**5.2 Kupffer cells**

60 Liver Transplantation – Basic Issues

activation of K+ channels leads to cellular hyperpolarization and relaxation. Finally, stimulation of cGMP-dependent protein kinase activates of myosin light chain phosphatase leading to dephosphorylation of myosin light chains resulting in smooth muscle relaxation. NOSs are related but encoded by distinct genes. Classically, the ability of NO to elicit vasorelaxation is due to its ability to increase intracellular levels of cyclic guanosine monophosphate (cGMP) through the activation of soluble guanylate cyclase (sGC). cGMP– dependent protein kinases in turn decrease the sensitivity of myosin to calcium-induced contraction and lower intracellular calcium by activation of calcium-sensitive potassium channels and inhibits the release of calcium from the sacroplasmic reticulum. Mechanisms

Fig. 2. Multifaceted mechanism are involved in the causation of hepatic ischemia-reperfusion injury (IRI). Kupffer and endothelial cells produce cytokines and chemokines, recruiting neutrophils that further accentuate injury. EC, endothelial cell. NO (nitric oxide) is decreased as a result of IRI allowing for decreased perfusion and exaggerated injury (Massip-Salcedo,

Roselló-Catafau, Prieto, Avíla, & Peralta, 2007). KC, Kuppfer cell. ATP, adenosine triphosphate. TNF, tumor necrosis factor. IL, interleukin. ICAM, intercellular adhesion molecule. PAF, platelet activation factor. LTB4, leukotrien B4. GMS-CSF, granulocyte macrophage colony stimulating factor. INF, interferon. ROS, reactive oxygen species. (Slighty modified with permission of Dr. Joan Rosello-Catafau, Barcelona, Spain)

of smooth muscle relaxation are shown on Figure 1.

**4. Brief review of the pathophysiology of IRI** 

Kupffer cells are crucial in liver injury orchestration. Metabolic alterations of these cells occur during no-flow ischemia leading to the formation of reactive oxygen species during early reperfusion (Jaeschke, Bautista, Spolarics, & Spitzer, 1991). Additionally, at the onset of reperfusion Kupffer cells undergo further activation by toll-like receptor 4 signaling and/or by complement. Subsequently, Kupffer cells release pro-inflammatory cytokines such as TNF-α and Interleukin-1 which themselves can perpetuate inflammatory injury by leukocyte activation.

While major participants in the promotion of injury, during cold ischemia they undergo intracellular energetic bioenergetic perturbations that reduce ATP stores due to mitochondrial dysfunction and predispose these cells to injury during reperfusion (Kamiike et al., 1988).

#### **5.3 Leukocytes and lymphocytes**

As a result of IRI, cellular adhesion molecules (ie, intracellular adhesion molecule-1 or ICAM-1, vascular adhesion molecule-1 or VCAM-1), selectins and integrins are activated and upregulated on the surface of endothelial cells, neutrophils and platelets. The activated neutrophils adhere to endothelial cells at the initial stages of reperfusion, and subsequently transmigrate the endothelium where they continue to orchestrate tissue injury. The accumulation of activated neutrophils contributes to microcirculatory disturbances both locally and remotely. Activated neutrophils release reactive oxygen species, specifically superoxide radical (O2- •), proteases and various cytokines (Teoh & Farrell, 2003). Monocytes and macrophages are also activated shortly following reperfusion (Ysebaert et al., 2000). Recent studies propose an important role for lymphocytes, especially CD4+ T cells, in augmenting injury responses after IRI. However, lymphocytes may also play a protective role, but this is probably dependent on cell type and time course of injury (Ysebaert et al., 2000).
