Polymyxin B-induced bronchial neutrophilia does not alter airway responsiveness to methacholine in cynomolgus monkeys.
The purpose of this study was to develop a primate model of chronic bronchial neutrophilia to investigate the role of neutrophils in the pathogenesis of airway hyperresponsiveness. Ten adult male cynomolgus monkeys (Macaca fascicularis) were anaesthetized and intubated for each study. Six animals each received a total of seven inhalation treatments with polymyxin B (200 micrograms) over a 24 day period. Four control animals received an identical treatment regime with vehicle inhalations. Airway cellular composition was assessed by bronchoalveolar lavage (BAL). Airway responsiveness was assessed by methacholine cumulative dose response determinations. There were no significant changes in airway cellular composition or airway responsiveness in the control group. In contrast, Polymyxin B inhalation resulted in an influx of neutrophils (PMN) into the lungs which peaked at day 10 of the study (%PMN in BAL fluid rose from 5 +/- 2 to 51 +/- 8, P less than 0.001) and persisted out to day 24 (41 +/- 8, P less than 0.01). Increases in PMNs were associated with an increase in BAL levels of myeloperoxidase (MPO levels in BAL fluid increased from 2 +/- 3 to 180 +/- 23 OD P less than 0.05). Although airway PMN percentages and MPO concentrations were chronically elevated, airway responsiveness did not change. These results suggest that the neutrophil does not play a functional role in the onset of hyperresponsive airways in primates.
Gundel
R H
RH
Department of Pharmacology, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut 06877.
Gerritsen
M E
ME
Wegner
C D
CD
D000280:Administration, Inhalation; D000818:Animals; D001982:Bronchial Diseases / Q000097:blood / Q000150:complications; D016535:Bronchial Hyperreactivity / Q000097:blood / Q000139:chemically induced / Q000209:etiology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D007964:Leukocytosis / Q000139:chemically induced*; D008252:Macaca fascicularis; D008297:Male; D016210:Methacholine Chloride / Q000008:administration & dosage*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D011112:Polymyxin B / Q000494:pharmacology*; D012130:Respiratory Hypersensitivity / Q000097:blood / Q000139:chemically induced / Q000209:etiology*
D016210:Methacholine Chloride; D011112:Polymyxin B