Chapter 3 in chemotaxis of leukocytes and increased adhesion of leukocytes to the endothelium and increase in the permeability of the postcapillary venules. Free radical chemistry is also initiated during ischemia. The activated leukocytes release ROS in addition to more inflammatory mediators that in turn recruit more leukocytes and cause further tissue damage. In the affected tissue, mitochondrial scavengers of O2‐ are depleted, and xanthine dehydrogenase is converted to xanthine oxidase. This leads to formation of ROS in the mitochondria when oxygen is reintroduced at reperfusion. The complement system is a well‐described component of IR injury. The complement system is part of the innate immune system, and its activation during IR injury leads to activation of C3 and C5. Complement C3a and C5a attract and activate leucocytes, while others promote leucocyte‐endothelium interaction by stimulation of the adhesion molecules. Complement activation induces mast cell degranulation and release of histamine and other proinflammatory mediators. The formation of complement membrane attack complexes damages cells’ membranes, leading to tissue necrosis. Therefore, complement inhibition or depletion reduces IR injury in experimental studies.19‐22 Primary ischemia causes a series of molecular and structural changes, especially at the level of the endothelial cells, ultimately leading to (1) narrowed capillary diameters caused by endothelial swelling, vasoconstriction, and interstitial edema; (2) sequestration and activation of leucocytes; (3)endothelial dysfunction caused by failure to synthesize vasodilators and degrade vasoconstrictors; (4) cell‐transport‐impaired function with intra‐ and extracellular accumulation of toxins; and (5) production of proinflammatory mediators.23‐26 Ischemia is thus damaging in itself and, if sustained long enough, leads to tissue necrosis. Ischemia therefore, causes a tissue state that is prone to further destruction once reperfusion occurs.27‐29 Reperfusion Leucocyte‐endothelial interaction The main event at the start of reperfusion is the massive influx of neutrophils by chemotactic agents produced during the ischemia period. After reperfusion, the central parts of the flap are hyperemic, whereas the distal flap perfusion is gradually increased.15,30 Within a (free) flap, the distal part of the flap is thus exposed to prolonged ischemia, termed secondary ischemia, and is more severely affected by IR injury. The recruitment, extravasation, and activation of neutrophils lead to a burst of ROS species, adding to further oxidative damage to marginal parts of the flap.31 In the first step, the leucocytes bind loosely to endothelium through the coupling of surface adhesion molecules. The most important binding molecules on the endothelium are the 42
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