Inhaled A23187 produces a preferential sensitization to substance P.
We examined the effect of A23187-induced lung injury on airway responses to a variety of bronchoconstrictive aerosols in conscious guinea pigs. Guinea pigs were exposed to aerosolized A23187 or vehicle for 12 min or until labored breathing began. Animals were allowed to recover for 24 h, and then they were challenged with inhaled histamine, leukotriene D4 (LTD4), platelet-activating factor (PAF), or substance P. Eight minutes after start of the bronchoprovocative aerosol, the guinea pigs were killed and excised lung gas volume (ELGV) measurements were used as an index of in vivo airway obstruction. No differences in ELGV dose-response curves to LTD4 were seen in A23187- and vehicle-exposed animals. A23187 exposure produced small increases in both histamine and PAF sensitivity. However, A23187 caused a much more pronounced leftward shift in the dose-response to substance P. Coadministration of the neutral endopeptidase inhibitor, thiorphan, did not reduce the A23187-related airway responses to substance P. Histologic evaluation of A23187-treated lungs revealed peribronchiolar inflammation, bronchiolar epithelial injury, and mild alveolitis. We conclude that A23187 treatment produces differential airway responses to bronchoactive agents, with a preferential sensitization to substance P.
Stengel
P W
PW
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
Bendele
A M
AM
Cockerham
S L
SL
Silbaugh
S A
SA
D000818:Animals; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects*; D000001:Calcimycin / Q000494:pharmacology*; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008176:Lung Volume Measurements; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors; D010972:Platelet Activating Factor / Q000494:pharmacology; D013189:SRS-A / Q000494:pharmacology; D013373:Substance P / Q000494:pharmacology*; D015244:Thiorphan / Q000494:pharmacology
D010972:Platelet Activating Factor; D013189:SRS-A; D013373:Substance P; D000001:Calcimycin; D006632:Histamine; D015244:Thiorphan; D015260:Neprilysin