Ischemia-Reperfusion Injury and Ischemic-Type Biliary Lesions following Liver Transplantation

Figure 2

Role of Kupffer cells and PMNs in cold and warm ischemia leading to the development of ITBLs following LT. The epithelial lining of the biliary tree is exposed not only to proinflammatory mediators derived from extrahepatic sources, via arterial circulation, but also to proinflammatory mediators derived from intrahepatic sources, such as inflammatory cells or Kupffer cells. These inflammatory mediators promote the invasion of PMNs into the interstitium. PMNs then penetrate the ductal basal membrane and contribute to bile duct injury. Thus the main event injury seems to be activation of Kupffer cells and recruitment and activation of PMNs leading to apoptosis of epithelial biliary cells. PMN: polymorphonuclear neutrophils; ROS: reactive oxygen species; ATP: adenosine triphosphate; Na(+), K(+)-ATPase: sodium pump; TNFα: tumor necrosis factor alpha; TNF-R1: tumor necrosis factor receptor 1; MPT: mitochondrial permeability transition; Bcl-2: B-cell CLL/lymphoma 2 protein; IQGAP1: regulator molecule of bile canaliculi structure; AP-2: endocytic multimeric adaptor; Clathrin: endocytic monomeric adaptors; FasL: Fas ligand; TRAIL-R1/DR4: tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) which binds TRAIL-receptor1/death receptor 4 (DR4); TRIAL-R2/DR5: tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) which binds TRAIL-receptor2/death receptor 5 (DR5); Muc1: mucine 1; Muc3A: mucine 3A; MMP-2: metalloproteinase-2.