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

Abstract

1 Aerosol administration of platelet activating factor (PAF) (80pjgml' for 60min) to neonatally immunized rabbits caused bronchoconstriction which was far in excess of that produced by a comparable aerosol of bovine serum albumin (BSA) D4 antagonist, at a dose of 10 mg (direct intratracheal administration) significantly inhibited the airway resistance (RL) component of the bronchoconstriction induced by PAF in neonatallyimmunized rabbits. Doses of 10 mg, 3 mg and 1 mg PF 5901 (direct intratracheal administration) were sufficient to inhibit significantly the PAF-induced increase in airways responsiveness to inhaled histamine in immunized rabbits. PF 5901 however, failed to alter the pulmonary cell infiltration induced by PAF, as assessed by BAL. 5 We suggest from the results of the present study that PAF induces consistent and long-lasting increases in airways responsiveness to histamine in immunized rabbits, which is mediated, at least in part, by products of the 5-lipoxygenase metabolic pathway. Furthermore, the inability of PF5901 to inhibit the influx of inflammatory cells into the airway lumen following PAF challenge may suggest that bronchial hyperresponsiveness and cellular infiltration are not strictly associated events.

Effect of PF 10040 on PAF‐induced airway responses in neonatally immunized rabbits

“…In agreement with previous studies PAF was found to induce an influx of inflammatory cells into the airways (predominantly neutrophils and eosinophils) as assessed by bronchoalveolar lavage (BAL) (Herd et al, 1992). The accumulation and activation of inflammatory cells within the airways has been suggested to lead to epithelial damage causing the exposure of nerve endings in the bronchial lumen, which are thought to initiate an increase in airway responsiveness (Barnes, 1986).…”

“…This observation supports previous findings in this model suggesting that eosinophil infiltration and airway hyperresponsiveness may be unrelated events. The 5-lipoxygenase activating protein (FLAP) inhibitor, PF 5901, did not inhibit PAF-induced cell infiltration despite inhibiting the associated airway hyperresponsiveness (Herd et al, 1992) and pretreatment of rabbits with capsaicin has been shown to inhibit airway hyperresponsiveness but not the pulmonary eosinophil infiltration induced by PAF (Spina et al, 1991). Furthermore, in guinea-pigs, capsaicin will inhibit allergeninduced airway hyperresponsiveness without modifying pulmonary eosinophil influx (Ladenius & Biggs, 1989;Matsuse et al, 1991) and certain cytokines have been shown to cause pulmonary eosinophilia without eliciting airway hyperresponsiveness (Kings et al, 1990).…”

“…A role for the lipoxygenase products of arachidonic acid, particularly leukotrienes formed by the 5-lipoxygenase pathway, has been suggested to account for a number of PAF-induced effects in rabbits, including bronchoconstriction and the increase in airway responsiveness to histamine following PAF exposure (Herd et al, 1992).…”

“…Furthermore, we have investigated the ability of PF 10040 to influence bronchoconstriction, pulmonary cell infiltration and airway hyperresponsiveness induced by PAF in spontaneously breathing rabbits. Immunized rabbits have been used as we have previously shown that while aerosolized PAF will induce airway hyperresponsiveness to inhaled histamine in only a proportion of normal rabbits, it is effective in all rabbits that have been neonatally immunized with antigen (Herd et al, 1992). ' Author for correspondence.…”

Effect of heparin and a low‐molecular weight heparinoid on PAF‐induced airway responses in neonatally immunized rabbits

“…PAF has been employed in this study to induce airway hyperresponsiveness in rabbits as we have previously reported that this is a useful test system for the evaluation of pharmacological agents and is simpler and more robust method than antigen challenge. We have utilized antigen-immunized rabbits in this study as we have previously shown that PAF can induce airway hyperresponsiveness to inhaled histamine in all neonatally immunized rabbits to some degree (Herd et al, 1992), whereas only in some, but not all normal rabbits (Coyle et al, 1990;Herd et al, 1992). Therefore, in the present study we have investigated the effects of heparin and related compounds on PAF-induced airway hyperresponsiveness and pulmonary cell infiltration in neonatally antigen-immunized rabbits in vivo.…”