Revisiting the usefulness of thromboxane-A₂modulation in the treatment of bronchoconstriction in asthma

Abstract

Airway smooth muscle (ASM) is the effector cell in the bronchoconstrictory pathway. It is believed that the bronchoconstriction present in asthma is associated with changes in the airway milieu that affect ASM excitation-contraction coupling and Ca(2+)-handling. Asthmatics also react differently to ventilatory mechanical strain. Deep inspiration (DI), which produces bronchodilation in healthy individuals, is less effective in asthmatics, and even enhances bronchoconstriction in moderate to severely affected patients. Our laboratory has previously studied the mechanotransductory pathway of airway stretch-activated contractions (Rstretch) leading to DI-induced bronchoconstriction. We demonstrated the ability of agonists acting through thromboxane A2 (TxA2) receptors to amplify airway Rstretch responses. Despite the involvement of excitatory prostanoids in bronchoconstriction, clinical trials on treatments targeting TxA2-synthase inhibition and TP-receptor antagonism have produced mixed results. Studies in Western populations produced mostly negative results, whereas studies performed in Asian populations showed mostly positive outcomes. In this review, we discuss the role of TxA2-synthase inhibition and TP-receptor antagonism in the treatment of asthmatics. We present information regarding variations in study designs and the possible role of TP-receptor gene polymorphisms in previous study outcome discrepancies. Perhaps future studies should focus on asthmatic patients with DI-induced bronchoconstriction in particular, planting the seed for the individualized treatments for asthmatics.

Platelets, Not an Insignificant Player in Development of Allergic Asthma

“…While TxA2 synthetase inhibitors and TP receptor antagonists were found to have positive effects on allergic asthma in Japan [109], studies from Western countries revealed no obvious curative effects. This discrepancy may be associated with the genetic polymorphism in TxA2 synthetase and TP receptors [108].…”

“…In allergic asthma, TxA2 causes bronchial contraction, increased vascular permeability, tissue edema, and airway hyperresponsiveness [107]. Blocking TxA2 synthesis reduces the concentration of TxA2 during asthma attacks, but another bronchoconstrictor, prostaglandin, which acts together with TxA2 by binding to the TxA2 receptor (TP receptors), is generated due to the diverted arachidonic acid metabolism pathway [108]. Therefore, the combined use of TxA2 synthase inhibitor and TP receptor antagonist could be more effective in the treatment of allergic asthma.…”

Emerging concepts in smooth muscle contributions to airway structure and function: implications for health and disease

“…In the context of continued discoveries of GPCRs in bronchoconstriction vs. dilation, the complex roles of prostaglandins (PGs) in the airway (99,215,372,447,455,586) are being teased out. Products of the COX pathway in arachidonic acid metabolism, the five primary PGs (PGD 2 , PGE 3 , PGF 2 , PGI 2 , and TXA 2 ), all signal through distinct GPCRs.…”

Comparison of oral montelukast with oral ozagrel in acute asthma: A randomized, double-blind, placebo-controlled study

“…[ 19 20 ] Studies from Japan have reported that thromboxane modulators may have role as an add-on therapy to inhaled corticosteroids in the event of poor response to corticosteroids, in the setting of chronic asthma. [ 4 9 ] However, to the best of our knowledge, this group of drugs does not appear to have been tested in acute asthma setting. In our study, ozagrel did not demonstrate any benefit over and above the standard treatment of acute asthma.…”

“…Hence, our endeavor in this study was to address the issues of any usefulness of montelukast and ozagrel in acute asthma. [ 9 ]…”