Lipoxygenase Products

Human mast cells generate 5-lipoxygenase products of arachidonic acid, starting with an unstable intermediate, 5-HPETE (which may be reduced to the monohydroxy fatty acid), 5-HETE, or (through leukotriene synthetase) LTC 4 by addition of glutathione through the action of LTC 4 synthase. The initial product of this pathway is LTC4, from which LTD4 may be generated by the removal of the terminal glutamine, and LTE4 by the further removal of glycine. A polymorphism in the LTC4 synthase gene is thought to alter the amount of this mediator generated during biologic reactions ( 39). The biologic activity of the sulfidopeptide leukotrienes occurs by its binding to two specific receptors termed Cys LTR I and II (40,4.1.). Degradation is rapid and is accomplished by various oxygen metabolites. Clinically useful inhibitors of 5-lipoxygenase or the Cys LTR I receptors are available and demonstrate efficacy in clinical asthma ( 42). No clinically available inhibitor of Cys LTR II has been assessed in vivo, and the contribution of this receptor to the physiologic manifestations of LTC 4, LTD4, or LTE4 remains speculative.

Leukotrienes are potent and possess a broad spectrum of biologic activity (43). They induce wheal-and-flare responses that are long lived and are accompanied histologically by endothelial activation and dermal edema. In the airway, they enhance mucus production and cause bronchoconstriction, especially by affecting peripheral units. In humans, LTD4 is most active, LTC4 is intermediate, and LTE4 is the least potent. LTE4 has been implicated as an inducer of nonspecific bronchial hyperreactivity. It has been suggested that LTD4 augments airway remodeling (44), possibly by stimulating matrix metalloproteinase release or activity. All depress cardiac muscle performance and diminish coronary flow rates. LTC4 and LTD4 have been recovered from nasal washings and bronchial lavage fluids of patients with allergic rhinitis or asthma, whereas LTE4 has been recovered from the urine.

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