Eicosanoids and GPCRs in Airway Physiology

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Linked publications & trials

Abstract

Many of the mediators that regulate airflow in healthy individuals and that contribute to altered airway physiology in patients with pulmonary diseases signal through G protein coupled receptors. These receptors include not only the acetylcholine responsive muscarinic receptors of the parasympathetic pathways but also receptors for a number of inflammatory mediators. Increased production of eicosanoids, lipid mediators derived from arachidonic acid, is observed in virtually all airway diseases. In particular, the inflamed lung produces substantial quantities of thromboxaneA2 (TXA2). Thromboxane activates a single GPCR Tp receptor that is broadly expressed in the lung. The mechanism(s) by which inflammatory mediators such as thromboxane contribute to altered airway physiology, in particular the development of hyperresponsive airways, is not well understood. Even less information is available concerning synergism between these inflammatory mediators and neuronal pathways that regulate airway smooth muscle tone in the healthy airway. TXA2 is a potent mediator of both bronchoconstriction and bronchial hyperreactivity in humans. The mechanism by which TXA2 mediates these actions is not well understood. The prevailing view is that TXA2, similar to other eicosanoids, regulates bronchial tone through direct, receptor-mediated effects on smooth muscle. However, based on our preliminary experiments, we suggest an alternative hypothesis: TXA2 regulates airway resistance in a complex manner that integrates direct actions on smooth muscle and indirect actions mediated by stimulating or amplifying specific cholinergic pathways or by altering mediator release by epithelial cells. In this application, we will test these hypotheses and determine the relative contributions of these distinct pathways for regulating airway resistance in the normal lung and during inflammation. Understanding of the interactions between the inflammatory Tp activated pathways and the cholinergic pathways that regulate airway tone will help define the events that lead to increased airway hyperresponsiveness and airway obstruction.