Abstract
BackgroundIschemia and reperfusion (I/R) causes tissue damage and intracellular calcium levels are a factor of cell death. Sodium calcium exchanger (NCX) regulates calcium extrusion and Trisulfated Disaccharide (TD) acts on NCX decreasing intracellular calcium through the inhibition of the exchange inhibitory peptide (XIP).ObjectivesThe aims of this research are to evaluate TD effects in liver injury secondary to I/R in animals and in vitro action on cytosolic calcium of hepatocytes cultures under calcium overload.MethodsWistar rats submitted to partial liver ischemia were divided in groups: Control: (n = 10): surgical manipulation with no liver ischemia; Saline: (n = 15): rats receiving IV saline before reperfusion; and TD: (n = 15): rats receiving IV TD before reperfusion. Four hours after reperfusion, serum levels of AST, ALT, TNF-α, IL-6, and IL-10 were measured. Liver tissue samples were collected for mitochondrial function and malondialdehyde (MDA) content. Pulmonary vascular permeability and histologic parameters of liver were determined. TD effect on cytosolic calcium was evaluated in BRL3A hepatic rat cell cultures stimulated by thapsigargin pre and after treatment with TD.ResultsAST, ALT, cytokines, liver MDA, mitochondrial dysfunction and hepatic histologic injury scores were less in TD group when compared to Saline Group (p<0.05) with no differences in pulmonary vascular permeability. In culture cells, TD diminished the intracellular calcium raise and prevented the calcium increase pre and after treatment with thapsigargin, respectively.ConclusionTD decreases liver cell damage, preserves mitochondrial function and increases hepatic tolerance to I/R injury by calcium extrusion in Ca2+ overload situations.
Highlights
Ischemia-reperfusion (I/R) injury remains a major problem in various clinical situations, including trauma, shock, hemorrhage, liver resection, and transplantation [1, 2]
AST, ALT, cytokines, liver MDA, mitochondrial dysfunction and hepatic histologic injury scores were less in Trisulfated Disaccharide (TD) group when compared to Saline Group (p
Expression of calcium-sensing receptors plays a vital role in apoptosis induced by I/R injury [12] and a decrease in mitochondrial Ca2+ levels are associated with decreased apoptosis and cellular changes [13]
Summary
Ischemia-reperfusion (I/R) injury remains a major problem in various clinical situations, including trauma, shock, hemorrhage, liver resection, and transplantation [1, 2]. Current therapeutic procedures, such as ischemic pre or post conditioning and intermittent vascular occlusion, can minimize but not prevent hepatic I/R injury [3,4,5,6]. When sodium is added to the incubation medium, the influx of calcium induced by lipid peroxidation diminishes, preventing cell death, this process being mediated by NCX [16]. Ischemia and reperfusion (I/R) causes tissue damage and intracellular calcium levels are a factor of cell death. Sodium calcium exchanger (NCX) regulates calcium extrusion and Trisulfated Disaccharide (TD) acts on NCX decreasing intracellular calcium through the inhibition of the exchange inhibitory peptide (XIP)
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