Change in bronchial responsiveness and cough reflex sensitivity in patients with cough variant asthma: effect of inhaled corticosteroids

BACKGROUND: Cough variant asthma (CVA) is a cause of chronic cough and a precursor of typical asthma. We retrospectively examined the longitudinal change in bronchial responsiveness and cough reflex sensitivity in CVA patients with respect to the effect of long-term inhaled corticosteroids (ICS). METHODS: Provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (PC20-FEV1) and provocative concentration of capsaicin eliciting 5 or more coughs (C5) were measured before treatment and during a follow up period following relief of cough (median; 2.0 (range; 0.5 to 8.0) years after the initial visit) in a total of 20 patients with CVA (7 males and 13 females, mean ± SD age of 49.9 ± 12.9 years). RESULTS: Three of 8 patients not taking long-term ICS developed typical asthma compared to none of 12 patients taking ICS (p = 0.0171). PC20-FEV1 significantly (p < 0.0001) increased from 1.80 (GSEM, 1.35) to 10.7 (GSEM, 1.63) mg/ml in patients taking ICS but did not change in patients not taking ICS [2.10 (GSEM, 1.47) compared to 2.13 (GSEM, 1.52) mg/ml]. Cough threshold did not change in patients whether taking or not taking ICS. CONCLUSION: Long-term ICS reduces bronchial hyperresponsiveness in CVA as recognized in typical asthma. Cough reflex sensitivity is not involved in the mechanism of cough in CVA

A Functional Analysis of EFL Students' Discourse in the Social Practice of Learning to Play a Board Game

How do second language (L2) students learn a social practice in their target language? This paper reports on some of the findings of a qualitative study that took a sociocultural approach (e.g., Bruner, 1983; Rogoff, 1990; Schieffelin & Ochs, 1986) to examine how a group of five EFL students learned the social practice of board gaming. A social practice theory analysis (Mohan, 2007) showed that the students worked together to help each other participate in the game and to create a shared understanding of its rules and procedures, revealing how action and reflection discourses were woven together. The analysis also illustrated how the students as active agents altered one of the rules of the game as well as how a relatively novice player, after receiving assistance from more experienced players and observing other players’ actions, assumed a more active role as the play progressed. These findings highlight the important co-construction of actions, roles, and understanding that takes place through L2 collaborative discourse in learning to play a game

Alcohol-induced asthma

金沢大学医薬保健研究域医学

好酸球性気管支炎の咳需容体感受性亢進のメカニズム

金沢大学医学部付属病院1.慢性乾性咳嗽に関する臨床的研究(1)咳型喘息とは異なる新しい疾患概念として「アトピー咳嗽」を提唱した.(2)アトピー咳嗽では,気管支拡張薬は無効であり,メサコリン気道過敏性は正常であり,カプサイシンに対する気道の咳受容体感受性は亢進している.(3)アトピー咳嗽の組織学特徴は,以下の成績より中枢気道の好酸球性炎症であることが示唆される.すなわち,気管支肺胞洗浄液中には好酸球はみられず,気管支洗浄液中には好酸球はみられず,気管支生検組織には好酸球が僅かにみられ,高張食塩水吸入による誘導喀痰中には気管支喘息に匹敵する程度の好酸球がみられた.(4)アトピー咳嗽の治療には,ヒスタミンHI-拮抗薬とステロイド薬が有効である.2.好酸球性気管支炎に関する動物実験(1)モルモットにポリミキシンBを1回/週,3週間経鼻投与することによって,好酸球性気管支炎の作製に成功した.(2)本モデルでは,ヒスタミンに対する気道過敏性は亢進しておらず,カプサイシンに対する気道の咳受容体感受性は亢進していた.(3)ニューロペプチド受容体拮抗薬(FK-224)とトロンボキサン受容体拮抗薬(S-1452)は,本モデルの咳受容体感受性亢進を有意に抑制したが,β_2交感神経刺激薬(プロカテロール)は抑制しなかった.(4)ヒスタミンHI-拮抗薬(アゼラスチン)は本モデルの咳受容体感受性亢進を抑制した.3.結論以上の研究成績より,慢性乾性咳嗽(病的咳嗽)には少なくとも二つの病態があることが示された.すなわち,アトピー咳嗽では中枢気道の好酸球性炎症のよる咳受容体感受性亢進,咳型喘息では気道全体の好酸球性炎症による気道過敏性亢進に基づく気管支平滑筋の収縮である.1.Clinical study on chronic nonproductive cough(1) A new clinical entity named as "ATOPIC COUGH" has been proposed, which is different from cough variant asthma.(2) Bronchodilator therapy is ineffective, bronchial responsiveness to methacholine is within normal range, and airway cough receptor sensitivity to inhaled capsaicin is heightened in atopic cough.(3) The histologic feature is considered to be large airway eosinophilic inflammation according to the following findings : no eosinophils in bronchoalveolar lavage fluid or bronchial lavage fluid, small number of eosinophils in biopsied bronchial specimens, and almost same number of eosinophils in hypertonic saline-induced sputum as bronchial asthma.(4) Histamine Hl-antagonists and steroids are effective for the treatment of atopic cough.2.Animal experiment on eosinophilic bronchitis(1) Eosinophilic bronchitis model of guinea pigs was successfully developed by intranasal administration of polymycin B twice a week for 3 weeks.(2) Airway cough receptor sensitivity to inhaled capsaicin was heightened but bronchial responsiveness to inhaled histamine was not increased in this model.(3) A neuropeptide inhibitor (FK-224) and a thromboxane receptor antagonist (S-1452) but not a beta2-agonist (procaterol) significantly reduced the heightened airway cough receptor sensitivity.(4) A histamine Hl-antagonist (azelastin) significantly suppressed the heightened airway cough receptor sensitivity.3.ConclusionFrom these results, it is suggested that there are at least 2 different mechanisms for the pathophysiology of persistent nonproductive cough (pathological cough) : heightened airway cough receptor sensitivity induced by eosinophilic inflammation of the large airway in atopic cough and bronchoconstriction based on bronchial hyperresponsiveness induced by eosinophilic inflammation of the central to peripheral airways in cough variant asthma.研究課題/領域番号:04807055, 研究期間(年度):1992 – 1994出典：研究課題「好酸球性気管支炎の咳需容体感受性亢進のメカニズム」課題番号04807055（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-04807055/048070551994kenkyu_seika_hokoku_gaiyo/）を加工して作

アトピー咳嗽におけるIgE非依存性機序と環境真菌の重要性

I.臨床的検討1.環境真菌Basidlomycetes属の重要性1)従来の検討によって、重要な環境真菌としてBasldiomycetes属が同定されていたが、難治性慢性咳嗽患者の誘発喀痰中から培養された真菌のDNAシークエンスによる解析によって、我々の注目している環境真菌がBasidiomycetes属に属するBjerkanderaadusta(和名:ヤケイロタケ)であることが判明した。2)アトピー咳嗽患者では、咽頭拭い液の爽菌培養によって、Basidiomycetes属はカンジダの次に多く(約20%)検出された。3)Basidiomyctets属の抗原抽出液に対する即時型皮内反応の検討では、アトピー咳嗽患者では陽性率が約20%程度でり、非アトピー健常者の5%以下に比較して高率だった。4)喀痰からBjerkandera adustaが培養同定された難治性慢性咳嗽患者8例の検討では、同真菌の抽出抗原に対するリンパ球刺激試験と抗原吸入負荷試験が陽性であったが、皮膚反応は3例のみが陽性を示し、IgE非依存性のアレルギー反応の重要性が示された。2.アトピー咳嗽における呼気一酸化炭素(NO)濃度の検討好酸球性気道炎症のバイオマーカーである呼気NO濃度は、喘息や咳喘息に比べて、アトピー咳嗽では低値を示した。II.基礎的検討1)モルモットを用いて、アトピー咳嗽と咳喘息のデルを作成し、その病態の比較を行った。アトピー咳嗽ではニューロキニンとヒスタミンが重要であるが、咳喘息ではロイコトリエンが重要であることが示された。2)咳発作による気道への圧ストレスが咳感受性に対して増幅回路を形成することが明らかとなった。すなわち、咳嗽は強力に止めることが治療の成功に必要であることが示された。I. Clinical research1) Importance of environmental fungi, basidiomycetous fungi, in chronic cough(1) In previous studies basidiomycetous fungi had been documented as important environmental fungi in severer cases of atopic cough, The DNA sequence analysis revealed that the fungi which were cultured from sputum of patients with intractable chronic cough was Bjerkandera adusta.(2) Basidiomycetous fungi was detected from fungal culture of pharyngeal swab in 20% of patients with atopic cough. The rate was the second following Candida.(3) We succeeded to prepare the antigen extract of basidiomycetous fungi. Immediate type skin reaction using the antigen extract solution was positive in 20% of patients with atopic cough, which was significantly higher than that (5%) in non-atopic healthy subjects.(4) In 8 patients with intractable chronic cough whose sputum yielded Bjerkandera adusta cultured, lymphocyte stimulation test and inhalation provocation test using the fungal antigen were positive while the skin reaction was positive in only 3 patients. These findings suggest that lgE non-mediated allergic reaction is important in the fungal-associated chronic cough.2) Exhaled nitric oxide (NO) concentration in atopic coughExhaled nitric oxide (NO) is a biomarker of eosinophilic airway inflammation and the levels have been shown to be elevated in bronchial asthma, cough variant asthma and non-asthmatic eosinophilic bronchitis. We investigated whether the exhaled NO levels were increased in atopic cough in comparison with those in bronchial asthma and cough variant asthma. The exhaled NO levels were significantly lower in atopic cough compared with bronchial asthma and cough variant asthma.II. Basic research1) We developed guinea pig models of atopic cough and cough variant asthma. Neurokinins and histamine were important in the atopic cough model while leukotrienes were important in the cough variant asthma model.2) We hypothesized that cough attacks are mechanical stress to the airways and influence the cough reflex sensitivity. Transient rapid negative pressure was repeatedly given to anesthetized and artificially ventilated guinea pigs. Cough reflex sensitivity to inhaled capsaicin was increased 6 hours after the negative pressure stress which was associated with neutrophilic airway inflammation. Cough stress to airway makes a self-perpetuating cough-reflex cycle, in which antigen-induced increase in cough reflex sensitivity results in pathologic cough, and the cough in turn amplifies cough reflex sensitivity.研究課題/領域番号:17607003, 研究期間(年度):2005-2007出典：「アトピー咳嗽におけるIgE非依存性機序と環境真菌の重要性」研究成果報告書　課題番号17607003 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）)　　　本文データは著者版報告書より作

慢性咳嗽の病態解明に基づく診断・治療法の開発

I.基礎的研究1.モルモットを用いてアトピー咳嗽と咳喘息それぞれの動物モデルの作成に成功した。1)アトピー咳嗽モデルに関する研究によって、咳感受性の亢進には、ニュートラルエンドペプチダーゼ活性の阻害によるサブスタンスPが重要な役割を担っており、ヒスタミンがサブスタンスPとの相互作用によって関与することが解明された。2)咳喘息モデルに関する研究によって、本モデルの抗原誘発咳嗽は気管支平滑筋収縮によって発生し、ロイコトリエンが関与するも、タキキニンは関与しないことが解明された。2.咳感受性に与える気道への機械的圧ストレスの影響咳発作を想定した気道への定量的圧負荷装置を開発し、気道への圧負荷が咳感受性を亢進させ、さらに気道への好中球浸潤を引き起こすことを発見した。すなわち、咳嗽発作が咳感受性性をさらに亢進し、好中球性気道炎症を惹起することによって、咳嗽と咳感受性亢進に増幅回路(悪循環回路)が形成されることが明かとなった。II.臨床的研究1.アトピー咳嗽と咳喘息は、生理学的および病理学的基本病態が異なることに加えて、予後も異なることを明らかにした。すなわち、咳喘息は数年の内に約30%の患者が喘息を発症するが、アトピー咳嗽は喘息を発症しないことが明かとなった。2.咳喘息から喘息を発症する危険因子が、気道過敏性亢進と長期吸入ステロイド療法を実施しないことの2つであることがわかった。3.慢性咳嗽の原因疾患の頻度多施設共同前向き研究によって検討した結果、慢性咳嗽の三大原因疾患は咳喘息、アトピー咳嗽、副鼻腔気管支症候群であることが明かとなり、本邦におけるアトピー咳嗽の重要性が確認された。I. Basic research1. guinea pig models for atopic cough and cough variant asthma have been developed.1) Using the atopic cough model, it has been disclosure d that increased level of substance P resulted from antigen-induced inactivation of neutral endopeptidase is important in the antigen-induced increase in cough sensitivity, and that there may bean interaction between histamine and substance P.2) Using the cough variant asthma model, It is clarified that cough is elicited via antigen-induced bronchoconstridion, and that leukotrienes, but not tachykinins, are involved in the cough.2. We developed a apparatus to give quantitative mechanical pressure stress to guinea pig airway. The Mechanical pressure stress to airway induced cough reflex hypersensitivity associated with airway neutrophilic inflammation., suggesting self-perpetuating cycle between cough and cough hypersensitivity.II. Clinical research1. In addition to the difference of pathophysiologic feature between atopic cough and cough variant astluna, we elucidated the long-term outcome is also different between these two condition.: Nearly 30% patients with cough variant asthma develops typical asthma within several years but no patient with atopic cough does.2. Bronchial hyperresponsiveness and no use of long-tern inhaled corticosteroids were risk factors of typical asthma onset from cough variant asthma.3. Our prospective study confirmed that cough variant asthma, atopic cough and sinobronchial syndrome are common causes of chronic cough in Japan.研究課題/領域番号:14570546, 研究期間(年度):2002-2004出典：「慢性咳嗽の病態解明に基づく診断・治療法の開発」研究成果報告書　課題番号14570546 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）)　　　本文データは著者版報告書より作

気管支喘息の重要な病態である気道過敏性亢進の成立機序と化学伝達物質の役割

金沢大学医学部研究課題/領域番号:62770515, 研究期間(年度):1987出典：研究課題「気管支喘息の重要な病態である気道過敏性亢進の成立機序と化学伝達物質の役割」課題番号62770515（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-62770515/）を加工して作