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Isoflurane activates intestinal sphingosine kinase to protect against renal ischemia-reperfusion-induced liver and intestine injury.

ABSTRACT: Renal ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury and often leads to multiorgan dysfunction and systemic inflammation. Volatile anesthetics have potent antiinflammatory effects. We aimed to determine whether the representative volatile anesthetic isoflurane protects against acute kidney injury-induced liver and intestinal injury and to determine the mechanisms involved in this protection.Mice were anesthetized with pentobarbital and subjected to 30 min of left renal ischemia after right nephrectomy, followed by exposure to 4 h of equianesthetic doses of pentobarbital or isoflurane. Five hours after renal IRI, plasma creatinine and alanine aminotransferase concentrations were measured. Liver and intestine tissues were analyzed for proinflammatory messenger RNA (mRNA) concentrations, histologic features, sphingosine kinase-1 (SK1) immunoblotting, SK1 activity, and sphingosine-1-phosphate concentrations.Renal IRI with pentobarbital led to severe renal, hepatic, and intestinal injury with focused periportal hepatocyte vacuolization; small-intestinal apoptosis; and proinflammatory mRNA up-regulation. Isoflurane protected against renal IRI and reduced hepatic and intestinal injury via induction of small-intestinal crypt SK1 mRNA, protein and enzyme activity, and increased sphingosine-1-phosphate. We confirmed the importance of SK1 because mice treated with a selective SK inhibitor or mice deficient in the SK1 enzyme were not protected against hepatic and intestinal dysfunction with isoflurane.Isoflurane protects against multiorgan injury after renal IRI via induction of the SK1/sphingosine-1-phosphate pathway. Our findings may help to unravel the cellular signaling pathways of volatile anesthetic-mediated hepatic and intestinal protection and may lead to new therapeutic applications of volatile anesthetics during the perioperative period.

SUBMITTER: Kim M

PROVIDER: S-EPMC3650623 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Isoflurane activates intestinal sphingosine kinase to protect against renal ischemia-reperfusion-induced liver and intestine injury.

Kim Minjae M Park Sang Won SW Kim Mihwa M D'Agati Vivette D VD Lee H Thomas HT

Anesthesiology 20110201 2

<h4>Background</h4>Renal ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury and often leads to multiorgan dysfunction and systemic inflammation. Volatile anesthetics have potent antiinflammatory effects. We aimed to determine whether the representative volatile anesthetic isoflurane protects against acute kidney injury-induced liver and intestinal injury and to determine the mechanisms involved in this protection.<h4>Methods</h4>Mice were anesthetized with pentobarbital an ...[more]

PMID: 21245730

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Project description:This study examined volatile anesthetic-mediated protection against intestinal ischemia-reperfusion injury (IRI).Intestinal IRI is a devastating complication in the perioperative period leading to systemic inflammation and multiorgan dysfunction. Volatile anesthetics, including isoflurane, have anti-inflammatory effects. We aimed to determine whether isoflurane, given after intestinal ischemia, protects against intestinal IRI and the mechanisms involved in this protection.: After IACUC approval, mice were anesthetized with pentobarbital and subjected to 30 minutes of superior mesenteric artery ischemia, followed by 4 hours of equianesthetic doses of pentobarbital or isoflurane. Five hours after reperfusion, small intestine tissues were analyzed for morphological injury, apoptosis, neutrophil infiltration, proinflammatory mRNAs, and TGF-(Transforming Growth Factor-)?1 levels. We also assessed hepatic and renal injury after intestinal IRI.Intestinal IRI with pentobarbital led to significant small intestinal dysfunction with increased mucosal injury, TUNEL (transferase biotin-dUTP nick end-labeling)-positive cells, neutrophil infiltration, and proinflammatory mRNAs as well as elevated plasma alanine aminotransferase and creatinine levels. Isoflurane exposure after IRI led to significant attenuation of intestinal, hepatic, and renal injuries. Furthermore, the protective effects of isoflurane were abolished by treatment with a TGF-?1 neutralizing antibody before induction of IRI. Finally, isoflurane exposure led to increased TGF-?1 levels in intestinal epithelial cells and in plasma.Our findings demonstrate that isoflurane post-conditioning protects against small intestinal injury and hepatic and renal dysfunction after severe intestinal IRI via induction of intestinal epithelial TGF-?1. Our findings support therapeutic applications of volatile anesthetics during the intraoperative and postoperative periods and imply an important role of TGF-?1 signaling in modulating multiorgan injury.

Dataset Information

Isoflurane activates intestinal sphingosine kinase to protect against renal ischemia-reperfusion-induced liver and intestine injury.

Publications

Isoflurane activates intestinal sphingosine kinase to protect against renal ischemia-reperfusion-induced liver and intestine injury.

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