Assessment of respiratory hypersensitivity in guinea-pigs sensitized to diphenylmethane-4,4'-diisocyanate (MDI) and challenged with MDI, acetylcholine or MDI-albumin conjugate.
Guinea-pigs were sensitized to monomeric diphenylmethane-4,4'-diisocyanate (MDI) by two intradermal injections (1-10% MDI, injection volumes of 50-100 microliters/day, on days 0, 2 and 4) or by a single brief high-concentration inhalation exposure (135 or 360 mg/m3, 15 min). Starting with day 21 following sensitization the animals were subjected to inhalation-challenge exposures (30 min) with non-irritating and irritating concentrations of the hapten (MDI). MDI-challenge concentrations ranged from 3.4 +/- 0.9 to 60 +/- 14.3 mg/m3 air. In some groups guinea-pigs were also challenged with acetylcholine (ACh) aerosol or the MDI-guinea pig serum albumin (GPSA) conjugate. Experimental findings indicated that from intradermally sensitized animals an immediate onset respiratory hypersensitivity response could only be elicited with concentrations exceeding the irritant threshold concentration for MDI, i.e. with concentrations greater than approximately 20 mg/m3 air. Guinea-pigs challenged with the MDI-GPSA conjugate (35.3 +/- 2.8 mg/m3 air) also experienced a weak immediate-type respiratory hypersensitivity response. An increased non-specific airway hyper-responsiveness following ACh-challenge was only observed from animals challenged with approximately 60 mg MDI/m3 air. The histopathological evaluation of lungs and lung-associated lymph nodes revealed an association of the increase in eosinophilic granulocytes and concentration of MDI used for challenge exposures. It appeared, in most instances, that this influx was more pronounced in animals sensitized with MDI as compared with concurrent controls challenged with the same MDI concentration. Guinea-pigs sensitized by a single 15-min inhalation exposure to either 135 or 360 mg MDI/m3 air were challenged sequentially with 12 +/- 2.1 mg MDI/m3 air, ACh and MDI-GPSA conjugate. Following the inhalation-induction, an airway hyper-responsiveness was elicited both after challenge with MDI and with the MDI-GPSA conjugate. The influx of eosinophilic granulocytes was more pronounced from animals sensitized by inhalation when compared with guinea-pigs sensitized intradermally and challenged with the same concentration of MDI. Thus, experimental findings suggest that elicitation of respiratory hypersensitivity is concentration-dependent and that challenge concentrations should slightly exceed the threshold concentration for irritation (approximately 20 mg/m3). Sensitization by inhalation increased the susceptibility to irritant stimuli and thus confounds the selection of the most appropriate concentration for challenge. However, the combined assessment of specific pathologic features such as airway eosinophilia and the evaluation of several breathing parameters during hapten- and ACh-challenge make it easier to distinguish effects caused by irritation and respiratory hypersensitivity.(ABSTRACT TRUNCATED AT 400 WORDS)
Pauluhn
J
J
Institute of Toxicology, BAYER AG, Wuppertal, Germany.
Mohr
U
U
D000109:Acetylcholine / Q000276:immunology*; D000280:Administration, Inhalation; D000818:Animals; D001273:Atmosphere Exposure Chambers; D004804:Eosinophils; D005260:Female; D006168:Guinea Pigs; D006241:Haptens / Q000008:administration & dosage / Q000276:immunology*; D007271:Injections, Intradermal; D017953:Isocyanates / Q000008:administration & dosage / Q000276:immunology*; D008168:Lung / Q000473:pathology; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D012129:Respiratory Function Tests; D012130:Respiratory Hypersensitivity / Q000139:chemically induced* / Q000473:pathology; D012709:Serum Albumin / Q000276:immunology; D001559:Benzhydryl Compounds
D000109:Acetylcholine; D006241:Haptens; D017953:Isocyanates; D012709:Serum Albumin; C005969:4,4'-diphenylmethane diisocyanate; D001559:Benzhydryl Compounds