Asthma & The Leukotriene Receptor

Asthma is a chronic inflammatory disease of the airways that is complicated by episodes of acute inflammation. For asthma , there are a limited number of treatments. Traditionally, asthma has been treated with oral and inhaled bronchodilators . These agents help the symptoms of asthma, but do nothing for the underlying inflammation. Recognition during the last 10 years of the importance of inflammation in the etiology of asthma has led to the increased use of corticosteroids, but many patients continue to suffer from uncontrolled asthma.

Even patients with mild disease show airways inflammation, including infiltration of the mucosa and epithelium with activated T cells, mast cells, and eosinophils. T cells and mast cells release cytokines that promote eosinophil growth and maturation and the production of IgE antibodies, and these, in turn, increase microvascular permeability, disrupt the epithelium, and stimulate neural reflexes and mucus- secreting glands. The result is airways hyperreactivity, bronchoconstriction, and hypersecretion, manifested by wheezing, coughing, and dyspnea.

Now the FDA has approved the first of a new class of antiasthma drugs -- the leukotriene inhibitors and antagonists -- with the potential to interfere with the initial steps in the inflammatory cascade.

Leukotrienes war reported back in 1979, when the so-called "slow reacting substance of anaphylaxis" was identified as an arachidonic acid derivative and given the name "leukotriene C." Since that time, scientists have determined that the leukotrienes (of which there are A, B, C, D, and E subtypes) play a crucial role in asthma.

Asthma is generally characterised by showing airways inflammation, including infiltration of the mucosa and epithelium with activated T cells, mast cells, and eosinophils. T cells and mast cells release cytokines that promote eosinophil growth and maturation and the production of IgE antibodies, and these, in turn, increase microvascular permeability, disrupt the epithelium, and stimulate neural reflexes and mucus- secreting glands. The result is airways hyperreactivity, bronchoconstriction, and hypersecretion, manifested by wheezing, coughing, and dyspnea. Besides that it also cause airways smooth muscle spasm , increased vascular permeability , edema , enhanced mucus production , reduced mucociliary transport and leukocyte chemotaxis.

SYNTHESIS OF LEUKOTRIENES

Like the related prostaglandins, leukotrienes are synthesized from arachidonic acid in the cell membrane. Arachidonic acid in mast cells, macrophages, monocytes, eosinophils, and basophils is released from membrane phospholipids by the activation of phospholipase A2. After its release, arachidonic acid undergoes metabolism via two major pathways: the cyclooxygenase pathway (which produces various prostaglandins and thromboxanes) and the 5-lipoxygenase pathway (which produces leukotrienes). The prostaglandins, thromboxanes, and leukotrienes are known collectively as eicosanoids.

There are a number of anti-leukotrienes under investigation that either block leukotriene receptors or prevent leukotriene synthesis by blocking the enzyme 5-lipoxygenase (just as aspirin and the nonsteroidal anti-inflammatory agents block the other enzyme -- cyclooxygenase -- involved in arachidonic acid metabolism).

The leukotriene inhibitors are a varied lot: some block 5-lipoxygenase directly, some inhibit the protein that "presents" arachidonate to 5- lipoxygenase, and some displace arachidonate from its binding site on the protein.

The leukotriene antagonists, by contrast, block the receptors themselves that mediate airways hyperreactivity, bronchoconstriction, and hypersecretion.

Thus both inhibit bronchoconstrictor and inflammatory responses to allergen and other triggers of asthma.