Stimulation of protease-activated receptor-2 inhibits airway eosinophilia, hyperresponsiveness and bronchoconstriction in a murine model of allergic inflammation.
1. An emerging body of evidence indicates that PGE(2) has a privileged anti-inflammatory role within the airways. Stimulants of protease-activated receptor-2 (PAR(2)) inhibit airway smooth muscle tone in vitro and in vivo predominantly via cyclooxygenase (COX)-dependent generation of prostaglandin E(2) (PGE(2)). Thus, the current study tested the hypothesis that PAR(2)-induced generation of PGE(2) inhibits the development of allergic airways inflammation and hyperresponsiveness. 2. Bronchoalveolar lavage (BAL) fluid recovered from ovalbumin (OVA)-sensitised and -challenged (allergic) mice contained elevated numbers of eosinophils, which peaked at 48 h postchallenge. Intranasal (i.n.) administration of a PAR(2)-activating peptide (PAR(2)-AP) SLIGRL (25 mg kg(-1), at the time of OVA challenge) caused a 70% reduction in the numbers of BAL eosinophils (compared to the scrambled peptide LSIGRL, 25 mg kg(-1)). 3. Pretreatment of allergic mice with either indomethacin (1 mg kg(-1), dual COX inhibitor) or nimesulide (3 mg kg(-1), COX-2-selective inhibitor) blocked SLIGRL-induced reductions in BAL eosinophils. 4. I.n. SLIGRL, but not LSIGRL, inhibited the development of antigen-induced airways hyperresponsiveness. The inhibitory effect of SLIGRL was blocked by indomethacin. 5. Exposure of isolated tracheal preparations from allergic mice to 100 microM SLIGRL was associated with a 5.0-fold increase in PGE(2) levels (P<0.05, compared to 100 microM LSIGRL). SLIGRL induced similar increases in PGE(2) levels in control mice (OVA-sensitised, saline-challenged). 6. I.n. administration of PGE(2) (0.15 mg kg(-1)) to allergic mice significantly inhibited eosinophilia and airways hyperresponsiveness to methacholine. 7. In anaesthetised, ventilated allergic mice, SLIGRL (5 mg kg(-1), i.v.) inhibited methacholine-induced increases in airways resistance. Consistent with this bronchodilator effect, SLIGRL induced pronounced relaxation responses in isolated tracheal preparations obtained from allergic mice. LSIGRL did not inhibit bronchomotor tone in either of these in vivo or in vitro experiments. 8. In summary, a PAR(2)-AP SLIGRL inhibited the development of airway eosinophilia and hyperresponsiveness in allergic mice through a COX-dependent pathway involving COX-2-mediated generation of the anti-inflammatory mediator PGE(2). SLIGRL also displayed bronchodilator activity in allergic mice. These studies support the concept that PAR(2) exerts predominantly bronchoprotective actions within allergic murine airways.
De Campo
Benjamin A
BA
Respiratory Pharmacology Group, School of Medicine and Pharmacology, University of Western Australia, 35 Stirling Hwy, Nedlands, Australia.
Henry
Peter J
PJ
D000818:Animals; D016535:Bronchial Hyperreactivity / Q000378:metabolism*; D016084:Bronchoconstriction / Q000502:physiology*; D002452:Cell Count / Q000379:methods; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011657:Pulmonary Eosinophilia / Q000378:metabolism*; D044464:Receptor, PAR-2 / Q000378:metabolism*; D012130:Respiratory Hypersensitivity / Q000378:metabolism*
D044464:Receptor, PAR-2