Inhibition of airway hyperreactivity, edema, and lung cell infiltration by compound U-83836E in sensitized guinea pigs Celso Carvalho, Sonia Jancar, and Pierre Sirois Abstract: Sensitized guinea pigs were used to assess the effect of treatment with the compound U-83836E ((–)-2-[[4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]methyl]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran- 6-ol, dihydrochloride) on the antigen-induced late-phase (16 h) airway hyperreactivity, increase in inflammatory cell number, edema, and release of inflammatory mediators in the bronchoalveolar lavage (BAL) fluid. After antigen challenge, an increase of the in vitro reactivity of the trachea and upper bronchi to acetylcholine and histamine and an increase in the number of leukocytes in the BAL fluid, mainly eosinophils and mononuclear cells, were observed. The concentrations of proteins, histamine, and PGE 2 in the BAL fluid were also significantly increased by 53, 57, and 216%, respectively, after antigen challenge. Treatment with U-83836E (10 mg/kg) given i.p. 17 and 3 h before and 6 h after antigen challenge inhibited by approximately 80% the total cell number in the airways and the BAL fluid protein content. Moreover, this treatment totally inhibited airway hyperreactivity. Histamine and PGE 2 levels in the BAL fluid were not significantly affected by U-83836E treatment. These results indicate that U-83836E is effective against some of the characteristic features of asthma in ovalbumin-sensitized guinea pigs. Key words: U-83836E, aminochroman, hyperreactivity, lung inflammation, edema. Résumé : On a utilisé des rats sensibilisés pour évaluer l’effet d’un traitement au moyen du composé U-83836E ((–)-2-[[4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-pipérazinyl]méthyl]-3,4-dihydro-2,5,7,8-tétraméthyl-2H-1-benzopyran-6-ol, dichlorhydrate) sur la phase tardive (16 h) de l’hyperréactivité des voies aériennes induite par un antigène, l’augmentation du nombre de cellules inflammatoires, l’oedème et la libération de médiateurs inflammatoires dans le liquide de lavage bronchoalvéolaire (BAL). Après l’épreuve antigénique, une augmentation de la réactivité in vitro de la trachée et des bronches supérieures à l’acétylcholine et à l’histamine ainsi qu’une augmentation du nombre de leucocytes, principalement des éosinophiles et des cellules mononucléaires, dans le liquide BAL ont été observées. Les teneurs en protéines, histamine et PGE 2 du liquide BAL ont aussi été augmentées de façon significative (de 53, 57 et 216% respectivement). Le traitement à l’U-83836E, 10 mg/kg administré par voie i.p. 17 et 3 h avant et 6 h après l’épreuve antigénique, a inhibé de près de 80% le nombre total de cellules dans les voies aériennes et la teneur en protéines du liquide BAL. De plus, ce traitement a totalement inhibé l’hyperréactivité des voies aériennes. Les taux d’histamine et de PGE 2 dans le liquide BAL n’ont pas été significativement affectés par le traitement à l’U-83836E. Ces résultats indiquent que l’U-83836E est efficace contre certaines caractéristiques de l’asthme chez les cobayes sensibilisés à l’ovalbumine. Mots clés : U-83836E, aminochromane, hyperréactivité, inflammation pulmonaire, oedème. [Traduit par la Rédaction] Carvalho et al. 720 Asthma is characterized by reversible airway obstruction, airway hyperreactivity to exogenous and endogenous stimuli, and airway inflammation. Microscopic analysis of asthmatic airways shows evidence of a multicellular process with infil- tration of leukocytes, mainly eosinophils and mononuclear cells, in the mucosa (Djukanovic et al. 1990). Experimental evidence suggests that bronchial hyperreactivity (BHR) and the eosinophil counts are elevated in the airways during the late-phase reaction of the disease (Frigas et al. 1981; deMonchy et al. 1985). Activated eosinophils were shown to release lipid mediators, such as platelet-activating factor (PAF), leukotrienes B 4 and C 4 (Shaw et al. 1985; Cromwell et al. 1990), and several cytotoxic proteins, such as the eosinophil peroxidase, which can cause inflammation and damage to the airway ep- ithelium (Gleich 1990). It has been shown that eosinophil- derived cationic proteins cause epithelium shedding and BHR in guinea pigs and monkeys (Frigas et al. 1980; Flavahan et al. 1988; Gundel et al. 1991). Airway microvascular leakage and edema are other in- flammatory events frequently observed in asthmatic airways, which have been hypothesized to contribute directly to the disease process (Van de Graaf et al. 1991). Hui et al. (1992) Can. J. Physiol. Pharmacol. 76: 715–720 (1998) © 1998 NRC Canada 715 Received November 27, 1997. C. Carvalho and P. Sirois. 1 Department of Pharmacology, Medical School, University of Sherbrooke, Sherbrooke, QC J1H 5N4, Canada. S. Jancar. Department of Immunology, University of Sao Paulo, S.P., Brazil. 1 Author to whom all correspondence should be addressed (e.mail: p.sirois@courrier.usherb.ca).