LTC4LTD4LTE4

LTC4, LTD4 and LTE4 are a closely related group of lipid mediators collectively known as cysteinyl leukotrienes (CysLTs). They are derived from arachidonic acid through the 5-lipoxygenase pathway in leukocytes and other cells of the immune system. The synthesis begins with the formation of the unstable epoxide LTA4, which is converted to LTC4 by the enzyme LTC4 synthase through the conjugation of glutathione. LTC4 is then released and rapidly and sequentially converted to LTD4 and LTE4 by extracellular peptidases, yielding increasingly stable molecules. LTE4 is the most stable of the trio and is commonly measured in urine as a systemic marker of CysLT production.

As signaling mediators, CysLTs act on two G-protein coupled receptors, CysLT1 and CysLT2. LTD4 has the highest affinity for CysLT1, which mediates many of the physiologic and pathophysiologic effects. Activation of these receptors leads to bronchoconstriction, increased vascular permeability, mucus secretion, and recruitment of eosinophils, contributing to airway inflammation and hyperresponsiveness.

Clinical relevance: CysLTs play a significant role in asthma and allergic rhinitis and are particularly elevated in aspirin-exacerbated respiratory disease. Therapeutic strategies include CysLT1 receptor antagonists such as montelukast, zafirlukast, and pranlukast, which blunt receptor signaling, and 5-lipoxygenase inhibitors such as zileuton, which reduce the synthesis of all leukotrienes.

Measurement and biomarkers: urinary LTE4 is commonly used as a noninvasive biomarker of systemic CysLT production; plasma LTC4 and LTD4 can be measured but are less stable and more technically challenging.