**5.5 Cytokines**

Cytokines play a vital role in IRI, both by inducing and sustaining the inflammatory response, and by modulating IRI severity. Tumor necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1) are the two cytokines most commonly implicated in liver IRI. TNF-α is a pleiotropic cytokine generated by various different cell types in response to inflammatory and immunomodulatory stimuli. TNF-α modulates leukocyte chemotaxis and activation, and induces ROS production in Kupffer cells (Colletti et al., 1996). Additionally, IL-1 is known to promote production of ROS, induce TNF-α synthesis by Kupffer cells and induce neutrophil recruitment (Kato, Gabay, Okaya, & Lentsch, 2002).

#### **5.6 Complement**

The complement system also contributes significantly to IRI and is composed of approximately thirty soluble and membrane-bound proteins. This system can be stimulated in three pathways: (1) the antibody-dependent classical pathway, (2) the alternative pathway, or (3) the mannose-binding lectin pathway (Qin & Gao, 2006). When activated, complement acts as a membrane-attacking complex that stimulates the production of proinflammatory cytokines and chemotactic agents. Furthermore, it can regulate adaptive immunity (Boros & Bromberg, 2006).
