Abstract
Objective Ischemia-reperfusion injury (IRI) produces systemic inflammation with the potential for causing organ failure in tissues peripheral to the initial site of injury. We speculate that treatment strategies that dampen inflammation may be therapeutically beneficial to either the initial site of injury or peripheral organs. To test this, we evaluated the impact of FTY720-induced sequestration of circulating mature lymphocytes on renal IRI and secondary organ injury. Methods A microvascular clamp was surgically placed around the left renal pedicle of anesthetized male Sprague-Dawley rats with either vehicle or FTY720 treatment (0.3 mg/kg) intravenously injected after 15 min of ischemia. Blood flow was restored after 60 min. Cohorts of anesthetized rats were euthanized at 6, 24, or 72 hrs with tissue samples collected for analysis. Results FTY720 treatment resulted in profound T lymphocyte reduction in peripheral blood. Histopathologic examination, clinical chemistries, and gene transcript expression measurements revealed that FTY720 treatment reduced hepatocellular degeneration, reduced serum markers of liver injury (ALT/AST), and reduced the expression of gene targets associated with IRI. Conclusion These findings support an anti-inflammatory effect of FTY720 in the liver where the expression of genes associated with apoptosis, chemotaxis, and the AP-1 transcription factor was reduced. Findings presented here provide the basis for future studies evaluating FTY720 as a potential therapeutic agent to treat complications resulting from renal IRI.
Highlights
Renal ischemia-reperfusion injury (IRI) can result from both transplantation and pathophysiologic processes such as massive hemorrhage and resuscitation or from the development and treatment of abdominal compartment syndrome
The induction of unilateral renal ischemia followed by reperfusion after 60 min resulted in transient alterations in the number and type of circulating leukocytes
Using a clinically relevant rat model of renal IRI, we observed a significant improvement in secondary organ injury due to FTY720 treatment that was reflected in histopathology, serum chemistry, gene expression, and CBC analysis
Summary
Renal ischemia-reperfusion injury (IRI) can result from both transplantation and pathophysiologic processes such as massive hemorrhage and resuscitation or from the development and treatment of abdominal compartment syndrome. Ischemic tissue damage results in the release of danger-associated molecular patterns (DAMPs) [3] which stimulate the innate immune system to produce inflammatory cytokines that increase vascular permeability, recruit additional leukocytes to the site of inflammation, and exacerbate tissue damage [4, 5]. Following reperfusion of the ischemic tissue, these mediators are released systemically where they may promote an inflammatory cascade leading to the systemic inflammatory response syndrome (SIRS). This inflammatory response can result in local and Mediators of Inflammation distant (peripheral) tissue injury with infiltration of neutrophils, activation of the endothelium, and release of ROS leading to organ dysfunction beyond the initial ischemic insult. Inflammation plays a critical role in driving pathogenesis after traumatic injury such that greater inflammatory cytokine expression is associated with significantly higher mortality [7, 8]
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