Chapter 3 caspase inhibitor showed increased survival of fasciocutaneous flap, demonstrating its role in IR injury.39 Neutrophil effects At reperfusion, leucocytes, mainly neutrophil granulocytes and macrophages, are attracted and activated as described above. The formation of ROS in neutrophils in IR injury is referred to as the respiratory burst.1 Activated leucocytes produce O2‐ from oxygen by the enzyme NADPH oxidase. O2‐ formed is subsequently converted to other free radicals (e.g., hydroxyl radical OH, hypochlorous acid HOCL, and H2O2). It can also react with NO to produce peroxynitrate (ONOO‐). Peroxynitrate reacts with hydrogen ion (H+, abundant because of acidity) to form peroxynitrous acid. This in turn dissociates in NO2 and the highly reactive OH.41 Selective depletion of neutrophils or immune suppression has been shown to reduce IR injury; however, it’s clinical application is not possible or practical.42‐44 Antioxidants Antioxidants possess the capacity to neutralize ROS and thereby reduce IR injury. Some antioxidants occur endogenously in the body, such as GSH and SOD. Exogenous antioxidants are provided through diet (e.g. vitamins C and E, fatty acids, carotenoids). Increased ROS and/or decreased antioxidant defense can be defined as oxidative stress. During IR injury, ROS evolve in a short period, and the endogenous antioxidant mechanisms are flooded. In IR injury patients, there is a decline in antioxidant level, and patients may benefit from antioxidant therapy. Animal studies have shown that administration of various antioxidants (e.g. vitamins C and E, SOD, GSH) improves the survival of skin flaps.45‐47 The mechanism of injury does not seem to be species specific, and application of antioxidant therapy may be beneficial in humans too. Microcirculation: Endothelial dysfunction and NO The molecular and cellular changes during IR injury result in microcirculatory insufficiency, which is demonstrated by microcirculatory models using intravital microscopy. Structural changes with endothelial dysfunction because of IR injury lead to microvessel narrowing, increased perfusion pressures, decreased vasodilatator release, leakage of capillaries and interstitial edema, and in consequence microcirculatory insufficiency. Because of microcirculatory stasis and increased inflammatory mediators, platelets are also attracted and activated in a comparable fashion as the leucocytes, and thrombosis follows. Reperfusion injury may lead to the no‐reflow phenomenon, which is well documented in the plastic and reconstructive surgery literature. In 1978, May et al. first described this phenomenon and described it as progressive vascular damage during reperfusion and an expanding zone of poor blood flow.48 44
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