Role of tachykinins in sephadex-induced airway hyperreactivity and inflammation in guinea pigs.
We have studied the effect of selective tachykinin NK(1) and NK(2) receptor antagonists on airway hyperreactivity to acetylcholine and increase of inflammatory cells on bronchoalveolar lavage fluid induced by sephadex beads (20 mg/kg, i.v.) in guinea pigs. Airway hyperreactivity was assessed by measuring the increase of bronchial insufflation pressure to acetylcholine (0.01-30 micromol/kg, i.v.) at 3 h (early phase) and 24 h (late phase) after sephadex administration. An increase in inflammatory cells in bronchoalveolar lavage fluid (eosinophils and macrophages) was detected at 24 h (from 11.6 x 10(6) to 49.3 x 10(6) cells) but not at 3 h from sephadex administration. Neurokinin A and substance P levels in bronchoalveolar lavage fluid showed a significant increase at 24 h (from 31.7+/-11.6 to 561+/-231 pg/ml and from 5.9+/-2.6 to 29.3+/-4.1 pg/ml for neurokinin A and substance P, respectively). At this time point, the tachykinin in bronchoalveolar lavage cellular content was depleted from 232+/-43 to 21+/-20 pg/sample and from 56.6+/-6.7 to 2+/-2 pg/sample for neurokinin A and substance P, respectively. Capsaicin pretreatment abolished the early but not the late phase of airway hyperreactivity induced by sephadex without modifying bronchoalveolar lavage total cells number and bronchoalveolar lavage levels of neurokinin A and substance P. Administration of the tachykinin NK(2) (nepadutant) and/or the NK(1) receptor antagonist (MEN 11467 or (1R,2S)-2-N[1(H)indol-3-yl-carbonyl]-1-N[N-(p-tolylacetyl)-N-(methyl)-D-3(2-naphthyl)alanyl)diaminocyclohexane)), 5 min before sephadex, prevented the early phase of airway hyperreactivity to acetylcholine but only nepadutant prevented the late phase. Nepadutant was able to abolish the early phase of airway hyperreactivity if given after sephadex administration and reduced by about 50% the increase of cell number in bronchoalveolar lavage fluid during the late phase, without affecting the levels of neurokinin A and substance P. These findings indicate an involvement of endogenous tachykinins in the genesis of airway hyperreactivity in a guinea-pig model of non-allergic asthma. Early airway hyperreactivity apparently involves release of tachykinins from capsaicin-sensitive afferent nerves acting via tachykinin NK(1)/NK(2) receptors. Late airway hyperreactivity involves tachykinins acting via tachykinin NK(2) receptors: inflammatory cells activated/recruited in response to sephadex challenge appear a likely source of tachykinins involved in the late phase of the response.
Tramontana
Manuela
M
Pharmacology Department, Menarini Ricerche S.p.A., Via Rismondo, 12 A, 50131, Florence, Italy. chimfarm@menarini-ricerche.it
Santicioli
Paolo
P
Giuliani
Sandro
S
Catalioto
Rose-Marie
RM
Lecci
Alessandro
A
Carini
Francesca
F
Maggi
Carlo Alberto
CA
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D002452:Cell Count; D003514:Cyclohexylamines / Q000494:pharmacology; D003911:Dextrans / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects; D006168:Guinea Pigs; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D008297:Male; D015288:Neurokinin A / Q000032:analysis; D010456:Peptides, Cyclic / Q000494:pharmacology; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors; D013373:Substance P / Q000032:analysis; D015320:Tachykinins / Q000502:physiology*; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology
D001993:Bronchodilator Agents; D003514:Cyclohexylamines; D003911:Dextrans; D007211:Indoles; C107754:MEN 11420; C121095:MEN 11467; D010456:Peptides, Cyclic; D018039:Receptors, Tachykinin; D015320:Tachykinins; D014665:Vasodilator Agents; D013373:Substance P; D015288:Neurokinin A; C025614:sephadex; D000109:Acetylcholine; D002211:Capsaicin