Received for publication February 8, 2006.
Revised August 18, 2006.
Accepted for publication August 18, 2006.

Role of cyclooxygenase isoforms and nitric oxide synthase in the modulation of tracheal motor responsiveness in normal and antigen-sensitized guinea-pigs

Abstract

The effects of selective cyclooxygenase isoform (COX-1, COX-2) inhibition, alone or in combination with nitric oxide synthase (NOS) blockade, on in vitro tracheal muscle responsiveness to histamine were investigated in healthy and ovalbumin (OVA)-sensitized guinea-pigs. Immunohistochemistry showed that COX-1 and COX-2 are constitutively present in normal guinea-pig trachea, particularly in the epithelial layer, and that COX-2 expression is enhanced in OVA-sensitized animals both in epithelial and subepithelial tissues. In normal guinea-pigs, SC-560 (COX-1 inhibitor) or DFU (COX-2 inhibitor) significantly increased the contractile response to histamine, these effects being not additive. NOS inhibition by L-NAME did not affect histamine-induced contraction, but reversed the increase caused by COX-1 blockade, while not modifying the enhancement associated with COX-2 inhibition. In guinea-pigs subjected to OVA-sensitization and challenge, COX-2, but not COX-1, inhibition enhanced the motor responses to histamine, without any influence by L-NAME. In normal, but not in sensitized animals, the removal of epithelial layer from tracheal preparations abolished the enhancing action of DFU on histamine-mediated contraction. A COX-2-dependent release of PGI₂, but not PGE₂, was observed in tracheal tissues from normal and OVA-sensitized guinea-pigs. In conclusion: a) both COX-1 and COX-2 are constitutive in guinea-pig trachea, and COX-2 expression is enhanced by OVA-sensitization; b) in normal animals epithelial COX-2 exerts a PGI₂-dependent inhibitory control on tracheal contractility, and this isoform is subjected to upstream regulation by epithelial COX-1 and NOS, through a complex interplay; c) following antigen sensitization, the inhibitory control on tracheal contractility is maintained by COX-2 induced at subepithelial cell sites.

Key words: COX-1, COX-2, guinea-pig, histamine, nitric oxide synthase, trachea