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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Role of Cyclooxygenase Isoforms and Nitric-Oxide Synthase in the Modulation of Tracheal Motor Responsiveness in Normal and Antigen-Sensitized Guinea Pigs

Section of Pharmacology, Department of Psychiatry, Neurobiology, Pharmacology, and Biotechnology (P.N., C.M., R.G., M.C.B.), Division of Pharmacology and Chemotherapy, Department of Internal Medicine (C.B., M.D.T.), and Section of Histology, Department of Human Morphology and Applied Biology (N.B., C.I.), University of Pisa, Pisa, Italy

The effects of selective cyclooxygenase (COX) 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 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole] (COX-1 inhibitor) or DFU [5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone] (COX-2 inhibitor) significantly increased the contractile response to histamine, these effects being not additive. NOS inhibition by L-N^G-nitro-arginine methyl ester (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 prostacyclin (PGI₂), but not prostaglandin E₂, was observed in tracheal tissues from normal and OVA-sensitized guinea pigs. In conclusion, both COX-1 and COX-2 are constitutive in guinea pig trachea, and COX-2 expression is enhanced by OVA sensitization; 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; and following antigen sensitization, the inhibitory control on tracheal contractility is maintained by COX-2 induced at subepithelial cell sites.

Address correspondence to: Dr. Paola Nieri, Dipartimento di Psichiatria, Neurobiologia, Farmacologia, e Biotecnologie, via Bonanno no. 6, 56126 Pisa, Italy. E-mail: paola.nieri{at}farm.unipi.it