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'-diisocya nate (MDI) by two intradermal injections (1-10% MDI, injection volumes of 50-100 mu l/day, on days 0, 2 and 4) or by a single brief high-con centration inhalation exposure (135 or 360 mg/m(3), 15 min). Starting with day 21 following sensitization the animals were subjected to inha lation-challenge exposures (30 min) with non-irritating and irritating concentrations of the hapten (MDI). MDI-challenge concentrations rang ed from 3.3 +/- 0.9 to 60 +/- 14.3 mg/m(3) air. In some groups guinea- pigs were also challenged with acetylcholine (ACh) aerosol or the MDI- guinea pig serum albumin (GPSA) conjugate. Experimental findings indic ated that from intradermally sensitized animals an immediate onset res piratory hypersensitivity response could only be elicited with concent rations exceeding the irritant threshold concentration for MDI, i.e. w ith concentrations greater than similar to 20 mg/m(3) air. Guinea-pigs challenged with the MDI-GPSA conjugate (35.3 +/- 2.8 mg/m(3) air) als o experienced a weak immediate-type respiratory hypersensitivity respo nse. An increased non-specific airway hyper-responsiveness following A Ch-challenge was only observed from animals challenged with approximat ely 60 mg MDI/m(3) air. The histopathological evaluation of lungs and lung-asso iated 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 sensi tized by a single 15-min inhalation exposure to either 135 or 360 mg M DI/m(3) air were challenged sequentially with 12 +/- 2.1 mg MDI/m(3) a ir, ACh and MDI-GPSA conjugate. Following the inhalation-induction, an airway hyper-responsiveness was elicited both after challenge with MD I and with the MDI-GPSA conjugate. The influx of eosinophilic granuloc ytes was more pronounced from animals sensitized by inhalation when co mpared with guinea-pigs sensitized intradermally and challenged with t he same concentration of MDI. Thus, experimental findings suggest that elicitation of respiratory hypersensitivity is concentration-dependen t and that challenge concentrations should slightly exceed the thresho ld concentration for irritation (similar to 20 mg/m(3)). Sensitization by inhalation increased the susceptibility to irritant stimuli and th us confounds the selection of the most appropriate concentration for c hallenge. However, the combined assessment of specific pathologic feat ures such as airway eosinophilia and the evaluation of several breathi ng parameters during hapten- and ACh-challenge make it easier to disti nguish effects caused by irritation and respiratory hypersensitivity. It would also appear that the intradermal-induction inhalation-challen ge protocol is less susceptible to influences pertinent to irritation- induced airway hyper-reactivity than the inhalation-induction inhalati on-challenge protocol.