Leukotrienes, lipids primarily produced by white blood cells, play important roles in the immune response. An integral part of the immune response, they recruit and activate many types of white blood cells to defend the body against foreign invaders. Scientists know that a malfunction in leukotrienes contributes to asthma and suspect that leukotrienes have a role in other diseases too.
Production
Through a series of chemical reactions catalyzed by various enzymes, white blood cells called leukocytes generate leukotrienes from arachidonic acid. Some other types of cells can take intermediate products in the leukotriene pathway and convert them into biologically active leukotrienes as well.
Types
Leukotriene types, identified with letters A through E, differ in their chemical structure and actions. Leukotriene A does not act on tissues but is the precursor for all other leukotrienes. Leukotriene B powerfully attracts and activates immune cells called cytokines. Leukotrienes C, D and E are classified as cysteinyl leukotrienes. According to Dr. Marc Peters-Golden and Dr. William Henderson Jr. in their November 2007 paper in "The New England Journal of Medicine," of all the leukotrienes, leukotriene D has the strongest effect in terms of constricting air passages and causing asthma.
Mechanism
Leukotrienes bind to specialized receptors in the cell membrane, triggering a cascade of events that affect activities ranging from cell movement to regulating the read-out of genes. The cysteinyl leukotrienes can bind to CysLT1 or CysLT2 receptors. CysLT1 receptors have important roles in controlling the airways, while CysLT2 receptors act in the inflammatory response and regulate the passage of substances in and out of blood. Leukotriene B binds strongly to BLT1 receptors to prompt most of leukotriene B's effect on cytokines. It is not clear what BLT2 receptors do.
Effects
Cysteinyl leukotrienes cause contraction of smooth muscle in the airways, constricting them. Leukotriene B attracts neutrophils, white blood cells that engulf bacteria and other foreign particles. Both types of leukotrienes cause leukocytes to leave the bloodstream and enter tissues, and both types play important roles in causing allergic reactions.
Role in Disease
According to Drs. Peters-Golden and Henderson, leukotrienes definitely contribute to asthma, and possibly contribute to allergies, fibrotic disease, atherosclerosis, some types of cancer, and inflammatory diseases including arthritis, psoriasis and lupus. Cancer cells have high levels of the enzymes to make leukotrienes that could increase their proliferation and survival. Drs. Peter-Golden and Henderson cite evidence that over-expression of leukotrienes correlates with rates of stroke and heart attack in some populations, and the Merck Manual says that leukotrienes constrict blood vessels, contributing to coronary spasms.
Medications
According to Drs. Peters-Golden and Henderson, the Food and Drug Administration has approved three drugs that interfere with leukotrienes to treat asthma. Montelukast and zafirlukast antagonize CysLT1 receptors to block the action of cysteinyl leukotrienes, and zileuton inhibits the enzyme that produces cysteinyl leukotrienes and leukotriene B.
References
- "New England Journal of Medicine"; Leukotrienes; Marc Peters-Golden and William Henderson, Jr.; November 2007
- Merck Manual: Coronary Artery Diseases
