Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes

Abstract

Cysteinyl leukotriene (cysLT) overproduction is a hallmark of aspirin-exacerbated respiratory disease (AERD), but its mechanism is poorly understood. Because adherent platelets can convert the leukocytederived precursor leukotriene (LT)A 4 to LTC 4 , the parent cysLT, through the terminal enzyme LTC 4 synthase, we investigated the contribution of platelet-dependent transcellular cysLT production in AERD. Nasal polyps from subjects with AERD contained many extravascular platelets that colocalized with leukocytes, and the percentages of circulating neutrophils, eosinophils, and monocytes with adherent platelets were markedly higher in the blood of subjects with AERD than in aspirintolerant controls. Platelet-adherent subsets of leukocytes had higher expression of several adhesion markers than did platelet nonadherent subsets. Adherent platelets contributed more than half of the total LTC 4 synthase activity of peripheral blood granulocytes, and they accounted for the higher level of LTC 4 generation by activated granulocytes from subjects with AERD compared with aspirintolerant controls. Urinary LTE 4 levels, a measure of systemic cysLT production, correlated strongly with percentages of circulating platelet-adherent granulocytes. Because platelet adherence to leukocytes allows for both firm adhesion to endothelial cells and augmented transcellular conversion of leukotrienes, a disturbance in plateletleukocyte interactions may be partly responsible for the respiratory tissue inflammation and the overproduction of cysLTs that characterize AERD. (Blood. 2012;119(16):3790-3798) IntroductionAspirin-exacerbated respiratory disease (AERD) is a distinctive syndrome characterized clinically by a triad of asthma, nasal polyposis, and aspirin sensitivity. It is a chronic inflammatory disease associated with eosinophilic infiltration of respiratory tissues, peripheral eosinophilia, and excessive production of cysteinyl leukotrienes (cysLTs), a class of inflammatory lipid mediators that are thought to contribute to several of the characteristic features of AERD. Individuals with this syndrome account for 4% to 11% of all adult patients with asthma, and for a disproportionate share (ϳ 30%) of patients with severe asthma. 1 The confirmatory diagnostic feature of AERD is an idiosyncratic respiratory reaction, including symptoms of acute bronchoconstriction, nasal congestion, and eye watering, on ingestion of aspirin or another nonselective cyclooxygenase (COX) inhibitor. Despite the strikingly consistent clinical phenotype of AERD, the pathogenesis of the disease remains unclear.CysLTs derive from the metabolism of arachidonic acid by effector cells of the innate immune system. In inflammatory leukocytes (neutrophils, monocytes, eosinophils, mast cells, and basophils), arachidonic acid is oxidized by 5-lipoxygenase (5-LO) to form the unstable intermediate leukotriene (LT)A 4 . 2 In neutrophils, LTA 4 is preferentially hydrolyzed by LTA 4 hydrolase to form LTB 4 , whereas in monocytes, mast cells, eosinophils, and basophils, it i...

Prostaglandin E2deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

“…Platelets lack 5-LO, but possess LTC 4 S and convert unmetabolized LTA 4 to LTC 4 when they adhere to the granulocyte surface via P-selectin (54). We previously demonstrated that platelet-adherent eosinophils and neutrophils are more frequent in the peripheral blood and sinonasal tissues from patients with AERD than in samples from aspirin-tolerant controls (9). Adherent platelets were the dominant source of LTC 4 S activity in granulocytes from subjects with AERD and they correlate with urinary LTE 4 levels (9).…”

“…These lesions limit basal EP receptor signaling that normally prevents the severe persistent respiratory mucosal eosinophilia. Impaired EP receptor input compromises control of TP receptor signaling by PKA (28), increasing the adherence of platelets to granulocytes, inducing endothelial ICAM-1 (28), activating 5-LO, and enabling platelet-adherent leukocytes to mediate LT generation (9). The residual local PGE 2 derives principally from COX-1, which may explain why only COX-1 active drugs provoke clinical reactions (6) and why COX-2-selective drugs are well tolerated by these patients (20).…”

“…Cysteinyl leukotrienes (cysLTs) (LTC 4 , LTD 4 , and LTE 4 ) drive these reactions, as well as some of the chronic features of AERD (7,8). CysLTs derive from arachidonic acid metabolized by 5-lipoxygenase (5-LO) to LTA 4 , conjugated to reduced glutathione by leukotriene C 4 synthase (LTC 4 S) to LTC 4 in mast cells (MCs), eosinophils, basophils, macrophages, and granulocyte-platelet complexes (9). After export, LTC 4 is converted sequentially to LTD 4 and LTE 4 .…”

Leukotriene E4elicits respiratory epithelial cell mucin release through the G-protein–coupled receptor, GPR99

“…cysteinyl leukotrienes | mast cells | mucosal immunology | lung | epithelial cell C ysteinyl leukotrienes (cysLTs), leukotriene C 4 (LTC 4 ), LTD 4 , and LTE 4 are lipid mediators detected during asthma exacerbations triggered by allergen (1), aspirin (2,3), and respiratory viruses (4). The cysLTs elicit vascular permeability, inflammation, and bronchoconstriction through three G-protein-coupled receptors.…”

Effects of Sugar, Salt and Distilled Water on White Blood Cells and Platelet Cells

“…Following is the series of causes of thrombocytosis, blood clotting in legs or arms, infection, diseases like anemia cancer etc [32][33][34] .…”