Abstract
The leukotrienes (LTs) are metabolic products of arachidonic acid via the 5-lipoxygenase (5-LO) pathway. The biological activities of LTs suggest that they are mediators of acute inflammatory and immediate hypersensitivity responses. In particular, the 5-LO activation has been proposed to be an important regulator for pathogenesis in multicellular organisms. The role of LTs in tissue damage, associated with septic and nonseptic shock and ischemia-reperfusion, has been extensively studied by the use of 5-LO inhibitors, receptor antagonists, and mice with a targeted disruption of the 5-LO gene (5-LOKO). In particular, several data indicate that LTs regulate neutrophil trafficking in damaged tissue in shock and ischemia-reperfusion, mainly through the modulation of adhesion molecule expression. This concept may provide new insights into the interpretation of the protective effect of 5-LO inhibition, which may be useful in the therapy of pathological conditions associated with septic and nonseptic shock and ischemia-reperfusion injury.
Highlights
Intestinal IschemiaIntestinal ischemia is generally the result of arterial occlusion by thrombi or emboli and, more frequently, by nonocclusive processes, such as in situations of low mesenteric flow, which occurs in cardiac insufficiency, sepsis, and administration of alpha-adrenergic agents or digitalics[130,131]
5-Lipoxygenase (5-LO), whose activity was first described in 1976 by Borgeat et al.[1], is the key enzyme in leukotriene (LT) biosynthesis from arachidonic acid (AA)
The enzyme contains, in the active site, a nonheme iron that is essential for its enzymatic activity[5].Post-translational modifications, i.e., phosphorylation by p38 kinase–dependent mitogen-activated protein kinase (MAPK)[6], phosphorylation on Ser 663 by extracellular signal-regulated kinase (ERK)[7], and the subsequent translocation to the nuclear envelope are fundamental for the activity of the enzyme[8]
Summary
Intestinal ischemia is generally the result of arterial occlusion by thrombi or emboli and, more frequently, by nonocclusive processes, such as in situations of low mesenteric flow, which occurs in cardiac insufficiency, sepsis, and administration of alpha-adrenergic agents or digitalics[130,131]. The absence of an increased expression of the adhesion molecules, in the intestine as well as in the lung tissue of SAO-shocked 5-LOKO mice, was associated with the reduction of leukocyte infiltration, as assessed by the specific granulocyte enzyme MPO, and with the attenuation of tissue damage as evaluated by histological examination. It is noteworthy, that tissue MPO activity was not completely abolished. As previously underlined, the concept that 5-LO regulates neutrophil trafficking through up-regulation of adhesion molecules may provide new insights into the interpretation of reports that demonstrate the protective effect of 5-LO inhibition in experimental models of I/R injury and inflammation
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