Long-term effects of allergen sensitization and exposure in adult asthma: a prospective study.

BACKGROUND: : We investigated the effects of sensitization and exposure to common domestic allergens on longitudinal changes in lung function and bronchial hyperresponsiveness. METHODS: : Subjects attended 2 visits that were 4 years apart. Skin prick testing was performed and household dust samples were collected for quantification of mite, dog, and cat allergens at baseline. Measurements of lung function, exhaled nitric oxide, and bronchial hyperresponsiveness were completed at both visits. RESULTS: : Dust samples were collected in 165 of the 200 subjects completing both visits. Mean length of follow-up was 47 months. Bronchial hyperresponsiveness, measured at both visits in 86 subjects, deteriorated in those exposed to high mite allergen levels compared with those not exposed [mean (95% CI) doubling dose change PD20 = -0.44 (-1.07 to 0.19) vs 0.82 (0.27 to 1.36)], but improved in those exposed to high dog allergen levels compared with those not exposed [1.10 (0.33 to 1.86) vs 0.10 (-0.39 to 0.58)]. The associations were significant in the multivariate models. Cat allergen exposure was not associated with any changes in lung function, exhaled nitric oxide, or bronchial hyperresponsiveness. CONCLUSIONS: : In a 4-year prospective cohort of persons with asthma, exposure to high levels of dust mite allergens at baseline was associated with a subsequent increase in bronchial hyperresponsiveness

高齢者気管支喘息における気道過敏性と温泉療法

Clinical effects of spa therapy were examined in 150 patients with asthma in relation tobronchial hyperresponsiveness and patient age. 1. The efficacy rate of spa therapy was larger as the patient age was higher: the rate was 73.3% in patients under age 49, 81.8% in those between the ages of 50 and 59, 86.4% in those between the ages of 60 and 69, and 90.6% in those over age 70. The mean of efficacy rates was 83.3% in all subjects. 2. The bronchial hyperresponsiveness (BH) was lower as patient age was higher: the BH in patients between the ages of 60 and 69 and in those over age 70 was significantly lower compared to the BH in those under age 49 (p < O.OOl). 3. Clinical effects of spa therapy tended to be lower in patients with increased bronchial hyperresponsiveness. The bronchial hyperresponsiveness showed a tendency to decrease after spa therapy in whom the therapy was effective, however, the BH did not change in patients with slight or no efficacy during spa therapy.1.温泉療法では,年齢が高くなるほどその有効率も高くなると言う傾向が見られ､49才以下の症例では73.3% ,50-59才の症例では81.8% , 60-69才の症例では86.4% ,70才以上では90.6% であり,全症例の平均有効率は73.3% であった｡　 2.気道過敏性は,年齢が高くなるほど低下する傾向が見られ,60-69才および70才以上の症例の気道過敏性は,49才以下の症例と比べ有 意に低い値を示した(P < 0.001)。　 3.温泉療法の臨床効果は,気道過敏性が強くなるにつれて低下する傾向が見られた｡また,温泉療法の著効例や有効例では,治療により 気道過敏性が低下してくるが､やや有効例や無効例では,気道過敏性はほとんど変化しないことが示された

The effect of lipoprotein-associated phospholipase A2 deficiency on pulmonary allergic responses in Aspergillus fumigatus sensitized mice.

BackgroundLipoprotein-associated phospholipase A2 (Lp-PLA2)/platelet-activating factor acetylhydrolase (PAF-AH) has been implicated in the pathogenesis of cardiovascular disease. A therapeutic targeting of this enzyme was challenged by the concern that increased circulating platelet activating factor (PAF) may predispose to or increase the severity of the allergic airway response. The aim of this study was to investigate whether Lp-PLA2 gene deficiency increases the risk of PAF and IgE-mediated inflammatory responses in vitro and in vivo using mouse models.MethodsLp-PLA2-/- mice were generated and back crossed to the C57BL/6 background. PAF-AH activity was measured using a hydrolysis assay in serum and bronchoalveolar lavage (BAL) samples obtained from mice. Aspergillus fumigatus (Af)-specific serum was prepared for passive allergic sensitization of mice in vivo and mast cells in vitro. β- hexosaminidase release was studied in bone marrow derived mast cells sensitized with Af-specific serum or DNP-IgE and challenged with Af or DNP, respectively. Mice were treated with lipopolysaccharide (LPS) and PAF intratracheally and studied 24 hours later. Mice were sensitized either passively or actively against Af and were studied 48 hours after a single intranasal Af challenge. Airway responsiveness to methacholine, inflammatory cell influx in the lung tissue and BAL, immunoglobulin (ELISA) and cytokine (Luminex) profiles were compared between the wild type (WT) and Lp-PLA2-/- mice.ResultsPAF-AH activity was reduced but not completely abolished in Lp-PLA2-/- serum or by in vitro treatment of serum samples with a high saturating concentration of the selective Lp-PLA2 inhibitor, SB-435495. PAF inhalation significantly enhanced airway inflammation of LPS treated WT and Lp-PLA2-/- mice to a similar extent. Sensitized WT and Lp-PLA2-/- bone-marrow derived mast cells released β-hexosaminidase following stimulation by allergen or IgE crosslinking to equivalent levels. Wild type and Lp-PLA2-/- mice responded to passive or active allergic sensitization by significant IgE production, airway inflammation and hyperresponsiveness after Af challenge. BAL cell influx was not different between these strains while IL-4, IL-5, IL-6 and eotaxin release was attenuated in Lp-PLA2-/- mice. There were no differences in the amount of total IgE levels in the Af sensitized WT and Lp-PLA2-/- mice.ConclusionsWe conclude that Lp-PLA2 deficiency in C57BL/6 mice did not result in a heightened airway inflammation or hyperresponsiveness after PAF/LPS treatment or passive or active allergic sensitization and challenge

長期間喫煙による気管支唱息,肺気腫の病態的変化

The influence of long-term cigarette smoking on the pathophysiology of chronic respiratory diseases with obstructive ventilatory dysfunction was discussed in patients with asthma and pulmonary emphysema (PE). 1. In patients with asthma, significant differences in the pathophysiology of the disease were observed between smokers and nonsmokers. A positive RAST score against inhalant allergens, bronchial hyperresponsiveness, and LTB4 generation by leucocytes were significantly more increased in smokers than in nonsmokers. The values of FEV1/FVC and OLco were significantly more decreased, and % RV was significantly more increased in smokers than in nonsmokers. 2. In comparison of asthma with PE, IgE-mediated allergy was significantly more increased in smokers with asthma than in nonsmokers with asthma and in smokers with PE. The values of % FEV1, FEVl %, and % OLco were significantly higher in nonsmokers with asthma than in smokers with PE, however, the % OLco and % RV were not significantly different between smokers with asthma and those with PE. The % LAA of the lungs on HRCT was larger in patients with PE than in smokers and nonsmokers with asthma. The results suggest that cigarette smoking influences the pathophysiology of asthma and PE.長期間喫煙による気管支喘息および肺気腫の病態的変化について若干の検討を加えた｡1.気管支嘱喘息に関しては,喫煙例と非喫煙例との間に以下のような病態的特徴に差が見られた｡吸入抗原に対する特異的IgE抗体の陽性率,気道過敏性,白血球のI:TB4産生能はいずれも,喫煙例で非喫煙例に比べ有意の亢進を示した｡また,喫煙例では,非喫煙例に比べ,FEV1%や% DLcoは有意の低下,% RVは有意の増加傾向を示した｡2.喘息と肺気腫の比較では,IgEにmediateされるア レルギー反応は,喘息の非喫煙例や肺気腫(全て喫煙例)に比べ,喘息の喫煙例で有意の亢進が見られた｡% FEVl,FEV1,% DLco値はいずれも喘息の非喫煙例で,肺気腫と比べ有意に高い値を示したが,% DLcoと% RV値には,喘息の喫煙例と肺気腫の間に有意の差は見られなかった｡また,肺のHRCT上の% I.AAは,肺気腫において,喘息の喫煙例,非喫煙例いずれよりも有意に高い値を示した｡以上の結果より,長期間の喫煙が喘息や肺気腫の病態に影響を与えることが示された

Bronchial thermoplasty : a new therapeutic option for the treatment of severe, uncontrolled asthma in adults

Bronchial thermoplasty is a young yet promising treatment for severe asthma whose benefit for long-term asthma control outweighs the short-term risk of deterioration and hospitalisation in the days following the treatment. It is an innovative treatment whose clinical efficacy and safety are beginning to be better understood. Since this is a device-based therapy, the overall evaluation of risk-benefit is unlike that of pharmaceutical products; safety aspects, regulatory requirements, study design and effect size assessment may be unfamiliar. The mechanisms of action and optimal patient selection need to be addressed in further rigorous clinical and scientific studies. Bronchial thermoplasty fits in perfectly with the movement to expand personalised medicine in the field of chronic airway disorders. This is a device-based complimentary asthma treatment that must be supported and developed in order to meet the unmet needs of modern severe asthma management. The mechanisms of action and the type of patients that benefit from bronchial thermoplasty are the most important challenges for bronchial thermoplasty in the future

The Endogenous Th17 Response in NO<inf>2</inf>-Promoted Allergic Airway Disease Is Dispensable for Airway Hyperresponsiveness and Distinct from Th17 Adoptive Transfer

Severe, glucocorticoid-resistant asthma comprises 5-7% of patients with asthma. IL-17 is a biomarker of severe asthma, and the adoptive transfer of Th17 cells in mice is sufficient to induce glucocorticoid-resistant allergic airway disease. Nitrogen dioxide (NO2) is an environmental toxin that correlates with asthma severity, exacerbation, and risk of adverse outcomes. Mice that are allergically sensitized to the antigen ovalbumin by exposure to NO2 exhibit a mixed Th2/Th17 adaptive immune response and eosinophil and neutrophil recruitment to the airway following antigen challenge, a phenotype reminiscent of severe clinical asthma. Because IL-1 receptor (IL-1R) signaling is critical in the generation of the Th17 response in vivo, we hypothesized that the IL-1R/Th17 axis contributes to pulmonary inflammation and airway hyperresponsiveness (AHR) in NO2-promoted allergic airway disease and manifests in glucocorticoid-resistant cytokine production. IL-17A neutralization at the time of antigen challenge or genetic deficiency in IL-1R resulted in decreased neutrophil recruitment to the airway following antigen challenge but did not protect against the development of AHR. Instead, IL-1R-/- mice developed exacerbated AHR compared to WT mice. Lung cells from NO2-allergically inflamed mice that were treated in vitro with dexamethasone (Dex) during antigen restimulation exhibited reduced Th17 cytokine production, whereas Th17 cytokine production by lung cells from recipient mice of in vitro Th17-polarized OTII T-cells was resistant to Dex. These results demonstrate that the IL-1R/Th17 axis does not contribute to AHR development in NO2-promoted allergic airway disease, that Th17 adoptive transfer does not necessarily reflect an endogenously-generated Th17 response, and that functions of Th17 responses are contingent on the experimental conditions in which they are generated. © 2013 Martin et al

Mechanisms altering airway smooth muscle cell Ca(2+) homeostasis in two asthma models

Background: Asthma is characterized by airway remodeling, altered mucus production and airway smooth muscle cell (ASMC) contraction causing extensive airway narrowing. In particular, alterations of ASMC contractility seem to be of crucial importance. The elevation of the cytoplasmic Ca(2+) concentration is a key event leading to ASMC contraction and changes in the agonist- induced Ca(2+) increase in ASMC have been reported in asthma. Objective: The aim of this study was to investigate mechanisms underlying these changes. Methods: Murine tracheal smooth muscle cells (MTSMC) from T- bet KO mice and human bronchial smooth muscle cells (HBSMC) incubated with IL-13 and IL-4 served as asthma models. Acetylcholine- induced changes in the cytoplasmic Ca(2+) concentration were recorded using fluorescence microscopy and the expression of Ca(2+) homeostasis regulating proteins was investigated with Western blot analysis. Results: Acetylcholine- induced Ca(2+) transients were elevated in both asthma models. This correlated with an increased Ca(2+) content of the sarcoplasmic reticulum (SR). In MTSMC from T-bet KO mice, the expression of the SR Ca(2+) buffers calreticulin and calsequestrin was higher compared to wild- type mice. In HBSMC incubated with IL-13 or IL-4, the expression of ryanodine receptors, inositol-3-phosphate receptors and sarcoplasmic/ endoplasmic reticulum Ca 2+ ATPases 2 was increased compared to HBSMC without incubation with interleukins. The enlarged acetylcholine- induced Ca(2+) transients could be reversed by blocking inositol-3- phosphate receptors. Conclusions: We conclude that in the murine asthma model the SR Ca(2+) buffer capacity is increased, while in the human asthma model the expression of SR Ca(2+) channels is altered. The investigation of the Ca(2+) homeostasis of ASMC has the potential to provide new therapeutical options in asthma. Copyright (C) 2008 S. Karger AG, Basel

UNDULY ENHANCED RESPONSE TO TOLVAPTAN IN A WOMAN SHOWING SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION: AN INVESTIGATION OF POSSIBLE CAUSES

Objective: To investigate possible causes of an excessive response to tolvaptan in a woman with syndrome of inappropriate antidiuretic hormone secretion (SIADH). Methods: A 32-year-old woman was admitted to our cardiologic unit 3 months after delivery for hypertension and severe hyponatremia (120 mEq/L). Two hyponatremic episodes had already been documented in her medical history. SIADH was diagnosed and treatment with tolvaptan, an arginine vasopressin (AVP) antagonist, was instituted. After the first 15-mg dose, excessive polyuria (1 L/ hour) and a rapid increase in serum sodium (13 mEq/L in 8 hours) occurred, so that therapy was stopped and restarted 2 days later at a reduced dose (5 mg). This level was effective and well tolerated. To explore the possible pharmacokinetic and pharmacodynamic mechanisms underlying the patient\u2019s hyperresponsiveness, the following tests were carried out: (1) in vivo phenotyping of CYP3A4 activity, the cytochrome responsible for tolvaptan metabolism, with two probe drugs (omeprazole and dextromethorphan); and (2) search for mutations in genes involved in AVP signaling (AVP, V2R, AQP2, OXT)

温泉療法による気管支喘息に対する年間薬剤費の削減

Costs of drugs used for the treatment for 1 year were compared before and after spa therapy in 16 patients with asthma in relation to disease severity. Asthma severity was classified as : stage 1 (intermittent), 2 (mild persistent), 3(moderate persistent), and 4(severe persistent). 1. The total cost of drugs used for each pa-tient for 1 year clearty decreased in all groups. The % decrease of the costs of drugs in each group was 27.2% in patients with stage 1, 43.5% in those with stage 2 and 34.1% in those with stage 3-4 (mean 34.5% ). The reduction of the cost of bronchodilators was predominant in patients with stage 3-4, and the decrease in the cost of corticosteroids predominant in those with stage 2. The reduction of costs of antiallertgics, mucolytics, and antibiotics was predominant in patients with stage 2 and stage 3-4. The % reduction in the cost of corticostroids was remarkable in patients with stage 2. The % decrease in the costs of mucolytics and antibiotics was predomi-nant in patients with stage 2 and stage 3-4. The results obtained here suggest that the costs of drugs used for asthmatics could be reduced by long-term spa therapy, and the reduction of the costs was larger as asthma stage became more severe.気管支喘息16例を対象に,治療のために要した年間薬剤費が温泉療法により削減可能であるのかどうかについて,国際ガイドラインの重症度分類(stageト4)別に若干の検討を加えた｡1.年間の総薬剤費は重症度別の全てのグループにおいて明らかに減少した.2.その削減率は,ステージ1で27.2%,ステージ2で43.5%,ステージ3-4で34.1%であり,その平均は34.5%であった｡3.気管支拡張剤の薬剤費の減少はステージ3-4で高度であり,副腎皮質ホルモンの薬剤費の減少はステージ2で著明であった｡また,抗アレルギー薬,去痩薬,抗生物質などの薬剤費の削減は,ステージ2および3-4で高度であった｡4.削減率では,去壊薬,抗生物質の削減率が,2および3-4で著明であった｡ 以上の結果より,温泉療法により,気管支喘息の治療に必要な薬剤費は削減可能であること,そして,温泉療法による薬剤費の削減は職息の重症度が高い症例でより高度であることが示唆された