Asthma: a simple concept but in reality a complex disease

Holgate, Stephen T.

doi:10.1111/j.1365-2362.2011.02534.x

Cited by 64 publications

(69 citation statements)

References 118 publications

(112 reference statements)

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“…in agreement with what happens in a range of human severe asthma phenotypes. Historically, asthma has been considered as an allergic, eosinophilic, Th2-mediated and corticosteroid-responsive disease [1]. However, it is now evident that asthma is not a single disease, but a heterogeneous condition consisting of clinically recognizable phenotypes [3].…”

Section: Discussionmentioning

confidence: 99%

“…Asthma is a chronic and heterogeneous respiratory condition characterized by airflow obstruction, airway inflammation and AHR (airway hyperresponsiveness) with symptoms of wheeze, cough, chest tightness and shortness of breath [1]. Although eosinophil accumulation and Th2 cell activation is fundamental to mild-moderate asthma, patients with severe asthma manifest a more diverse inflammatory pattern with several prominent subphenotypes [2,3].…”

Section: Introductionmentioning

confidence: 99%

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Double-stranded RNA evokes exacerbation in a mouse model of corticosteroid refractory asthma

et al. 2015

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RNA viruses are a major cause of respiratory infections and are known to exacerbate asthma and other respiratory diseases. Our aim was to test the ability of poly(I:C) (polyinosinic:polycytidylic acid), a viral surrogate, to elicit exacerbation in a model of severe asthma driven by HDM (house dust mite) in FCA (Freund's complete adjuvant). Poly(I:C) was administered intranasally around the HDM challenge in FCA-HDM-sensitized animals. Changes in AHR (airway hyperresponsiveness), BALF (bronchoalveolar lavage fluid) inflammatory infiltrate, HDM-specific immunoglobulins and cytokine/chemokine release were evaluated at different points after the challenge. The effect of oral dexamethasone was also assessed. Exacerbation was achieved when poly(I:C) was administered 24 h before the HDM challenge and was characterized by enhanced AHR and an increase in the numbers of neutrophils, macrophages and lymphocytes in the BALF. Th1, Th2 and Th17 cytokines were also elevated at different time points after the challenge. Peribronchial and alveolar inflammation in lung tissue were also augmented. AHR and inflammatory infiltration showed reduced sensitivity to dexamethasone treatment. We have set up a model that mimics key aspects of viral exacerbation in a corticosteroid-refractory asthmatic phenotype which could be used to evaluate new therapies for this condition.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Double-stranded RNA evokes exacerbation in a mouse model of corticosteroid refractory asthma

et al. 2015

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“…The slow progress in asthma therapy (Holgate 2011, von Mutius & Drazen 2012, despite the extensive and long-standing research interest for that lung disorder, suggests that important mediators might have been overlooked. The endocrine regulation of airway contractility and its dysregulation in asthma are key areas of research that clearly deserve further investigation.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

“…The regulation of ASM contractility by remote organs can provide important clues to further our understanding of asthma pathogenesis and to elucidate the origin of asthma heterogeneity (Holgate 2011, Wenzel 2013. It may also lead to the development of alternative treatments, which would be important to fulfill an unmet need in patients who are either refractory or not adequately controlled by current asthma treatments (Barnes & Adcock 2009, Bousquet et al 2009).…”

Section: Mediators Released By Remote Organs On Asm Contractionmentioning

confidence: 99%

Endocrine regulation of airway contractility is overlooked

Bossé

2014

Journal of Endocrinology

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Asthma is a prevalent respiratory disorder triggered by a variety of inhaled environmental factors, such as allergens, viruses, and pollutants. Asthma is characterized by an elevated activation of the smooth muscle surrounding the airways, as well as a propensity of the airways to narrow excessively in response to a spasmogen (i.e. contractile agonist), a feature called airway hyperresponsiveness. The level of airway smooth muscle (ASM) activation is putatively controlled by mediators released in its vicinity. In asthma, many mediators that affect ASM contractility originate from inflammatory cells that are mobilized into the airways, such as eosinophils. However, mounting evidence indicates that mediators released by remote organs can also influence the level of activation of ASM, as well as its level of responsiveness to spasmogens and relaxant agonists. These remote mediators are transported through circulating blood to act either directly on ASM or indirectly via the nervous system by tuning the level of cholinergic activation of ASM. Indeed, mediators generated from diverse organs, including the adrenals, pancreas, adipose tissue, gonads, heart, intestines, and stomach, affect the contractility of ASM. Together, these results suggest that, apart from a paracrine mode of regulation, ASM is subjected to an endocrine mode of regulation. The results also imply that defects in organs other than the lungs can contribute to asthma symptoms and severity. In this review, I suggest that the endocrine mode of regulation of ASM contractility is overlooked.

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“…1 This description provided the basis for using inhaled pharmacologic agents to relieve ''bronchospasm.'' 2 The recognition that asthma is an inflammatory disorder of the airways in the early 1950s led to the discovery of the beneficial effect of corticosteroids and the development of inhaled formulations. The discovery of cysteinyl leukotrienes (leukotrienes C 4 , D 4 , and E 4 ) as the mediators of slow-reacting substance of anaphylaxis opened up a further therapeutic opportunity for intervening with oral inhibitors of 5-lipoxygenase (eg, zileutin) and cysteinyl leukotriene receptor 1 antagonists (eg, montelukast).…”

mentioning

confidence: 99%