Table 1 summarizes some aspects of the involvement of leukotrienes in human physiology, particularly in inflammatory settings. As shown in Figure 1, the 5-lipoxygenase pathway can lead to the synthesis of either LTB4 through the LTA4 hydrolase or to the cys LTs (LTC4, LTD4, and LTE4) through the LCT4 synthase. The top portion of Table 1 shows the cell types in which one or the other LTA4 metabolizing enzyme predominates to produce one of the two types of leukotrienes. The middle portion of Table 1 lists major target cells of the two leukotriene types, along with an example or two of the response of the target cells to either LTB4 or a cys-LT. The bottom portion of Table 8-3 lists some human diseases associated with each type of LT, a few of which are discussed in the following. For other diseases, such as chronic pulmonary obstructive disease (COPD), pulmonary fibrosis, and irritable bowel disease, circumstantial evidence has implicated leukotrienes in the disease process but a clear dominant role has not yet been established.

Fig1. Leukotriene biosynthesis. The pathway from arachidonic acid through 5-lipoxygenase (5-LO) is shown. 5-LO requires a membrane protein, FLAP (5-lipoxygenase activating protein) for the two reactions it catalyzes to form leukotriene A4 (LTA4), which is converted to leukotriene B4 (LTB4) through the removal of a water molecule by LTA4 hydrolase. LTC4 arises from the addition of glutathione to carbon-6 by LTC4 synthase. The sequential removal of glutamate and glycine leads to the active leukotrienes D4 and E4. These three LTs are referred to as the cysteinal leukotrienes or cys-LTs.

Table1. Leukotrienes: Biological Actions and Human Disease

1. Asthma and Other Upper Respiratory Conditions

Asthma is a complex disease resulting in part from narrowing of the airways. For decades the agent that causes the bronchoconstriction of asthma was known as the slow-reacting substance of anaphylaxis (SRS-A), but was not structurally characterized until the early 1980s. The identification of SRS-A as a mixture of leukotrienes led to the elucidation of the 5-LO pathway and, in particular, the role of the products of LTC4 synthase, the cysteinyl leukotrienes (cys-LTs), in the pathogenesis of bronchial asthma. Linking the cys-LTs to asthma were the observations that, as bronchoconstrictors, they are more potent than histamine on a molar basis by three orders of magnitude. In the 1990s, the efficacy of the 5-LO inhibitor zileurton in human asthma was demonstrated and effective anti-asthma drugs became available.

In addition to asthma, reactions such as immediate hypersensitivity to allergens and hyperactivity in response to cold and exercise are mediated by leukotrienes. For example, cys-LTs are elevated in allergen-challenged subjects and the 5-LO inhibitor zileuton decreases these responses.

2. Atherosclerosis

Atherosclerosis is a chronic inflammatory vascular disease. There is much evidence supporting a role for the 5-lipoxygenase and, in particular, LTB4 in the development of human atherosclerosis. Blocking the pathway with a BLT1 antagonist protected against atherosclerosis in a mouse model. Also in mice, genetic removal of 5-LO pathway decreases the size of atherosclerotic plaques and specific inhibition of 5-LO reduces monocyte adhesion and infiltration. In humans atherosclerotic plaque levels of 5-LO correlate positively with disease stage. Genetic polymorphism studies in humans suggest that individuals with some variants of 5-LO show a greater risk of myocardial infarction and stroke. Clinical trials of inhibitors of the 5-lipoxygenase patthway are underway in patients with cardiovascular disease.

3. Arthritis

There is considerable evidence from various mouse models that LTB4, working through both the BLT1 and BLT2 receptor plays a critical role in autoantibody- or collagen-induced arthritis pathology. Interventions such as blockage of the BLT1 receptor with antagonists, deletion of the gene for the 5-LO activating protein (ALOX5AP), or deletion of the genes for BLT1 and/or BLT2 demonstrate that interference with the pathway for LTB4 production and action leads to diminished arthritic inflammation, cell infiltration, and loss of bone and cartilage resulting from the disease. Synovial fluid from patients with rheumatoid arthritis has LTB4 and studies with human cells from arthritic sites confirm that the LTB4 pathway operates and has effects on the arthritic process in humans.

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