“…Further production of reactive oxygen and nitrogen species (ROS, RNS), H + and toxic metabolites amplify injury and attract water into the cell and the resultant edema further impairs cellular function. As cell death begins within the hepatocytes, nearby endothelial cells and Kupffer cells begin to express adhesion molecules and chemokines, that recruit neutrophils to the site of injury and amplify tissue injury [7] . Below we discuss individual cell types implicated in liver IRI during transplantation and their respective roles in controlling the redox milieu ( Figure 1).…”