Neurogenic goblet cell secretion and bronchoconstriction in guinea pigs sensitised to trimellitic anhydride

Abstract

Trimellitic anhydride is a cause of occupational asthma in humans. We have previously found that tracheal instillation of trimellitic anhydride conjugated to guinea pig serum albumin induces acute bronchoconstriction and airway plasma exudation in sensitised animals, responses mediated primarily via histamine release. In the present study, neural mechanisms mediating bronchoconstriction and goblet cell secretion were determined in trimellitic anhydride-sensitised guinea pigs using the ganglionic blocker hexamethonium to eliminate efferent reflex mechanisms, pretreatment with capsaicin to eliminate afferent mechanisms, or cimetidine and mepyramine to eliminate histamine-mediated mechanisms. The magnitude of secretion of intracellular mucus from tracheal goblet cells was quantified morphometrically as a mucus score which is inversely related to the degree of discharge. Guinea pigs were injected intradermally either with 0.1 ml 0.3% trimellitic anhydride in corn oil or with corn oil alone as control. Fourteen to eighteen days later all sensitised animals had developed specific immunoglobulin (Ig) G1 antibodies whereas the controls had not. Tracheal instillation of conjugated trimellitic anhydride in anaesthitised animals significantly increased airway lung resistance (R_L) 24-fold in sensitised guinea pigs (34.3 ± 7.9 cm H₂O · ml⁻¹ · s) compared with controls (1.4 ± 0.1 cm H₂O · ml⁻¹ · s). Mucus score was significantly reduced by 51% (indicating goblet cell secretion) in sensitised guinea pigs (183 ± 22 mucus score units) compared with controls (372 ± 41 mucus score units). The antihistamines significantly inhibited conjugated trimellitic anhydride-induced bronchoconstriction by 89%, but did not significantly affect goblet cell discharge. Hexamethonium alone did not significantly affect conjugated trimellitic anhydride-induced bronchoconstriction or goblet cell secretion. Capsaicin pretreatment (in combination with hexamethonium) significantly inhibited golet cell discharge (by 80%) but had no significant effect on bronchoconstriction. We conclude that conjugated trimellitic anhydride challenge of trimellitic anhydride-sensitised guinea pigs induces goblet cell discharge and bronchoconstriction via different mechanisms with activation of capsaicin-sensitive sensory nerves responsible for secretion and histamine release responsible for airway constriction. The guinea pig model of trimellitic anhydride-induced occupational asthma may prove useful in examination of mechanisms of goblet cell secretion in allergic diseases.