Regional and time-dependent effects of inflammatory mediators on airway microvascular permeability in the guinea pig

Abstract

1. Airway oedema resulting from increased microvascular permeability is a characteristic pathological finding of asthma. The regional effects of putative mediators involved in asthma on airway microvascular permeability have been studied. 2. The effects of histamine, leukotriene (LT) D4 and platelet-activating factor (PAF) on microvascular permeability in the nasal mucosa, larynx, trachea, main bronchi and intrapulmonary airways of the guinea pig were assessed by measuring the extravasation of intravenously administered Evans Blue dye. 3. PAF and LTD4 caused increased microvascular leakage throughout the respiratory tract, although their effects were maximal in different regions. Histamine had no significant effect on intrapulmonary airways. PAF was more potent than LTD4 and histamine at all airway levels. For example, in the trachea the doses required to cause leakage of 50% of maximal (ED50) were 10.4 nmol/kg, 138 nmol/kg and 11.2 mumol/kg, respectively, for PAF, LTD4 and histamine. 4. The effect of the three mediators was maximal 5 min after intravenous administration. Histamine, but neither LTD4 nor PAF, still caused significant leakage 30 min after administration. 5. The increased microvascular leakage induced by the mediators was inhibited by their respective specific receptor antagonists, suggesting that the effect was mediated via specific receptors. 6. Histamine, LTD4 and PAF have varying potencies in increasing microvascular permeability in the guinea-pig respiratory tract, exert their maximal effect in different regions and have varying durations of action.

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

“…There are several reports that the cys-LTs increase microvascular permeability in guinea pig airways (Woodward et al, 1983a,b;Evans et al, 1989;Bochnowicz and Underwood, 1995); the mechanism may involve contraction of endothelial cells resulting in gaps in the endothelium of venules (Joris et al, 1987). This influence of the cys-LTs, which appeared to involve both direct and indirect pathways, was inhibited by either FPL 55712 (Woodward et al, 1983a) or pranlukast Bochnowicz and Underwood, 1995) indicating that a CysLT 1 receptor was involved.…”

“…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;…”

Therapeutic Effect of Pranlukast, a Selective Cysteinyl Leukotriene Receptor Antagonist, on Bronchial Asthma

“…Cysteinly leukotrienes (LTs) are now well recognized as inducing potent constriction of the human bronchi [1], in flammation in the airways [2,3], and increasing human bronchial hyperresponsiveness in asthmatics [4], These re sults suggest that LTs could play an essential role in the pathogenesis of bronchial asthma. Pranlukast, a selective LTC4/D 4/E4 receptor antagonist, developed in Japan, has been in clinical use since June 1995 for the treatment of bronchial asthma, and its clinical usefulness is now being K ARfiFR © 1997 S. Karger AG, Basel C l \ | 0lg 2438/97/1141 0097S 12.00/0 E-Mail kargere« karger.ch Fax +41 61 306 12 34 This article is also accessible online at: http://www.karger.ch http://BioMedNet.com/karger evaluated by physicians.…”

Increase in vascular permeability produced in rat airways by PAF: potentiation by adrenalectomy

“…The effect of inflammatory mediators on airway vascular permeability is regionally dependent (Evans et al, 1989), and indeed we observed that a significant amount of plasma extravasation was induced by a lower dose of PAF (500 ng kg-') in the larynx and trachea compared with smaller airways. We also observed that adrenalectomy potentiates PAF-induced increase in vascular permeability in the larynx, trachea, main bronchi, but not in the intrapulmonary airways.…”