Leukotriene E4-induced airway hyperresponsiveness of guinea pig tracheal smooth muscle to histamine and evidence for three separate sulfidopeptide leukotriene receptors.

Abstract

Bronchial hyperresponsiveness to contractile agonists and nonspecific irritants is a characteristic feature of bronchial asthma. The mechanisms causing this hyperirritability are unknown. The existence of separate receptors for leukotrienes C4 and D4 (LTCC4 and LTD4) has been, demonstrated previously by physiologic and radioligand binding studies. The rank order of potency of the sulfidopeptide leukotrienes for contracting tracheal spirals [leukotrwiene E4 (LTE4) > LID4 = LTC4J is different from that for contracting parenchymal strips (LTD4> LTE4> LTC4), thereby suggesting the existence of a separate receptor for LTE4. We now report that 'LTE4, the most stable of the leukotrienes comprising slow reacting substance of anaphylaxis, enhances the contractile response of guinea pig tracheal spirals but not of parenchymal strips, to histamine in a time-and dose-dependent fashion., The ability of LTE4 to increase histamine responsiveness occurred after removal of the free agonist and recovery of the tissues to baseline tensions and was not produced by lemkotrienes C4 and Lr4, which elicited the same magnitude of contraction of tracheal smooth muscle as LTE4. These findings suggest that LTE4-induced airway hyperirritability is not mediated by the contractile response per se and may be modiated through a receptor distinct from those for leukotrienes C4 and D4.

Identification of GPR99 Protein as a Potential Third Cysteinyl Leukotriene Receptor with a Preference for Leukotriene E4 Ligand

“…In contrast, pretreatment with LTE 4 , but not LTC 4 or LTD 4 , enhanced the response of guinea pig trachea (9) or human bronchial smooth muscle to histamine (10). Furthermore, in limited studies, LTE 4 was comparable with LTC 4 or LTD 4 in eliciting a vascular leak in skin in guinea pigs (11) or humans (12), and inhalation of LTE 4 , but not LTD 4 , by patients with asthma elicited an accumulation of eosinophils and basophils into the bronchial mucosa (13,14).…”

Aerosolized and intravenously administered leukotrienes: effects on the bronchoconstrictor potency of histamine in the guinea‐pig

“…It may be concluded that, under physiological conditions, neither LTC4 nor LTD4 induces increased responsiveness to histamine on airways smooth muscle. However, the sensitivity oftracheal smooth muscle to histamine determined by Lee et al, (1984) was considerably less (approx. 0.7 log units) that that determined in the present study and by other workers (cf.…”

“…This occurred (i) under conditions of lowered Ca2" concentration (0.1 mM), but not where Ca2+ (2.5 mM) was used (Creese & (Lee et al, 1984). It may be concluded that, under physiological conditions, neither LTC4 nor LTD4 induces increased responsiveness to histamine on airways smooth muscle.…”

“…There is increasing pharmacological (Fleisch et al, 1982;Gleason et al, 1982;Lee et al, 1984) and biochemical evidence (Hogaboom et al, 1983;Cheng & Townley, 1984) of multiple receptors for the leukotrienes. The lack ofenhancement by LTC4 may be explained by the existence ofa receptor for LTD4 which is not activated by LTC4.…”

“…A number of studies suggest that airways inflammation may be responsible for the increased airways reactivity which 'Present address and address for correspondence: Department is a characteristic feature of asthma (Empey et al, 1976;Hogg, 1981;Cartier et al, 1982;Malo et al, 1983;Kaliner, 1984. ) Thus, the possibility that leukotrienes may contribute to airways hyperreactivity has gained attention in recent studies which have provided experimental evidence for supra-additive interactions of leukotrienes with: histamine in vitro (Creese & Bach, 1983; Lee et al, 1984) in the guinea-pig; histamine in vivo in the guinea-pig (Stewart et al, oxygenase products (Vargaftig et al, 1981;Folco et al, 1982;, when administered by aerosol, they appear to elicit a direct bronchoconstrictor effect (Hamel et al, 1982;Dahlen, 1983;Leitch et al, 1983).…”