Effect of a 5‐lipoxygenase inhibitor and leukotriene antagonist (PF 5901) on antigen‐induced airway responses in neonatally immunized rabbits

Abstract

1 The effect of a single intratracheal dose (10 mg) of phenoxymethyl] quinoline hydrochloride, a specific inhibitor of the 5-lipoxygenase pathway of arachidonic acid metabolism and a leukotriene D4 antagonist) on airway changes induced in response to Alternaria tenuis aerosol challenge was assessed in adult rabbits neonatally immunized. Leukotriene generation was determined in vivo by measuring leukotriene B4 (LTB4) levels in bronchoalveolar lavage (BAL) fluid and ex vivo by measuring calcium ionophore-stimulated production of LTB4 in whole blood. 2 While PF 5901 (10 mg) had no significant effect on the acute bronchoconstriction induced by antigen, this dose was sufficient to inhibit significantly the increase in airway responsiveness to inhaled histamine 24 h following antigen challenge (P<0.05). 3 Total leucocyte infiltration into the airways induced by antigen, as assessed by bronchoalveolar lavage, was significantly inhibited by pretreatment with PF 5901 (10 mg). However, the pulmonary infiltration of neutrophils and eosinophils induced by antigen was unaltered by prior treatment with PF 5901 (10 mg). 4 PF 5901 (1O mg) had no effect on ex vivo LTB4 synthesis in whole blood. However, the antigeninduced increase in LTB4 levels in BAL 24 h following challenge was significantly inhibited (P<0.05). 5 We suggest from the results of the present study that the antigen-induced airway hyperresponsiveness to inhaled histamine in immunized rabbits is mediated, at least in part, by products of the 5-lipoxygenase metabolic pathway, and is not dependent on the extent of eosinophil or neutrophil influx into the airway lumen.

Effect of the glucocorticosteroid budesonide and a novel phosphodiesterase type 4 inhibitor CDP840 on antigen‐induced airway responses in neonatally immunised rabbits

“…Since capsaicin (Herd et al, 1995) and the mixed 5-lipoxygenase/leukotriene D4 antagonist PF5901 (Herd et al, 1994) inhibited the development of airway hyperresponsiveness following antigen challenge in the rabbit, it has been suggested that a leukotriene-mediated activation of sensory C-fibres may contribute to antigen-induced airway hyperresponsiveness in this model. Interestingly, a range of PDE 4 inhibitors have been shown to inhibit electrical field stimulated excitatory nonadrenergic, non-cholinergic (eNANC) contraction of guineapig isolated bronchi in vitro whilst having no effect on contraction due to exogenous substance P (Qian et al, 1994;Spina et al, 1995).…”

“…Inhaled antigen in adult rabbits can elicit a similar sequence of events as seen in atopic asthmatics, including an acute bronchospasm and late phase obstruction (Larsen et al, 1987), airway hyperresponsiveness (AHR) (Bloom et al, 1988;Herd et al, 1994) and pulmonary eosinophil recruitment (Marsh et al, 1985;Herd et al, 1994).…”

A method for the long-term exposure of rabbits to environmental pollutant gases

“…These responses are attenuated by clinically useful anti-asthma drugs [16], and the animals develop 2-6 fold increases in acute airway responsiveness, which resolves in one week [14,15,17,18]. Repeated measurements of lung function are readily made in the rabbit, and each animal may be used as its own control [18,19]. Taking this all together, led us to use the rabbit as the species of choice in our experiments investigating the effects of exposure to pollutant gases from birth.…”

The effect of prolonged exposure to NO2 from birth on airways responsiveness in rabbits sensitized at birth

“…They undergo early and late airways responses following antigen challenge [16][17][18], which is associated with airways oedema and inflammatory cell infiltration [19,20], are hyperresponsive to inhaled histamine and methacholine compared with naive rabbits [21,22], and exhibit airways hyperresponsiveness following challenge with either antigen or platelet-activating factor [18][19][20][21]. Repeated measurements of lung function are readily made in the rabbit, and each animal may be used as its own control [22][23][24]. We have, therefore, chosen the rabbit as the species in which to conduct our experiments investigating the effects of exposure to pollutant gases from birth.…”