New leads for asthma therapy

Abstract

The role of tryptic enzymes, such as epithelial trypsin and mast-cell tryptase, in airway function has long been an enigma in lung physiology. Stimulation of protease-activated receptors (PARs) on airway smooth muscle cells can lead to bronchoconstriction, and it has been assumed that mast-cell proteases contribute to allergy-mediated asthma symptoms. Now, Cocks et al.1xA protective role for protease-activated receptors in the airways. Cocks, T.M. et al. Nature. 1999; 398: 156–160Crossref | PubMed | Scopus (295)See all References present compelling evidence for protease-mediated bronchorelaxation via stimulated PAR2 receptors on airway epithelial cells. PAR2 is expressed on endothelial or epithelial cells, and its levels are particularly high in the gut epithelium where it protects against digestive proteolytic enzymes. It is remarkable that a similar mechanism has been adopted to protect the airways against protease-mediated bronchoconstriction. Activation of mouse airway epithelial cell PAR2 by trypsin or by the PAR2 tethered-ligand sequence peptide, SLIGRL-NH2 (which mimics the protease-activated PAR2) relaxed bronchi that had been constricted with 5-hydroxytryptamine (5HT) or with carbachol, bronchoconstrictors that act via airway smooth muscle cell serotonergic and muscarinic receptors, respectively. Relaxation was lost following epithelial cell removal, indicating that the relevant PAR2 were located there. PAR2-induced relaxation of the bronchi was blocked by the cyclooxygenase inhibitor indomethacin, suggesting that relaxation was mediated by prostaglandin E2 (PGE2), the most abundant airway epithelium prostanoid. Indeed, PGE2 is a potent bronchial relaxing agent1xA protective role for protease-activated receptors in the airways. Cocks, T.M. et al. Nature. 1999; 398: 156–160Crossref | PubMed | Scopus (295)See all References. The bronchorelaxing effects of inhaled SLIGRL-NH2 aerosol were evident in vivo: it inhibited 5HT-induced changes in airway resistance in anaesthetized rats, suggesting that similar mechanisms might regulate normal airway tone1xA protective role for protease-activated receptors in the airways. Cocks, T.M. et al. Nature. 1999; 398: 156–160Crossref | PubMed | Scopus (295)See all References.Another new study showed that the arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) relaxed rabbit bronchi that had been contracted with histamine2xAirway synthesis of 20-hydroxyeicosatetraenoic acid: metabolism by cyclooxygenase to a bronchodilator. Jacobs, E.R. et al. Am. J. Physiol. 1999; 276: L280–L288PubMedSee all References. Similar to the PAR2 study, 20-HETE-mediated relaxation was blocked by indomethacin or by epithelium removal, implicating its conversion to a bronchial relaxant, probably PGE2, by epithelial cyclooxygenase.Enjoying the salty seaside air or venturing into deep salt mines can also relieve asthma symptoms. The third study addressed this phenomenon by demonstrating that intraluminally applied hyperosmotic NaCl or KCl solutions relaxed bronchi that had been contracted by muscarinic or electric-field stimulation. Relaxation was again epithelium-dependent and sensitive to Na+ and Cl− channel blockers3xOsmotic regulation of airway reactivity by epithelium. Fedan, J.S. et al. J. Pharmacol. Exp. Ther. 1999; 289: 901–910PubMedSee all References. However, this intriguing type of airway relaxation was not sensitive to indomethacin but to inhibitors of nitric oxide synthase. Thus several distinct mechanisms operate in orchestrating airway relaxation by epithelial cells.Research into the mechanisms of PAR2, 20-HETE and NaCl-induced bronchorelaxation should foster new leads for effective asthma drug targets. For example, inhaled proteases or PAR2 tethered-ligand mimetic peptides, as well as inhaled prostanoid precursors, such as 20-HETE, could promote epithelial PAR2-mediated airway relaxation. Aerosols of hyperosmotic NaCl might similarly mediate airway relaxation, possibly in synergy with PAR2 or prostanoid-operated pathways.