title: 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 (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 (PGI(2)), but not prostaglandin E(2), 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 PGI(2)-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.
authors.affiliation: Dipartimento di Psichiatria, Neurobiologia, Farmacologia, e Biotecnologie, via Bonanno no. 6, 56126 Pisa, Italy. paola.nieri@farm.unipi.it
authors.forename: Paola
authors.initials: P
authors.lastname: Nieri
authors.forename: Cinzia
authors.initials: C
authors.lastname: Martinelli
authors.forename: Corrado
authors.initials: C
authors.lastname: Blandizzi
authors.forename: Nunzia
authors.initials: N
authors.lastname: Bernardini
authors.forename: Rosamiria
authors.initials: R
authors.lastname: Greco
authors.forename: Chiara
authors.initials: C
authors.lastname: Ippolito
authors.forename: Mario
authors.initials: M
authors.lastname: Del Tacca
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Breschi
mesh_terms: D000818:Animals; D051545:Cyclooxygenase 1 / Q000032:analysis / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000502:physiology*; D015232:Dinoprostone / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D009119:Muscle Contraction; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000502:physiology*; D010047:Ovalbumin / Q000276:immunology*; D014132:Trachea / Q000201:enzymology / Q000502:physiology*
chemical_list: D006632:Histamine; D010047:Ovalbumin; D011464:Epoprostenol; D019001:Nitric Oxide Synthase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D019331:NG-Nitroarginine Methyl Ester