Theresa L. Buckley

Eosinophil infiltration precedes development of airway hyperreactivity and mucosal exudation after intranasal administration of interleukin-5 to mice

Recently, we demonstrated that antibody to interleukin-5 (IL-5) prevents the infiltration of eosinophils in the respiratory airways and the development of bronchial hyperreactivity in an animal model of allergic asthma. In this study we investigated the influence of long-term intranasal administration of IL-5 on airway responsiveness in vitro, the infiltration of inflammatory leukocytes, and mucosal exudation. Mice (BALB/c) received 1 microgram of recombinant human IL-5 in 30 microliters of saline solution or vehicle alone twice a day for 1, 3, and 7 days. At 3 and 7 days after IL-5 administration, the number of bronchoalveolar lavage eosinophils increased approximately fourfold and sixfold, respectively. Blood eosinophil numbers showed a similar increase. In addition, 7 days after IL-5 treatment, total lung eosinophil peroxidase activity was significantly increased by 170% as compared with controls. The maximal responsiveness of the trachea in vitro to methacholine was significantly increased by 34%, as compared with controls, only at 7 days after IL-5 administration. Furthermore, mucosal exudation was also only increased significantly at 7 days after IL-5 administration. It can be concluded that the IL-5-induced eosinophil infiltration precedes the development of airway hyperreactivity and mucosal exudation.

A ROLE FOR NEUROPEPTIDES IN UVB-INDUCED SYSTEMIC IMMUNOSUPPRESSION

The aim of this study was to investigate the possible role of sensory nerves in UV light‐induced systemic immunomodulation. Contact hypersensitivity to the low molecular weight compound picrylchloride was used as a model for cellular immunity that can be suppressed by low (i.e. suberythemal) doses of UV light even after exposure at a distant locus (i.e. systemic immunosuppression). In sensory nerve‐depleted mice, achieved by two subcutaneous injections with the neurotoxin capsaicin before the age of 4 weeks, UV light exposure failed to inhibit contact hypersensitivity responses to picrylchloride. This indicates that sensory nerves are at least partially involved in the induction of systemic immunosuppression by UV light. In order to analyze whether sensory neuropeptides, such as calcitonin gene‐related peptide (CGRP) and tachykinins, are involved in UV light‐induced systemic immunosuppression, mice were pretreated with selective antagonists prior to each UV light exposure. These experiments indicated that CGRP but not the tachykinins plays a crucial role in the UV light‐induced systemic immunosuppression.

Delayed-type hypersensitivity-induced increase in vascular permeability in the mouse small intestine: inhibition by depletion of sensory neuropeptides and NK1 receptor blockade.

1 This study investigates the effects of capsaicin‐induced depletion of sensory neuropeptides and of neurokinin! (NK1) receptor blockade on delayed‐type hypersensitivity (DTH)‐induced changes of vascular permeability in the small intestine of the mouse.

Olvanil : more potent than capsaicin at stimulating the efferent function of sensory nerves

The capsaicin analogue olvanil stimulated an increase in cutaneous blood flow when injected intradermally into the anaesthetised rabbit, as measured using a 133Xenon clearance method. Olvanil was found to be a 10-fold more potent vasodilator (on a molar basis) than capsaicin. The effect of both vasodilators was significantly inhibited by the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP-(8-37). These findings suggest that olvanil stimulates the efferent function of cutaneous sensory nerves in a more potent manner than capsaicin. We therefore suggest that olvanil is a useful pharmacological tool for studying the activity of neuropeptides released from sensory nerves.

13-hydroxyoctadecadienoic acid attenuates oedema formation induced by leukotriene B4 in vivo in rabbit skin.

Intradermal 13-hydroxyoctadecadienoic acid (13-HODE; 10(-11)-10(-9) mol/site) inhibited oedema formation induced by the neutrophil-dependent mediator leukotriene B4 (LTB4) in the presence of calcitonin gene-related peptide (CGRP; 10(-11) mol/site) in rabbit skin. In contrast, the responses to the direct acting mediators bradykinin and histamine were unaffected by 13-HODE. 13-HODE failed to induce oedema formation in rabbit skin when injected alone or in the presence of the potent vasodilator CGRP. These results present a novel interaction between 13-HODE and LTB4 that could have important implications in the pathogenesis of inflammation.

Hypotensive effect of 13-hydroxylinoleic acid in the rat : mediation via the release of a CGRP-like mediator from capsaicin-sensitive nerves

1 The effect of 13‐hydroxylinoleic acid (13‐HODE) on changes in blood pressure in the rat was measured. 2 13‐HODE (0.1 −100 μg kg−1) had no direct eifect on blood pressure in the rat and had no eifect on histamine (0.1–1000 μg kg−1‐induced changes in blood pressure. In contrast, it was found that 13‐HODE itself induced a decrease in diastolic arterial blood pressure when it was injected intravenously after either a single dose of histamine (10, 100 or 1000 μg kg−1) or after a dose‐response curve of histamine (0.1–1000 μg kg−1). 3 This hypotensive eifect of 13‐HODE was not observed after administration of the endothelium‐dependent vasodilator, acetylcholine (0.1–10 μg kg−1), the endothelium‐independent vasodilator, sodium nitroprusside (0.1–100 μg kg−1) or the inflammatory mediator, leukotriene B4 (0.1–300 μg kg−1). However, prior injection of bradykinin (0.1–100 μg kg−1) allowed a dose‐dependent hypotensive effect of 13‐HODE to be revealed. 4 The hypotensive effect of 13‐HODE after histamine and bradykinin could be inhibited by neonatal capsaicin treatment of the rats (50 mg kg−1, s.c. on day 1 and 2 after birth). 5 Ruthenium red (120 μg kg−1 min−1), an inhibitor of excitatory effects on sensory nerves, and the CGRP antagonist, CGRP8.37 (1–3 μg kg−1 min−1) also inhibited the hypotensive effect of 13‐HODE. 6 It is concluded that the hypotensive effect of 13‐HODE in the rat after histamine and bradykinin is due to the release of a CGRP‐like substance from sensory nerves. These results highlight the possibility that endogenous 13‐HODE could be involved in the neurogenic regulation of blood pressure.

LCB 2183 inhibits tracheal hyperreactivity and pulmonary inflammation in mouse airways

The pulmonary delayed-type hypersensitivity (DTH) reaction induced by picryl chloride is characterized by enhanced albumin concentration in the airway tissue in the early phase (2 h after challenge with picryl sulphonic acid). During the later phase (48 h after the challenge) enhanced tracheal reactivity to carbachol in vitro and cellular (mononuclear and polymorphonuclear leukocytes) accumulation into the airway tissue in vivo are prominent features. In this present study, the effects of a novel drug, LCB 2183, were examined in the pulmonary DTH reaction. LCB 2183 (25 mg/kg twice daily intragastric gavage) failed to inhibit the enhanced albumin accumulation in the early phase of this response. In contrast, LCB 2183 abolished the tracheal hyperreactivity and the leukocyte accumulation in the airways of picryl chloride-sensitized mice 48 h after the challenge. These results demonstrate that LCB 2183 could be effective in the treatment of airway hyperreactivity and pulmonary inflammation.