Aspirin sensitivity and severity of asthma: Evidence for irreversible airway obstruction in patients with severe or difficult-to-treat asthma

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

“…Short-term TP receptor blockade had no effect on histologic indices of inflammation, whereas tpr deletion markedly impaired the development of these features as in our previous study (28). Discussion AERD accounts disproportionately for severe asthma and chronic rhinosinusitis (3,4). Although the mechanisms responsible for the disease have been evasive (6), the pathognomonic reactions to COX-1-active drugs can be attenuated by inhibitors of 5-LO and CysLT 1 R (39) and by drugs that block MC activation (30,31).…”

“…The differences between that study and ours may relate to different allergens (Df vs. ovalbumin) and routes of sensitization (intranasal vs. intraperitoneal).The modest response of ptger2 −/− mice to Lys-ASA (Fig. S2D) likely reflects their capacity to maintain PGE 2 production and compensatory signaling through EP 3 and EP 4 receptors during aspirin challenge ( Fig. 2A).…”

“…2A). The EP 3 and EP 4 agonists also modestly reduced the change in R L induced by Lys-ASA ( Fig. 2A).…”

“…Thus, EP 2 receptor defects identified in AERD (46,47) may potentiate granulocyte infiltration of the airways, but may not be sufficient to cause a full "aspirin sensitive" phenotype, which depends on deficiency of inducible PGE 2 . Compensatory functions of EP 3 and EP 4 may account for the fact that inhaled PGE 2 prevents reactions to aspirin in subjects with AERD (29), even if EP 2 receptor protein on the target cells is reduced.…”

“…Lysine aspirin (Lys-ASA)-challenged PGE 2 synthase-1 null mice exhibit sustained increases in airway resistance, along with lung mast cell (MC) activation and cysLT overproduction. A stable PGE 2 analog and a selective E prostanoid (EP) 2 receptor agonist blocked the responses to Lys-ASA by ∼90%; EP 3 and EP 4 agonists were also active. The increases in airway resistance and MC products were blocked by antagonists of the type 1 cysLT receptor or 5-lipoxygenase, implying that bronchoconstriction and MC activation were both cysLT dependent.…”