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.