Leukotrienes and Asthma

It has long been known that leukotrienes play an important role in the inflammatory effects of asthma. Evidence for their effects have come from studies of inhaled LT4. Inhaled aerosol of LTC4 and LTF4 from a nebulizer in concentrations as low as 10micron have shown to decrease maximal expiratory airflow by as much as 30%. The bronchoconstrictor effects of leukotrienes are as much as 1000 fold more potent than that of histamine. Elevated LTC4, LTD4, and LTE4 have been identified in serum and urine of asthma patients. These findings have led to many experiments over the last 3 decades for antileukotriene therapy. Leukotrienes are synthesized from arachidonic acid by the 5-lipoxygenase pathway. CysLT1 is a leukotriene receptor on the surface of structural and inflammatory cells that mediates bronchoconstriction, mucus secretion, and edema in the airways. CysLT1 receptors are influenced at the transcriptional level by TH2 helper cell cytokines. Select drug antagonists for this receptor block the pro-inflammatory effects. Researchers have been developing drugs aimed at blocking synthesis of chronic levels of leukotrienes and their binding to receptors. The drug Zileuton was developed to inhibit 5-lipoxygenase pathway of leukotriene synthesis. This drug is a powerful blocker of leukotrienes, but it appears that it also causes hepatic toxicity. Two other drugs, Montelukast and Zafirlkukast, were developed and are used as CysLT1 antagonists. All of these drugs have been shown to increase pulmonary function. Montelukast has also been shown to be quite effective in treating exercise induced asthma. The discovery of leukotrienes and their role in bronchoconstriction have uncovered many possible avenues of treatment. Further investigation into the synthesis, receptor binding and effects of leukotrienes in the future may provide even more detailed and focused treatment of asthma that may be tailored to the individual patient.

http://universityofarizona.worldcat.org.ezproxy1.library.arizona.edu/title/leukotrienes

Boron W., Boulpaep E., Medical Physiology: A Cellular and Molecular Approach. 2nd ed., Elsevier 2009.