Regulation of AERD and eicosanoid homeostasis by TP receptors

The following is an abstract from “Trial of Thromboxane Receptor Inhibition with Ifetroban: TP Receptors Modulate Eicosanoid Homeostasis in Aspirin-Exacerbated Respiratory Disease,” published in the September 2023 issue of Allergy and Immunology Laidlaw et al.

Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, nasal polyposis, and respiratory responses to COX-1 inhibitors.This condition is associated with increased production of cysteinyl leukotrienes and decreased production of prostaglandin E₂ (prostaglandin E₂). Preclinical mouse models have implicated the thromboxane-prostaglandin (TP) receptor in AERD. In one study, researchers sought to investigate whether the TP receptor antagonist ifatroban could alleviate aspirin-induced respiratory symptoms in patients with AERD.

A total of 35 patients with AERD participated in a 4-week double-blind, placebo-controlled trial of ifatroban and received an oral aspirin challenge. The primary outcome measure was a change in aspirin challenge dose resulting in a 2-point increase in the total nasal symptom score. They also assessed changes in lung function, eicosanoid levels, and platelet and mast cell activation. Furthermore, human nasal fibroblasts were cultured and stimulated with or without the TP agonist U46619 to assess prostaglandin production.

Ifetroban was well tolerated by patients with AERD, but it did not significantly change the primary outcome measure, a 2-point increase in total nasal symptom score (P = .763).Interestingly, participants taking ifetroban experienced more severe aspirin-induced nasal symptoms and a greater decrease in FEV₁

Contrary to the initial hypothesis, TP receptor blockade exacerbated aspirin-induced responses in AERD patients, possibly by exacerbating dysregulation of the eicosanoid system.TP receptor signaling in stromal cells may play a key role in maintaining PGE₂

source: jacionline.org/article/S0091-6749(23)00457-8/fulltext