Abstract
The present study aimed to investigate the effects of intestinal remote ischemic preconditioning (iRIC) on ischemia-reperfusion injury (IRI) and gut barrier integrity in a rat model of total hepatic ischemia (THI). Male Wistar rats (n = 50; 250–300 g) were randomly allocated into two experimental groups: RIC/Control. Thirty minutes of THI was induced by clamping the hepatoduodenal ligament. iRIC was applied as 4-min of ischemia followed by 11-min of reperfusion by clamping the superior mesenteric artery. Animals were sacrificed at 1, 2, 6, 24 h post-reperfusion (n = 5/group/timepoint). RIC of the gut significantly improved microcirculation of the ileum and the liver. Tissue ATP-levels were higher following iRIC (Liver: 1.34 ± 0.12 vs. 0.97 ± 0.20 μmol/g, p = 0.04) and hepatocellular injury was reduced significantly (ALT: 2409 ± 447 vs. 6613 ± 1117 IU/L, p = 0.003). Systemic- and portal venous IL-6 and TNF-alpha levels were markedly lower following iRIC, demonstrating a reduced inflammatory response. iRIC led to a structural and functional preservation of the intestinal barrier. These results suggest that iRIC might confer a potent protection against the detrimental effects of THI in rats via reducing IRI and systemic inflammatory responses and at the same time by mitigating the dramatic consequences of severe intestinal congestion and bacterial translocation.
Highlights
Our group and others have intensively investigated the effects of Remote ischemic conditioning (RIC) applied on the skeletal muscle in partial hepatic ischemia and liver transplantation [10,11,12,13,14,15,16], only very limited data is available on the effects of intestinal RIC in total hepatic ischemia (THI) [17,18]
The present study is one of the first and most comprehensive reports showing a dual protective response triggered by intestinal RIC (iRIC) in a rat model of THI
Our results demonstrate the prominent effects of iRIC in mitigating remote hepatocellular damage and a reduction of local damage of the intestinal barrier induced by severe congestion and functional ischemia in a well-established rodent model of THI
Summary
Ischemia-reperfusion injury (IRI) is inevitably encountered in various clinical scenarios in liver transplantation and oncological liver surgery, representing an important risk factor for inferior outcomes with increased morbidity and mortality, prolonged intensive care/in-hospital stay, and a significant increase of costs [1,2].Following a landmark observation of Toledo-Perayra et al, demonstrating the presence of ischemic-reperfusion injury in transplanted livers of dogs in 1975, several methods have been introduced to reduce hepatic IRI in experimental and clinical settings [1,3,4,5,6,7].Remote ischemic conditioning (RIC) was introduced by Przyklenk et al in 1993, showing for the first time that brief ischemic-reperfusion attacks, applied at a remote organ or tissue (e.g., limbs or intestine), can protect certain target organs against the deleterious effects of IRI via triggering various protective pathways [8,9]. Ischemia-reperfusion injury (IRI) is inevitably encountered in various clinical scenarios in liver transplantation and oncological liver surgery, representing an important risk factor for inferior outcomes with increased morbidity and mortality, prolonged intensive care/in-hospital stay, and a significant increase of costs [1,2]. Following a landmark observation of Toledo-Perayra et al, demonstrating the presence of ischemic-reperfusion injury in transplanted livers of dogs in 1975, several methods have been introduced to reduce hepatic IRI in experimental and clinical settings [1,3,4,5,6,7]. Remote ischemic conditioning (RIC) was introduced by Przyklenk et al in 1993, showing for the first time that brief ischemic-reperfusion attacks, applied at a remote organ or tissue (e.g., limbs or intestine), can protect certain target organs against the deleterious effects of IRI via triggering various protective pathways [8,9]. Prolonged periods of THI of over 30-min are considered to be lethal in rats, leading to high mortality rates without intervention [17,19,20]
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