leukotrienes, prostanoids, and ..
The transcellular biosynthesis of eicosanoids can operate under physiological conditions as well as during pathological responses. For example, platelets that are marginalized and have direct contact with the vessel wall, either intact or partly damaged, become activated to synthesize endoperoxides (PGH2) that can be converted to antiadhesive vasoprotective agents, such as PGI2, by the neighboring endothelial cells during normal resolution. In pathological conditions, such as during an inflammatory event, marginating leukocytes must undergo the complex processes of diapedesis and tissue infiltration to fulfill their phagocytic duties. In cooperation with the endothelial cells via transcellular biosynthesis mechanisms, leukocytes may switch their production from LTB4 to cysteinyl leukotrienes, promoting the alteration of vascular permeability resulting in the formation of an edema. This represents a fundamental defense mechanism of the body that must become operative when and where needed, but if not properly controlled can clearly lead to tissue damage. Furthermore, transcellular biosynthesis of eicosanoids may represent a common mechanism to switch on (via enhanced production of prostaglandins and leukotrienes) and switch off (via the formation of lipoxins ) such complex events.
Prostaglandins and Leukotrienes: Advances in Eicosanoid ..
The body of evidence presented clearly supports the occurrence of transcellular biosynthesis in vivo, but additional information is needed in order to fully understand the complex picture of the transcellular biosynthetic pathway of eicosanoids. For instance, intermediates, such as LTA4 or PGH2, are extremely labile yet can undergo export from a donor cell, transport to and uptake by the acceptor cell, and finally enzymatic transformation. As the research highlighting the importance of adhesion between donor and acceptor cells pointed out [, ], it appears that the transcellular biosynthesis of eicosanoids is facilitated by physical contact between cells. However, there is also evidence that proteins may provide sufficient stabilization of the unstable intermediates to allow transport through the extracellular medium [, , , ]. Although little is known about membrane crossing or intra- and extracellular transport of intermediates, each step could indeed represent a target for therapeutic intervention. While the only pharmacological approaches of proven clinical efficacy are the inhibition of the primary oxidative enzymes (cyclooxygenase or lipoxygenase) or antagonism of the cysteine leukotriene receptor, each individual step controlling the final production of eicosanoids, including transcellular mechanisms, could have profound physiopathological implications and may represent a potential pharmacological target.
LT production is regulated at different levels (), including methylation of the 5LO promoter () and posttranslational control of 5LO activity through phosphorylation, interaction with FLAP (, ), and translocation induced by calcium or free AA (). Additionally, experimental evidence suggests that cells cooperate in the synthesis of LTB4 and LTC4. For example, human platelets, which express no 5LO, can interact with activated neutrophils, which do not express LTC4S, to generate LTC4 (). Many other instances of transcellular LT biosynthesis have been described (). The chemical half-life of LTA4 in buffer is less than 5 s (), which implies some protective mechanism of the epoxide ring during transfer from the donor cell to the acceptor cell.
Biosynthesis of the leukotrienes.
Transcellular biosynthesis makes it difficult to predict the profile of arachidonate products that will be formed in tissues and organs based on the knowledge of the potential contributions of individual cells. The expression of secondary enzymes in cells that do not possess the primary oxidative enzymes may significantly change the qualitative profile of the eicosanoids produced. While this observation has obvious pathophysiological implications, it is important to emphasize that it may also affect the pharmacological intervention. For example, the presence of infiltrating neutrophils in inflamed tissue might suggest that the use of LTB4 receptor antagonists could control phlogosis, however, if the activated leukocytes contributed LTA4 to acceptor cells (e.g., mast cells) for cysteinyl leukotriene synthesis, cys-LT1 or cys-LT2 receptor antagonists might be the correct therapeutic intervention.
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) …
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