Airway closure after antigen challenge in cynomolgus monkeys: effect of the histamine H1 receptor antagonist, chlorpheniramine maleate.
BACKGROUND
Airway closure is frequently observed in human asthma. However, limited information exists on the factors that cause this condition. In this study, an allergic cynomolgus monkey model was used to characterize the condition of airway closure and assess the contribution of histamine H1 receptors to this response.


METHODS
Oscillatory lung mechanics, arterial blood gases during ventilation on 100% O2 and functional residual capacity (FRC) assessed by helium dilution were measured before and then 10 min and 24 h after Ascaris aerosol challenge in 12 male Ascaris-sensitive cynomolgus monkeys. The monkeys were pretreated with intravenous saline or chlorpheniramine maleate (0.3 mg/kg) in a randomized crossover design.


RESULTS
Ascaris challenge produced a large increase in airway resistance, an increase in lung tissue damping (G) that measures ventilation inhomogeneity in the lung, a reduction in arterial oxygen tension (PaO2) during ventilation on 100% O2 and a reduction in FRC. These effects were seen 10 min after the Ascaris challenge, but by 24 h, these parameters had returned close to the baseline values. Chlorpheniramine maleate (0.3 mg/kg, i.v.) produced a 12-fold shift in the histamine bronchoconstrictor dose-response curve. Pretreatment of monkeys with chlorpheniramine maleate (0.3 mg/kg, i.v.) attenuated the increase in airway resistance induced by Ascaris challenge, but had only a small effect on the increase in G and the reductions in PaO2 and FRC after antigen.


CONCLUSIONS
These results demonstrate that airway closure occurs immediately after the antigen challenge in allergic cynomolgus monkeys and that histamine H1 receptors contribute very minimally to this response.
Skeans
Susan
S
Schering-Plough Research Institute, Kenilworth, NJ 07033-0539, USA.
Lamca
James E
JE
House
Aileen
A
Celly
Chander S
CS
Hey
John A
JA
Chapman
Richard W
RW
D000402:Airway Obstruction / Q000188:drug therapy* / Q000276:immunology*; D000818:Animals; D017165:Ascaris suum / Q000276:immunology*; D001784:Blood Gas Analysis; D002744:Chlorpheniramine / Q000494:pharmacology*; D018592:Cross-Over Studies; D004195:Disease Models, Animal; D006632:Histamine / Q000276:immunology; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006969:Hypersensitivity, Immediate / Q000188:drug therapy / Q000276:immunology*; D008252:Macaca fascicularis / Q000276:immunology* / Q000469:parasitology; D008297:Male; D011897:Random Allocation; D011969:Receptors, Histamine H1 / Q000276:immunology; D012129:Respiratory Function Tests; D018709:Statistics, Nonparametric
D006634:Histamine H1 Antagonists; D011969:Receptors, Histamine H1; D002744:Chlorpheniramine; D006632:Histamine