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We recently reported that inhaled acetaldehyde causes bronchoconstriction indirectly via histamine release in patients with asthma. The purpose of this study was to investigate a role of thromboxane [A.sub.2] in [...]

The purpose of this study was to evaluate the relationship between the wall structure assessed by using endobronchial ultrasonography (EBUS) and bronchial hyperresponsiveness in patients with asthma.

Chronic cough is the only symptom of cough variant asthma (CVA) and atopic cough (AC). Cysteinyl leukotriene receptor antagonists have been shown to be effective in CVA, but there are no reports on their effectiveness in AC. To evaluate the antitussive effect of montelukast, a leukotriene receptor antagonist, in CVA and AC.

Phosphodiesterase 4 selective inhibitor may prevent airway inflammation and remodeling.

30–80% of outgrown asthma subjects develop symptoms again later in life. We investigated inflammation and function of lower airway in adolescents with former asthma.

Bronchial asthma is a chronic inflammatory disease of the conducting airways. Current asthma treatment guidelines recommend inhaled corticosteroids (ICS) as the first-line maintenance therapy for mild to severe persistent asthma, because ICS are the most efficacious anti-inflammatory medication. Despite treatment with ICS, suppression of inflammation is often incomplete and blockade by ICS of cysteinyl leukotriene (CysLT) and thromboxane (TX) A2biosynthesis is limited. The addition of a CysLT1receptor antagonist to an ICS represents a reasonable alternative therapeutic approach for the treatment of asthma patients whose symptoms remain uncontrolled on ICS alone. Indeed, CysLT1receptor antagonists are demonstrated both to have an additive effect to ICS therapy and to allow the reduction of ICS dosage. Thromboxane modifiers also have an additive effect with low- to moderate-dose ICS. Although the long-term usefulness of add-on therapy of CysLT or TX modifiers (vs long-acting β2-adrenergic receptor agonists) to ICS is unclear, these alternatives are worthy of further consideration.

Phosphoinositide 3-kinase (PI3K) is thought to contribute to the pathogenesis of asthma by effecting the recruitment, activation, and apoptosis of inflammatory cells. We examined the role of class IA PI3K in antigen-induced airway inflammation and hyperresponsiveness by i.p. administration into mice of Δp85 protein, a dominant negative form of the class IA PI3K regulatory subunit, p85α, which was fused to HIV-TAT (TAT-Δp85). Intraperitoneal administration of TAT-Δp85 caused time-dependent transduction into blood leukocytes, and inhibited activated phosphorylation of protein kinase B (PKB), a downstream target of PI3K, in lung tissues in mice receiving intranasal FMLP. Antigen challenge elicited pulmonary infiltration of lymphocytes, eosinophils and neutrophils, increase in mucus-containing epithelial cells, and airway hyperresponsiveness to methacholine. Except for modest airway neutrophilia, these effects all were blocked by treatment with 3–10 mg/kg of TAT-Δp85. There was also significant reduction in IL-5 and IL-4 secretion into the BAL. Intranasal administration of IL-5 caused eosinophil migration into the airway lumen, which was attenuated by systemic pretreatment with TAT-Δp85. We conclude that PI3K has a regulatory role in Th2-cell cytokine secretion, airway inflammation, and airway hyperresponsiveness in mice.

Background:Prior investigations have demonstrated that β2-adrenoceptor stimulation is ineffective in inhibiting synthesis of eicosanoids in human eosinophils. This effect has been postulated to relate to density or structural differences in the β2-adrenoceptor or its coupled G-protein. However, recent reports indicate that cAMP-specific PDE4 activity in eosinophils is 10-fold that of other inflammatory cells. We postulated that selective blockade of PDE4 in eosinophils would unmask the inhibitory effect of β2-adrenoceptor stimulation and that this inhibition would result from decreased phosphor-ylation of cytosolic group IV-PLA2(gIV-PLA2). Objective:To determine (a) whether PDE4 inhibition alone with rolipram blocked secretions of arachidonic acid (AA) and leukotriene C4(LTC4) caused by activation of eosinophils with formyl-met-leu-phe plus cytochalasin B (FMLP/B), (b) to determine if PDE4 inhibition plus β2-adrenoceptor agonist act additively to augment endogenous cAMP concentration, and (c) to determine the mechanism by which additive inhibition of AA and LTC4synthesis is regulated by cAMP. Methods:Human eosinophils were pretreated with buffer, salmeterol or rolipram (singly or combination) before FMLP/B activation. Release of AA and LTC4, intracellular cAMP concentration, and phosphorylation and activation of gIV-PLA2were determined. Results:Rolipram unmasked the inhibitory effect of β2-adrenoceptor stimulation with salmeterol and significantly attenuated the stimulated release of AA and subsequent LTC4. Inhibition corresponded to increased cAMP production caused by rolipram alone or rolipram plus salmeterol and blocked proportionately the phosphorylation and activation of gIV-PLA2in FMLP/B-activated eosinophils. Conclusions:Inhibition of PDE4 by rolipram unmasks β2-adrenergic blockade of LTC4synthesis caused by FMLP/B. (J Allergy Clin Immunol 2003;112:404-10.)

We examined the mechanism by which interleukin (IL)‐5 causes β2‐integrin adhesion of human eosinophils. IL‐5 caused time‐dependent activation of extracellular signal‐regulated kinases 1 and 2 (ERK1/2) and p38α in eosinophils as detected by their phosphorylation. Preincubation of eosinophils with U0126, a mitogen‐activated protein kinase/ERK kinase inhibitor, suppressed IL‐5‐induced activation of cytosolic phospholipase A2(cPLA2) and eosinophil adhesion, and p38 inhibition by SB203580 had neither effect. ERK1/2 phosphorylation and eosinophil adhesion were blocked by inhibition of the src‐family tyrosine kinase, Janus tyrosine kinase (JAK)2, or phosphoinositide‐3 kinase (PI3K). Coimmunoprecipitation assay demonstrated that Lyn, a src‐family tyrosine kinase, was constitutively associated with PI3K. Inhibition of src‐tyrosine kinase but not JAK2 suppressed PI3K activation. Our data suggest that IL‐5 induces β2‐integrin adhesion of human eosinophils by regulation of cPLA2activation caused by ERK1/2 phosphorylation. This phosphorylation results from activation of PI3K and protein tyrosine kinases. We also find that src‐family tyrosine kinase, possibly Lyn, is the upstream kinase causing PI3K activation.

Acetaldehyde is thought to be a main factor of alcohol-induced asthma. The thromboxane (TX) synthetase inhibitor, ozagrel hydrochloride, inhibits acetaldehyde-induced bronchoconstriction in asthmatic patients. The present study evaluated the involvement of TXA2on alcoholic beverage-induced bronchoconstriction. Four patients with alcohol-induced asthma received ozagrel (400 mg for 4 days) or placebo using a single-blind, randomized, cross-over design. On two separate study days, each subject drank the same brand and volume of alcoholic beverage (beer or Japanese sake) and bronchoconstriction was assessed as the change in peak expiratory flow (PEF). The effect of ozagrel on the aerosolized challenge of acetaldehyde was investigated in the same subjects. Although aerosolized acetaldehyde-induced bronchoconstriction was significantly prevented by ozagrel, there were no differences in the time course of the decrease in PEF or the maximum fall in PEF after alcohol intake between placebo and ozagrel. We conclude that TXA2is not involved in alcoholic beverage-induced bronchoconstriction.

1Inhalation of ultrasonically nebulized distilled water (UNDW) can induce bronchoconstriction only in asthmatics, but mechanisms of the response are not well known. We recently reported a guinea‐pig model of UNDW‐induced bronchoconstriction (UNDW‐IB) in which UNDW induces bronchoconstriction when UNDW is inhaled 20 min after a challenge with aerosolized ovalbumin (OA) in passively sensitized, anaesthetized and artificially ventilated guinea‐pigs.2To elucidate the role of histamine in the UNDW‐IB, we examined the effects of antihistamines, diphenhydramine hydrochloride (DH) and chlorpheniramine maleate (CP), and measured histamine content in bronchoalveolar lavage fluid (BALF) in the animal model.3DH in doses of 0.1, 1.0 and 10 mg kg−1and CP in doses of 0.01, 0.1 and 1.0 mg kg−1administered intravenously 15 min after the OA challenge partially reduced the UNDW‐IB at 1 and 2 min after the UNDW inhalation in a dose‐dependent manner. Histamine content in BALF recovered 10 min after the UNDW inhalation following the OA provocation was significantly increased compared with that after saline inhalation and before the UNDW inhalation following the OA challenge.4Intravenous atropine in a dose of 0.5 mg kg−1or inhaled disodium cromoglycate in concentrations of 1 and 10 mg ml−1did not alter the UNDW‐IB.5These results suggest that histamine is involved in part in the UNDW‐IB in our animal model.

1Although repeated intranasal administration of interleukin‐8 (IL‐8) causes bronchial hyperresponsiveness (BHR) mediated via thromboxane A2(TXA2) and airway neutrophil accumulation in guinea‐pigs, the acute effect of inhaled IL‐8 is unclear. We performed this study to clarify the acute effect of IL‐8 on bronchial responsiveness and the role of TXA2.2The effects of inhaled IL‐8 on bronchial responsiveness and of the TXA2antagonists, S‐1452 (0.01 and 0.1 mg kg−1) and ONO‐NT‐126 (1.0 or 10 μg kg−1), on IL‐8‐induced BHR were examined by use of a modified Konzett‐Rössler method in guinea‐pigs.3Inhaled IL‐8 at 100 ng ml−1, which failed to induce significant changes in Pao (pressure at the airway opening), enhanced an increase in Pao induced by subsequent inhalations of ascending doses (50–200 μg ml−1) of methacholine and histamine, suggesting the potentiating effect of IL‐8 on bronchial responsiveness. No significant leukocyte infiltration was observed histologically sixteen minutes after the IL‐8 inhalation. Both S‐1452 and ONO‐NT‐126 reduced the IL‐8‐induced BHR.4In conclusion, IL‐8 rapidly causes BHR via TXA2release in guinea‐pigs.

The effects of an antimuscarinic agent, oxitropium bromide (200 µg), a beta-2 adrenoceptor agonist, fenoterol (200 µg), and their combination, were compared in ten patients with chronic obstructive pulmonary disease and ten patients with bronchial asthma, in a placebocontrolled, single blind crossover trial. In patients with chronic obstructive pulmonary disease, oxitropium and fenoterol produced a significant and similar degree of bronchodilatation. The duration of the bronchodilator effect was 3 h after oxitropium and 4 h after fenoterol, respectively. The combination of oxitropium and fenoterol produced a significantly greater degree of bronchodilatation than either drug alone. The duration of bronchodilatation in combination was 7 h and was considerably longer than that of each drug alone. In patients with bronchial asthma, oxitropium and fenoterol also caused bronchodilatation. Their combination produced a significantly greater degree of bronchodilatation than when either drug was used. The duration of the bronchodilator effects were 5 h after oxitropium, 4 h after fenoterol and 5 h after the combination. We conclude that the combination of oxitropium and fenoterol causes greater bronchodilatation in patients with chronic obstructive pulmonary disease and bronchial asthma than when compared to each drug alone. In the former, the duration of bronchodilatation is additionally prolonged. These combination effects may be of value in the clinical management of these common respiratory disorders.

Cough reflex testing with capsaicin has been used to study the pathophysiology of the cough reflex and the antitussive effects of various drugs. Although the reproducibility of capsaicin-induced cough has been well established in normal subjects, it is not known if prior challenge with capsaicin reduces the subsequent cough response to inhaled capsaicin in patients with the sinobronchial syndrome, a condition characterized by chronic upper and lower airway inflammation. Measurement of the capsaicin cough threshold, defined as the lowest concentration of capsaicin eliciting five or more coughs, was repeated four times at intervals of 15, 30 and 60 min in eleven patients with the SBS and ten normal subjects. The cough thresholds at 15, 30 and 60 min were greater than the initial value in patients with the SBS but not in normal subjects. In addition, we examined the effect of 4 days treatment with indomethacin (100 mg/day) on the cough thresholds measured twice at an interval of 15 min in eight patients with the SBS. Indomehacin increased the initial cough threshold and reduced the increment in the post-15 min cough threshold from the initial value compared with placebo, thus reducing the tachyphylaxis. These results indicate that chronic airway inflammation may be responsible for the decreased response (tachyphylaxis) to repeated inhalation of capsaicin, and suggest that cyclooxygenase products released by the airway inflammation may be involved in tachyphylaxis, cough receptor sensitivity to inhaled capsaicin, or both, in patients with the SBS.