Variant LTC4 synthase allele modifies cysteinyl leukotriene synthesis in eosinophils and predicts clinical response to zafirlukast

Clinical trials with leukotriene synthesis inhibitors and cysteinyl leukotriene (cys-LT) receptor antagonists have shown that cys-LTs (LTC4, LTD4, and LTE4) are the predominant mediators of bronchoconstriction in response to diverse asthma triggers including allergen, PAF, sulphur dioxide, and non-steroidal anti-inflammatory drugs (NSAIDs).1 In addition, inhalation of a single dose of a cys-LT causes persistent eosinophilia in the bronchial mucosa and sputum of asthmatic patients,2 3 and LT modifier drugs significantly reduce airway and blood eosinophilia in clinical asthma.4 We have shown that, in the asthmatic airway, eosinophils represent the majority of cells that express the terminal enzyme in the cys-LT pathway, LTC4 synthase, and hence have the capacity to generate cys-LT upon stimulation.5 6 Inflammation and bronchoconstriction in the asthmatic airway may be sustained by a vicious cycle of cys-LT synthesis and eosinophil recruitment (fig 1). Anomalies in the genetic and cytokine factors that regulate cys-LT pathway enzymes in eosinophils may thus be central to the pathophysiology of asthma. Figure 1 Schematic diagram illustrating that genetic and cytokine factors modulate the vicious cycle of cysteinyl leukotriene synthesis and eosinophil recruitment in the asthmatic airway. Cys-LTs are synthesised from membrane derived arachidonic acid. During stimulus-specific cell activation, arachidonic acid released by phospholipases including cytosolic phospholipase A2(PLA2)is translocated to the 5-lipoxygenase activating protein (FLAP) and converted in two steps to leukotriene (LT)A4 by 5-lipoxygenase (5- LO). LTA4 is converted to LTB4 by cells expressing LTA4hydrolase, and/or to LTC4 by cells expressing LTC4 synthase, which conjugates LTA4 to reduced glutathione. After carrier mediated cellular export of LTC4, the sequential cleavage of glutamate and glycine residues provides the extracellular receptor active metabolites LTD4 and LTE4, respectively. Cys-LTs act at specific …