The Role of Leukotrienes in Respiratory Tract and Asthma

Polyunsaturated fatty acids play a role as precursors of biolo­gically active compounds that can act as mediators or modulators  of various cell functions. Thus three main groups of derivatives­ the prostaglandins, the thromboxanes, and recently discovered  leukotrienes are formed by oxygenation and further transformation of various polyunsaturated fatty acids of which arachidonic acid  plays the most significant role. In man the predominant prostag­ landin precursor is arachidonic acid,released from membrane  phospholipids by one or more lipases. Arachidonic acid then be­ comes substrate for two enzymes: cyclooxygenase, Which transforms arachidonic acid into prostaglandins and thromboxanes, and lipoxy_ genase which is involved in the formation of the leukotrienes.  The enzyme cyclooxygenase in ubiquitous in mammalian tissues and  is a microsomal enzyme that in the presence of oxygen, attacks the  arachidonic acid, whereas 5-or 12-lipoxygenases have been indenti­fied only in platelets, lungs, white cells and epicardium. The soluble enzyme lipoxygenase introduces a hydroperoxide group into arachidonic acid, resulting in the formation of hydroperoxyeicosatetraenoate  (HPETE). This product can either be dicomposed to the hydroxyeicos­ atetraenoic acid(HETE) or to the unstable intermediate oxidoeicosa­tetraenoate, called leukotriene A4(LTA4). Hydrolysis of LTA4 leads  to the formation of leukotriene B4(LTB4). Alternatively, LTA4 can be conjugated with glutathione to yieled the formation of leuko­triene C4(LTC4). Successive decomposition of the amino acids leads to the metabolic products leukotriene D4(LTD4) and leukotriene E4(LTE4). Further steps in the metabolism of leukotrienes are as yet unknown. The prefix leuko in leukotrienes results from the fact that these compounds were originally isolated from leukocytes, and suffix triene indicates that the compounds all contain a triene structure. The capital letters A-E repre$ent the chronological division of  the discovered structures. Slow reacting substance of anaphylaxis  (SRS-A) is released by various stimuli, including immunological  challenge, and has long been considered as mediator of immediate hypersensitivity reactions,such as bronchoconstriction in  allergic asthma. The chemical composition of this mediator was recently determined and shwon to be a mixture of 5-lipoxygenase  derived products, namely leukotrienes. Leukotriene C4(LTC4) and  its two immediate metabolites, leukotriene D4 and E4 have been  identified the major active constituents of SRS-A. These three leukotrienes are outstanding bronchoconstrictors and potent  inducers of tissue edema-Perturbations that indeed play a major role in the pathophysiology of bronchial asthma. The purpose of this review is to present information which can help.