PubMed · 352190
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A Morton, A B Baker. 1978. Post-operative respiratory dysfunction.. https://doi.org/10.1177/0310057x7800600109
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Recently, we demonstrated that an increased airway responsiveness in vitro can be measured 4, 8, and 16 days, but not 2 days, after intratracheal inoculation of parainfluenza-3 (PI-3) virus to guinea pigs. In the present study airway responsiveness was measured in vivo, and the number, types and activity of broncho-alveolar cells was determined. A significant increase in airflow resistance was measured in spontaneously breathing anesthetized guinea pigs in response to histamine and methacholine, 4 and 8 days after PI-3 virus inoculation. 2 days after inoculation with control solution or PI-3 virus, no difference in the total number of inflammatory cells was observed in the broncho-alveolar lavage fluid. In contrast, on days 4, 8, and 16 after infection a significant increase in the number of alveolar macrophages (102%, 76%, 68%, respectively), monocytes (552%, 374%, 360%, respectively), and lymphocytes (253%, 675%, 396%, respectively) was found. The number of eosinophils was increased as well, but faded with time (378%, 312%, 63%, respectively). PI-3 virus was found to be a very potent activator of broncho-alveolar cells as measured by chemiluminescence. The increase in chemiluminescence production in response to PI-3 virus was reduced in cells obtained from PI-3 virus pretreated animals (day 2, 42%; day 4, 65%; day 8, 22%; and day 16, 30%). In conclusion, PI-3 virus can stimulate broncho-alveolar cells and the virus-induced airway hyperresponsiveness is associated with an influx of inflammatory cells in the respiratory tract.
A series of novel xanthine-based tricyclic heterocycles in 1H-imidazo[4,5-c]quinolin-4(5H)-ones was designed, synthesized, and tested as potential active bronchodilators. Inhibition of the Schulz-Dale (SD) reaction-induced contraction in trachea and inhibition of antigen inhalation-induced bronchospasm in passively sensitized guinea pigs served as primary in vitro and in vivo assays, respectively. Simultaneous measurement of acute lethal toxicity (minimum lethal dose; MLD, po) in mice allowed determination of a safety margin. The bronchodilatory activity of these heterocycles was considerably varied with the nature of substituents at the 5-position. The most active substituents at the 2- and 5-positions and on the aromatic ring were found to be hydrogen, n-butyl, and hydrogen, respectively. There was a bulk tolerance for lipophilic substituents at the 1-position. 5-Butyl-substituted compounds appeared to be less toxic than theophylline on the basis of MLD data. Thus 5-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-4(5H)-one (10) (IC50 value of the SD assay = 0.25 microM, MLD > 300 mg/kg) was selected for further studies. Compound 10 (KF15570) reduced bronchoconstriction produced by antigen (Konzett-Rössler preparation in anesthetized guinea pigs, ED50 = 0.42 mg/kg, iv) more effectively than aminophylline (ethylenediamine salt of theophylline, ED50 = 7.8 mg/kg, iv) but had fewer side effects on the heart and CNS than theophylline. Compound 10 and its derivatives showed weak adenosine antagonism and phosphodiesterase (PDE) inhibition which could not account for their potent bronchodilation. Although their precise mechanism of action remains unclear, this series of novel tricyclic heterocycles represents a new class of bronchodilator.
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