The effect of epithelium removal on leukotriene E4-induced histamine hyperresponsiveness in guinea-pig tracheal smooth muscle.

1. Removal of the epithelium resulted in a threefold increase in guinea-pig tracheal sensitivity to histamine without increasing the maximal response. 2. Preincubation of epithelially-denuded guinea-pig tracheal smooth muscle with leukotriene E4 (LTE4) in vitro increased the subsequent maximal response of the tissues to histamine. The sensitivity of the tissues to histamine was unaffected by LTE4 pretreatment. 3. Pretreatment of the epithelially-denuded tissues with the LTE4-analogue, 20-COOH LTE4, did not affect the maximal response to histamine. 4. LTE4 pretreatment increased the maximal response of the epithelially-denuded tissues to substance P (SP) but did not affect the maximal response to carbachol, KCl nor to the beta-adrenoceptor agonist, isoprenaline. 5. LTE4-induced airway histamine hyperresponsiveness was blocked by indomethacin (5 microM), GR32191 (3 microM) and atropine (1 microM). 6. Both LTE4 and U46619 pretreatment increased the contractile response of tracheal smooth muscle to electrical field stimulation. 7. It is proposed that LTE4 induces an increased maximal response of epithelially-denuded guinea-pig airway smooth muscle to both histamine and substance P via a facilitation of cholinergic neurotransmission, which is dependent upon the secondary generation of prostanoid mediator(s) acting on TP-receptors situated on cholinergic nerve terminals. Further, it is suggested that the increased maximal response of the epithelially-intact tissues to both histamine and substance P, after LTE4 pretreatment, may be suppressed by an epithelially-derived factor.