EPITHELIUM-LINKED SMOOTH-MUSCLE HYPERRESPONSIVENESS IN FERRET TRACHEAS EXPOSED TO ACROLEIN

The effects of acrolein exposure on tissue uptake and airway responses to substance P (SP) and nitroprusside (NIP) were determined in excise d ferret tracheae exposed for 60 min to a constant flow of air or 0.3 and 3.5 ppm acrolein-air mixtures. Histological examination indicated that whereas the epithelium of an air-exposed trachea was intact with no apparent injury, acrolein-induced epithelium damage was more pronou nced at 3.5 than at 0.3 ppm vapor concentration. The fractional uptake of acrolein into the tracheal tissue continually decreased during the 1 h of exposure and was found to be significantly concentration depen dent at the 60 min measurement point. This suggests that the uptake pr ocess of acrolein in the mucosal layer is not linear and is dominated by irreversible reaction. In the absence of the neutral endopeptidase inhibitor, phosphoramidon, acrolein significantly increased the maxima l response to SP. Pretreatment with phosphoramidon abolished the diffe rential effect of acrolein on airway smooth muscle response to SP. Nit roprusside relaxed acrolein-exposed tracheal rings precontracted with carbachol to their baseline tone, but it induced relaxation of air-exp osed tracheal rings below their initial resting tension, indicating th e presence of endogenous as well as induced tone. Pretreatment with NI P also abolished the differential effect of acrolein on airway respons e to carbachol and modified the potency of this agonist. We conclude t hat acrolein-induced hyperresponsiveness of the underlying airway smoo th muscle is linked to inactivation of neutral endopeptidase synthesis as well as to loss of epithelium-derived relaxation factor.