Effect of dexamethasone on antigen-induced high molecular weight glycoconjugate secretion in allergic guinea pigs.
The ovalbumin-sensitized guinea pig is commonly used as a small animal model of allergic asthma. This animal model exhibits many of the hallmark characteristics observed in patients afflicted with asthma including nonspecific airway hyperreactivity, airway eosinophilia, early and late phase bronchoconstriction, and plasma extravasation into the airways. In addition, mucous hypersecretion in the airways of asthmatic patients is thought to be responsible for the plugging of distal airways and to contribute to the morbidity and mortality associated with the disease process. In this study we examined whether the allergic guinea pig model exhibits an increase in airway high molecular weight glycoconjugate (HMWG) secretion in response to an antigen challenge and whether dexamethasone exerts any modulatory effects upon the response. Ovalbumin (OVA) -sensitized guinea pigs were challenged with OVA 2 wk following the initial exposure. Trachobronchoalveolar lavages (TBAL) were performed, and the samples were assayed for total eosinophil cell number, eosinophil peroxidase activity (EPO), and both acidic and neutral HMWG content. Morphometric analysis of mucous-containing cells was also performed on tissue sections prepared from the trachea, mainstem bronchus, and three lobes of the left lung. Within 24 h of an antigen challenge, TBAL samples obtained from the allergic guinea pigs exhibited increases in eosinophil cell number, measured EPO enzyme activity, and acidic HMWG content compared to TBAL samples prepared from vehicle-exposed animals. These antigen-induced changes were dependent on the concentration of aerosolized OVA administered. Exposing the animals to 0.3% OVA provoked a 6.23-fold increase in airway eosinophils, 15-fold elevation in TBAL EPO enzyme activity, and 175% increase in TBAL acidic HMWG. No significant changes in TBAL neutral HMWG were measured. The changes in measured EPO activity correlated with the levels of acidic HMWG found in the TBAL samples (r = 0.73, P < or = 0.001). The measured increase in TBAL acidic HMWG was time dependent and was found to be maximal at 2 h post-antigen challenge. Morphometric analysis of Alcian blue (pH 2.5) -stained airway sections showed a decline in stored mucosubstances following the antigen exposure, supporting the notion that the allergic guinea pig model exhibits a mucosecretory component. Pretreating the animals with dexamethasone attenuated the antigen-induced release of HMWG and changes in measured EPO activity. In conclusion, these data indicate that the allergic guinea pig may be a useful model for examining the neural and cellular mechanisms underlying mucus hypersecretion in individuals afflicted with bronchial asthma.
Savoie
C
C
Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada.
Plant
M
M
Zwikker
M
M
van Staden
C J
CJ
Boulet
L
L
Chan
C C
CC
Rodger
I W
IW
Pon
D J
DJ
D000818:Animals; D001249:Asthma / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D003907:Dexamethasone / Q000494:pharmacology*; D004195:Disease Models, Animal; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism; D006001:Glycoconjugates / Q000032:analysis / Q000378:metabolism*; D006168:Guinea Pigs; D006967:Hypersensitivity / Q000188:drug therapy*; D008297:Male; D008970:Molecular Weight; D009093:Mucus / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology / Q000378:metabolism*
D006001:Glycoconjugates; D003907:Dexamethasone; D010047:Ovalbumin