title: Intestinal ischemic preconditioning ameliorates hepatic ischemia/reperfusion injury in rats: role of heme oxygenase 1 in the second window of protection.
abstract: Preconditioning by brief ischemia protects not only the concerned organ but also other distant organs against subsequent lethal damage; this is called remote ischemic preconditioning (RIPC). This study was designed to investigate the impact of intestinal RIPC on hepatic ischemia/reperfusion injury (IRI) with a special interest in heme oxygenase 1 (HO-1) induction in the second window of protection (SWOP). Male Wistar rats were randomly assigned to 1 of 2 groups: an RIPC group or a sham group. Before hepatic IRI, either intestinal RIPC, consisting of 2 cycles of 4-minute superior mesenteric artery clamping separated by 11 minutes of declamping (RIPC group), or a sham procedure (sham group) was performed. After 48 hours of recovery, the rats were exposed to 30 minutes of total hepatic IRI. Transaminase releases and proinflammatory cytokines were determined at several time points after reperfusion. Histopathological analysis and animal survival were also investigated. Intestinal RIPC significantly lowered transaminase release (alanine aminotransferase at 2 hours: 873.3 ± 176.4 IU/L for the RIPC group versus 3378.7 ± 871.1 IU/L for the sham group, P < .001) as well as proinflammatory cytokine production (tumor necrosis factor α at 2 hours: 930 ± 42 versus 387 ± 17 pg/μL, P < .001). The morphological integrity of the liver and the ileum was maintained significantly better with intestinal RIPC; this reached statistical significance not only in Suzuki's liver injury score (3.5 ± 0.2 versus 0.7 ± 0.5, P = .007) but also in Park's score for intestinal damage (4.0 ± 0.4 versus 2.0 ± 0.2, P = .007). Animal survival was also markedly improved (83.1% versus 15.4%, P < .001). As a mechanism underlying this protection, HO-1 was substantially induced in liver tissue, especially in hepatocytes, with remarkable up-regulation of bradykinin in the portal blood, whereas HO-1 protein induction in enterocytes was not significant. In conclusion, intestinal RIPC remarkably attenuates hepatic IRI in the SWOP, presumably by HO-1 induction in hepatocytes.
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Kageyama
authors.forename: Koichiro
authors.initials: K
authors.lastname: Hata
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tanaka
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hirao
authors.forename: Toyonari
authors.initials: T
authors.lastname: Kubota
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Okamura
authors.forename: Keiko
authors.initials: K
authors.lastname: Iwaisako
authors.forename: Yasutsugu
authors.initials: Y
authors.lastname: Takada
authors.forename: Shinji
authors.initials: S
authors.lastname: Uemoto
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D003250:Constriction; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D022781:Hepatocytes / Q000201:enzymology* / Q000473:pathology; D018836:Inflammation Mediators / Q000097:blood; D007422:Intestines / Q000098:blood supply* / Q000201:enzymology / Q000648:ultrastructure; D019194:Ischemic Preconditioning / Q000379:methods*; D008099:Liver / Q000098:blood supply* / Q000201:enzymology* / Q000648:ultrastructure; D008297:Male; D017538:Mesenteric Artery, Superior / Q000601:surgery; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000097:blood / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat