Peptide Leukotriene Involvement in Pulmonary Eosinophil Migration upon Antigen Challenge in the Actively Sensitized Guinea Pig

Abstract

Male Dunkin Hartley guinea pigs, actively sensitized to ovalbumin (OA) and pretreated with mepyramine (1 mg/kg i.p.), were challenged with OA as an aerosol. Histological analysis of the lung for eosinophils (EOs) showed significant accumulations in the submucosa of the airways (8 h: 1,477.3 ± 43 EOs/mm² airway, n = 3, p < 0.01), after antigen challenge compared to saline control (478.6 ± 104 EOs/mm² airway, n = 4). Pretreatment with both mepyramine and cimetidine (10 mg/kg i.p.) did not affect this response. Aerosolization of OA to unsensitized guinea pigs resulted in no significant accumulation of EOs (360.2 ± 49 EOs/mm² airway, n = 4) when compared with the saline-challenged sensitized control group. Pretreatment with the leukotriene (LT)D₄ receptor antagonist MK-571 (1 mg/kg p.o.) significantly inhibited the OA-induced EO migration (95 ± 5% inhibition, n = 5, p < 0.01) compared to vehicle in the presence of mepyramine and cimetidine, while indomethacin (3 mg/kg p.o., n = 4) had no effect. Aerosolization of synthetic LTC₄ (0.3–30 μg/ml) resulted in a dose-dependent migration of EOs into the submucosal layer over 8 h, reaching significance at the 10-μg/ml dose, with comparable results obtained with LTD₄. Pretreatment of animals with MK-571 (1 mg/kg p.o.) before LTC₄ and LTD₄ aerosol results in inhibition of the response in both cases, suggesting that this effect may be mediated through the LTD₄ receptor. We conclude that peptide LTs produce eosinophilia in the airways of the guinea pig.

International Union of Pharmacology XXXVII. Nomenclature for Leukotriene and Lipoxin Receptors

“…Similar results were obtained with LTC 4 or LTD 4 in guinea pigs (Foster and Chan, 1991;Underwood et al, 1996), with single administration of inhaled LTD 4 elicited a marked increase in eosinophils, which was maintained for at least 4 weeks (Underwood et al, 1996). The receptor responsible for this phenomenon of the cys-LTs appears to be CysLT 1 receptor (Foster and Chan, 1991;Underwood et al, 1996) and, at least in guinea pigs, appeared to involve IL-5 (Underwood et al, 1996), a key cytokine in eosinophil proliferation, activation, and survival. Pobilukast inhibited LTD 4 -induced chemotaxis of peripheral blood eosinophils from nonasthmatic volunteers (Spada et al, 1994).…”

“…For example, inhaled LTE 4 (Laitinen et al, 1993) or LTD 4 selectively increased airway eosinophil numbers when assessed in bronchoalveolar lavage from humans (Smith et al, 1993). Similar results were obtained with LTC 4 or LTD 4 in guinea pigs (Foster and Chan, 1991;Underwood et al, 1996), with single administration of inhaled LTD 4 elicited a marked increase in eosinophils, which was maintained for at least 4 weeks (Underwood et al, 1996). The receptor responsible for this phenomenon of the cys-LTs appears to be CysLT 1 receptor (Foster and Chan, 1991;Underwood et al, 1996) and, at least in guinea pigs, appeared to involve IL-5 (Underwood et al, 1996), a key cytokine in eosinophil proliferation, activation, and survival.…”

“…Although LXA 4 and LXB 4 are similar in structure, these mediators display biological activities that are quite distinct. LXA 4 interactions with neutrophils involves binding sites that are not rec- Dihydroxy-leukotrienes (LTB 4 ) Leukocyte activation Bray et al, 1980;Ford-Hutchinson et al, 1980;Goetzl and Picket, 1980;Serhan et al, 1982 Cytokine secretion Luscinskas et al, 1990;Rola-Pleszczynski et al, 1993 Nuclear transcription (PPAR␣) Devchand et al, 1996IgE synthesis Odlander et al, 1988Yamaoki et al, 1994 Cysteinyl-leukotrienes (LTC 4 , LTD 4 , LTE 4 ) Bronchospasm Drazen et al, 1980;Weiss et al, 1982;Barnes et al, 1984;Jones et al, 1985;Davidson et al, 1987;Smith et al, 1993Plasma exudation Woodward et al, 1983Evans et al, 1985;Obata et al, 1992Vasoconstriction Smedegard et al, 1982Filep et al, 1985;Garcia et al, 1987;Evans et al, 1989Vasodilation Secrest et al, 1985Sakuma and Levi, 1988;Lawson et al, 1989;Pawloski and Chapwick, 1993b;Ortiz et al, 1995 Eosinophil recruitment Foster andChan, 1991;Laitinen et al, 1993;Smith et al, 1993;Spada et al, 1994;Underwood et al, 1996Cardiodepression Levi et al, 1980Burke et al, 1982;Bittl et al, 1985;Roth et al, 1985 Smooth muscle proliferation Wang et al, 1993;…”

Allergen-induced late-phase airways obstruction in the pig: mediator release and eosinophil recruitment

“…LTC 4 and LTD 4 induce a dose-dependent infiltration of eosinophils into the guinea-pig lung, which can be blocked by cys-LT-receptor antagonists [23]. LTD 4 induces both early-and late-phase allergen-induced bronchoconstriction in sheep of the dual-responder type [12], but this phenomenon was not found in humans [24].…”

Cysteinyl Leukotrienes Induce Nasal Symptoms of Allergic Rhinitis via a Receptor-Mediated Mechanism in Guinea Pigs

“…We found that nasal LTD4, but not histamine, challenge induced significant eosinophil infiltration into guinea pigs that persisted until 24 hr after LTD4 challenge. It has been reported that LTD4 (30 yg/ml) inhalation caused prolonged eosinophil infiltra tion into guinea pig lungs (15,16). These results collec tively suggest that LTD4 potently induces eosinophil infiltration.…”