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Contribution of inflammatory mediators to asthma
209
Pharmacological Research. Vol. 22. Supplement 2. 1990
CONTRIBUTION OF INFLAMMATORY MEDIATORS TO ASTHMA G.C. Folco, T. Vigano', M.T. Crivellari and A. Sala Institute of Parmacological SCiences, Univ. of Milan, Via Balzaretti, 9 - 20133 Milano The major pathological features of asthma are a) bronchoconstriction b) bronchial wall thickening c) increased mucus secretion d) bronchial hypersensitivity to constrictor stimuli. These events can be triggered by antigen inhalation or by inflammatory lipid mediators including sulfidopeptide leukotrienes (LT), prostaglandin D2 (PGD2) and platelet-activating factor (PAF). Normal human lung parenchyma releases inflammatory mediators following immunological challenge: their major sources seem to be mastcells and macrophages , although production of Iipoxygenase products and PAF has been described for human basophils and neutrophils (1-2). Specific endobronchial challenge with Dermatophagoides Pteronyssinus in allergic asthmatic patients triggers a significant release of LTE4 and PGD2, in amounts that are largely enough to cause edema of the bronchial mucosa and bronchoconstriction. In "in vitro" studies the immunological release of Iipoxygenase products was not affected by pretreatment with indomethacin , in spite of a 90% inhibition of the formation of PGD2' Morover the amount of LT recovered from nasal washes of aspirin sensitive patients challenged with Iysine-acetilsalicylate did not preceed the appearance of symptoms such as nasal obstruct ion and rhinorrea, suggesting that intolerance to NSAIDS might not depend on a redistribution of eicosanoids biosynthesis via the 5Iipoxygenase route. The immunological challenge of human lung parenchyma was also used to investigate the mechanism of action of Sch-37224, a novel pyrrolidine derivative of naphthyridinone with antiallergic activity (3). This compound was preincubated for 30' at varying concentrations (1 - 100 ~M) before challenge with an anti-human IgE antibody and caused a significant, dose response inhibition of LTE4 formation . Sch37224 did not affect PGD2 release indicating that the specific target of its of its pharmacological activity is at the level of LT synthase. Sch-37224 was also devoid of any activity at LT receptor level. 1) Arnoux N., Simoe-Caerio M.H. et at, Am. Rev. Dis., 1982,lli, 70. 2) Chilton F/HI, Hadley J.S. and Murphy R.C., Biochim. Acta, 1987, lli. 48 3) Kreutner W., Sherwood J. et at J. Pharmacol. Exp. Therap., 1988,lli, 997.
1043-6 618/90/22II0209---{)1/$03.00/0
© 1990 The Italian Pharmacological Society
Pharmacological Research. Vol. 22. Supplement 2. 1990
CONTRIBUTION OF INFLAMMATORY MEDIATORS TO ASTHMA G.C. Folco, T. Vigano', M.T. Crivellari and A. Sala Institute of Parmacological SCiences, Univ. of Milan, Via Balzaretti, 9 - 20133 Milano The major pathological features of asthma are a) bronchoconstriction b) bronchial wall thickening c) increased mucus secretion d) bronchial hypersensitivity to constrictor stimuli. These events can be triggered by antigen inhalation or by inflammatory lipid mediators including sulfidopeptide leukotrienes (LT), prostaglandin D2 (PGD2) and platelet-activating factor (PAF). Normal human lung parenchyma releases inflammatory mediators following immunological challenge: their major sources seem to be mastcells and macrophages , although production of Iipoxygenase products and PAF has been described for human basophils and neutrophils (1-2). Specific endobronchial challenge with Dermatophagoides Pteronyssinus in allergic asthmatic patients triggers a significant release of LTE4 and PGD2, in amounts that are largely enough to cause edema of the bronchial mucosa and bronchoconstriction. In "in vitro" studies the immunological release of Iipoxygenase products was not affected by pretreatment with indomethacin , in spite of a 90% inhibition of the formation of PGD2' Morover the amount of LT recovered from nasal washes of aspirin sensitive patients challenged with Iysine-acetilsalicylate did not preceed the appearance of symptoms such as nasal obstruct ion and rhinorrea, suggesting that intolerance to NSAIDS might not depend on a redistribution of eicosanoids biosynthesis via the 5Iipoxygenase route. The immunological challenge of human lung parenchyma was also used to investigate the mechanism of action of Sch-37224, a novel pyrrolidine derivative of naphthyridinone with antiallergic activity (3). This compound was preincubated for 30' at varying concentrations (1 - 100 ~M) before challenge with an anti-human IgE antibody and caused a significant, dose response inhibition of LTE4 formation . Sch37224 did not affect PGD2 release indicating that the specific target of its of its pharmacological activity is at the level of LT synthase. Sch-37224 was also devoid of any activity at LT receptor level. 1) Arnoux N., Simoe-Caerio M.H. et at, Am. Rev. Dis., 1982,lli, 70. 2) Chilton F/HI, Hadley J.S. and Murphy R.C., Biochim. Acta, 1987, lli. 48 3) Kreutner W., Sherwood J. et at J. Pharmacol. Exp. Therap., 1988,lli, 997.
1043-6 618/90/22II0209---{)1/$03.00/0
© 1990 The Italian Pharmacological Society