Role of NO in IR‐injury in surgical flaps E‐selectin and the L‐selectin on the leucocyte. The released chemoattractants such as leucotrienes, platelet activating factor, and complement C5a facilitate the next step, which is called firm adhesion. The increased permeability because of inflammatory mediators facilitates the next step where the leucocytes transmigrate into the interstitium using diapedesis.32 Once in the interstitium, the leucocytes are activated. The control of neutrophil adhesion may also be a possible therapeutic target as demonstrated by Kusterer et al.33 ROS and antioxidants During reperfusion, oxygen takes on a malicious role when it is used to form free radicals. ROS include oxygen ions, free radicals, and peroxides and are one of the main causes of further tissue damage after reperfusion. ROS are highly unstable oxygen molecules that are capable of oxidizing many biological molecules such as proteins, lipids, and DNA.34 ROS are mainly derived from two different processes: ROS is produced in the endothelial cells and mitochondria of the involved tissue by the xanthine oxydase system (XOS). The second process is the NADPH oxidative system in neutrophils. Tissue effects During ischemia, xanthine dehydrogenase is converted to xanthine oxidase as discussed previously. Xanthine oxidase is unable to utilize NADP+ as an electron acceptor and uses oxygen, which is reintroduced with reperfusion. This leads to formation of the highly reactive free radical O2‐.35 Mitochondria dysfunction adds to the cascade in IR injury. These organelles are sometimes described as “cellular power plants” because they generate most of the cell’s supply of ATP, used as a primary source of chemical energy.36 Under normal conditions, mitochondria reduce oxygen to water through the electron transport chain. Small amounts of O2‐ formed are scavenged by glutathione (GSH) and superoxide dismutase (SOD). Mitochondria contain outer and inner membranes. The inner membrane contains electron complexes and especially complex 1 (NAGH dehydrogenase) and 3 C0QH2‐c reductase, which are sensitive to ischemic injury. During ischemia, the electron chain of the mitochondria is thus damaged, and at the same time, free radical scavengers such as SOD and GSH are depleted. The result is that during reperfusion, leakage of electrons occurs, which reacts with oxygen, resulting to ROS and the respiratory burst.37 ROS itself also causes further damage to DNA and mitochondria, which are both also powerful inducers of apoptosis.38,39 Wang et al. reported that mitochondria‐dysfunction IR injury results in cytochrome c release into the cytosolic compartment where it activates cell apoptoses.40 IR injury is thus mediated by inflammation leading not only to cell necrosis but also to apoptosis in the affected tissue. Inhibition of apoptosis by a 43
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