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

特異的気道過敏症の病態生理

金沢大学医学部附属病院本研究では、交感神経遮断薬、蒸留水およびアルコールに対する特異的気道過敏症の病態生理について、それぞれの動物モデルを作成し、以下の研究成績を得た。1.アルコール誘発喘息の機序1)エタノールには気管支収縮作用はなく、その代謝産物であるアセトアルデヒドが気管支収縮を生じる。2)アセトアルデヒドは、ヒスタミンの遊離を介して気管支収縮を生じる。3)低用量のアセトアルデヒドは、気管支収縮を生じないが、非特異的気道過敏性を亢進する。4)アセトアルデヒドによる非特異的気道過敏性亢進には、トロンボキサンA2が重要である。2.交感神経遮断薬に対する特異的気道過敏性の動物(モルモット)モデルの作成と自律神経系,ケミカルメディエーター、ニューロペプチドの関与1)受動感作モルモットに抗原を吸入し、その20分後にプロプラノロールを吸入負荷すると、著名な気管支収縮が生じた。この動物モデルは,世界ではじめてのモデルである。2)この反応には、副交感神経およびα-交感神経活動の関与はない。3)この反応には、サブスタンスPやニューロキニンの関与はない。4)この反応には、トロンボキサンA2の関与が大きく、ロイコトリエンや血小板活性化因子も関与する。3.蒸留水吸入に対する特異的気道過敏性の動物(モルモット)モデルの作成と自律神経系、ケミカルメディエーター、ニューロペプチドの関与1)受動感作モルモットに抗原を吸入し、その20分後に蒸留水を吸入負荷すると、著明な気管支収縮が生じた。この動物モデルは,世界ではじめてのモデルである。2)この反応には、副交感神経の関与はない。3)この反応には、ヒスタミンとサブスタンスPの関与が重要である。4)この反応には、トロンボキサンA2の関与はない。1. Alcohol-induced bronchoconstriction in guinea pigs(1) Acetaldehyde, a metabolite of ethanol, causes bronchoconstriction but ethanol does not.(2) The acetaldehyde-induced bronchoconstriction is mediated via histamine release.(3) A low dose of acetaldehyde, which does not cause bronchoconstriction, enhances non-specific bronchial responsiveness.(4) Thromboxane A2 is involved in the acetaldehyde-induced non-specific bronchial hyperresponsiveness.2. A guinea big model of propranolol-induced bronchoconstriction and the role of autonomic nerve system, chemical mediators and neuropeptides(1) An inhalation of propranolo causes bronchoconstriction when it is inhaled 20 minutes after an aerosolized antigen provocation in passively sensitized guinea pigs.This is the first animal model or propranolol-induced bronchoconstriction.(2) Parasympathctic or alpha-adrenergic nerve activity is not involved in this response.(3) Ncuropeptides such as substance P and neurokinin A do not take a part in this response.(4) Lipid mediators, especially thromboxane A2, have an important role in this response.3. A guinea-pig model of untrasonically nebulized distillled water (UNDW) -induced bronchoconstriction and the role of autonomic nerve system, chemical mediators and neuropeptides(1) An inhalation of UNDW produces acute bronchoconstriction when it is inhaled 20 mimutes after an aerosolized antigen provocation in passively sensitized guinea pigs.This is the first animal model of UNDW-induced bronchoconstriction.(2) Parasympathetic nerve activity is not involved in this response.(3) Histamine and substance P,but not neurokinin A,take a large part in this response.(4) Thromboxane A2 does not have a role in this response.4. ConclusionForm these results, it is suggested that allergic airway response, or allergic airway inflammatory process, is important in development of specific bronchial responsiveness. Furthermore, the mechanism of specific bronchial hyperresponsiveness may be different each other, suggesting heterogeneity of contributing factors between several specific bronchial hyperresponsiveness in asthma.研究課題/領域番号:07670662, 研究期間(年度):1995 – 1997出典：研究課題「特異的気道過敏症の病態生理」課題番号07670662（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-07670662/076706621997kenkyu_seika_hokoku_gaiyo/）を加工して作

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