The leukotriene E4 puzzle: Finding the missing pieces and revealing the pathobiologic implications

The intracellular parent of the cysteinyl leukotrienes (cysLTs), leukotriene (LT) C4, is formed by conjugation of LTA4 and reduced glutathione by LTC4 synthase in mast cells, eosinophils, basophils, and macrophages. After extracellular export, LTC4 is converted to LTD4 and LTE4 through sequential enzymatic removal of glutamic acid and then glycine. Only LTE4 is sufficiently stable to be prominent in biologic fluids, such as urine or bronchoalveolar lavage fluid, of asthmatic individuals and at sites of inflammation in animal models. LTE4 has received little attention because it binds poorly to the classical type 1 and 2 cysLT receptors and is much less active on normal airways than LTC4 or LTD4. However, early studies indicated that LTE4 caused skin swelling in human subjects as potently as LTC4 and LTD4, that airways of asthmatic subjects (particularly those that were aspirin sensitive) were selectively hyperresponsive to LTE4, and that a potential distinct LTE4 receptor was present in guinea pig trachea. Recent studies have begun to uncover receptors selective for LTE4: P2Y12, an adenosine diphosphate receptor, and CysLTER, which was observed functionally in the skin of mice lacking the type 1 and 2 cysLT receptors. These findings prompt a renewed focus on LTE4 receptors as therapeutic targets that are not currently addressed by available receptor antagonists.