Role of SLc11a1 Gen in Warm Ischemia-Reperfusion Injury

Summary

Principal Investigator: Samuel Wyllie
Affiliation: Texas Medical Center
Country: USA
Abstract: While improvements in surgical techniques and pharmacological interventions have improved the outcome of liver resections, hemorrhagic shock, and organ transplantation, injury, rejection and eventual organ failure due to Ischemia-reperfusion (I/R) injury continue to be common place in the clinical setting. Accordingly, the development of novel treatment modalities to prevent or minimize I/R injury would be of tremendous benefit. Substantial evidence exist to support the notion that Kupffer cells (KC) are responsible for the early-phase of I/R injury, and sets the stage for the more severe polymorphonuclear leukocyte (PMN)-mediated late-phase injury. However, mechanisms by which KC and PMNs mediate their respective phases of I/R injury are not fully understood. This is reflected in the lack of success with conventional modes of therapeutic intervention both at the experimental and clinical levels. We have identified a gene, Slc11a1, which is induced during I/R injury, and mediates the production of pro-and anti-inflammatory cytokines. Consistent with this is the reduced levels of plasma TNF-alpha observed in Slc11a1-/- mice during the early phase of liver I/R injury. Slc11a1 proposed function of the regulating iron homeostasis in KC and PMNs, and its level of expression may ultimately determine if the liver is protected from I/R injury by modulating the degree of injury during both the early- and late-phases of I/R injury. To test this hypothesis we propose three aims: (1) We will determine if disruption of the Slc11a1 gene protects the mouse liver from I/R injury. To investigate this, we will look at both the early- and late-phases of I/R injury in the mouse liver model, in vivo. Standard biochemical and histological techniques will be employed to evaluate blood transaminases and H&E liver sections, in conjunction with molecular techniques to monitor the protein and mRNA levels of Slc11a1 and pro-and anti-inflammatory cytokines. (2) We will determine if disruption of the Slc11a1 gene blunts the activation/priming of KC and infiltrating PMNs during I/R injury. Slc11a1 mediates the activation of KC and PMNs. Therefore, we will isolate these cells from livers subjected to I/R, and use standard biochemical and molecular techniques to evaluate their degree of activation/priming by looking at spontaneous superoxide anion and NO production, and NF-kappaB activation. (3) We will determine the mechanism(s) by which the Slc11a1 gene elicits activation of KC and PMNs. If disruption Slc11a1 protects the liver from I/R injury by modulating mediation of iron homeostasis, then deferoxamine pretreatment of Slc11a1+/+ mice before I/R injury should protect the liver from I/R mediated injury, as observed for Slc11a1-/- mice. Furthermore, pretreatment with Fe2SO4 should reverse the protection observed in Slc11a11-/- mice. As in Aim #1, we will assess liver injury with use of standard biochemical and histological techniques. These studies will identify molecular mechanisms by which Slc11a1 modulates liver I/R injury, and will provide a novel target for therapeutic intervention in I/R-mediated organ injury.
Funding Period: 2003-06-01 - 2007-05-31
more information: NIH RePORT

Top Publications

  1. ncbi Liver ischemia and ischemia-reperfusion induces and trafficks the multi-specific metal transporter Atp7b to bile duct canaliculi: possible preferential transport of iron into bile
    John A Goss
    Michael E DeBakey Department of Surgery, Liver Transplant Center Laboratory, Baylor College of Medicine, Houston, TX 77030, USA
    Biol Trace Elem Res 122:26-41. 2008

Detail Information

Publications1

  1. ncbi Liver ischemia and ischemia-reperfusion induces and trafficks the multi-specific metal transporter Atp7b to bile duct canaliculi: possible preferential transport of iron into bile
    John A Goss
    Michael E DeBakey Department of Surgery, Liver Transplant Center Laboratory, Baylor College of Medicine, Houston, TX 77030, USA
    Biol Trace Elem Res 122:26-41. 2008
    ..Thus, we conclude that liver ischemia and ischemia-reperfusion induction and trafficking Atp7b to the bile duct canaliculi may contribute to preferential iron transport into bile...