Pathophysiology of asthma: What has our current understanding taught us about new therapeutic approaches?

Holgate, Stephen T.

doi:10.1016/j.jaci.2011.06.052

Cited by 125 publications

(88 citation statements)

References 133 publications

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“…Furthermore, whereas HDM can influence mast cell activity, OVA does not [24]. Moreover, relative to OVA-induced lung inflammation, the HDM-based model is characterized by epithelial involvement and mucosal defense, which is likely to be of influence on locally residing mast cells [25,26]. Taken together, mouse models using HDM as allergen relate better to human asthma, yet are sparsely investigated in mast cell-deficient settings.…”

Section: Discussionmentioning

confidence: 99%

Mast Cell-Deficient KitW-sh Mice Develop House Dust Mite-Induced Lung Inflammation despite Impaired Eosinophil Recruitment

Boer

Yang²,

Boogaard³

et al. 2013

J Innate Immun

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Background: Mast cells are implicated in allergic and innate immune responses in asthma, although their role in models using an allergen relevant for human disease is incompletely understood. House dust mite (HDM) allergy is common in asthma patients. Our aim was to investigate the role of mast cells in HDM-induced allergic lung inflammation. Methods: Wild-type (Wt) and mast cell-deficient Kit^w-sh mice on a C57BL/6 background were repetitively exposed to HDM via the airways. Results: HDM challenge resulted in a rise in tryptase activity in bronchoalveolar lavage fluid (BALF) of Wt mice, indicative of mast cell activation. Kit^w-sh mice showed a strongly attenuated HDM- induced recruitment of eosinophils in BALF and lung tissue, accompanied by reduced pulmonary levels of the eosinophil chemoattractant eotaxin. Remarkably, Kit^w-sh mice demonstrated an unaltered capacity to develop lung pathology and increased mucus production in response to HDM. The increased plasma IgE in response to HDM in Wt mice was absent in Kit^w-sh mice. Conclusion: These data contrast with previous reports on the role of mast cells in models using ovalbumin as allergen in that C57BL/6 Kit^w-sh mice display a selective impairment of eosinophil recruitment without differences in other features of allergic inflammation.

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Section: Discussionmentioning

confidence: 99%

Mast Cell-Deficient KitW-sh Mice Develop House Dust Mite-Induced Lung Inflammation despite Impaired Eosinophil Recruitment

Boer

Yang²,

Boogaard³

et al. 2013

J Innate Immun

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“…These cytokines, which have partially overlapping functions based on their shared IL4RA receptor component, stimulate JAK/STAT signaling cascades, and most cell types in the body are responsive to one or the other. The effects of IL4RA ligation vary based on cell type and range from stimulation of immune responses (T H 2 cell differentiation, B cell proliferation, eosinophil recruitment and IgE class switching) to enhancement of secretory processes (mucus production, collagen synthesis and chemokine expression) to induction of cellular structural changes (smooth muscle contraction and Goblet cell hyperplasia) (Hershey, 2003;Holgate, 2011;Wills-Karp and Finkelman, 2008;Wynn, 2003). Due to these effects, IL-4/IL-13 signaling has been extensively studied in connection to inflammatory diseases such as asthma and inflammatory bowel disease (IBD) (Mitchell et al, + immortalized B cells were treated with 500 ng/ml TM for 16 hours, and then 50 ng/ml IL-4 was added for 1 hour.…”

Section: Er Stress Leads To the Suppression Of Genes Involved In Inflmentioning

confidence: 99%

Endoplasmic reticulum stress impairs IL-4/IL-13 signaling through C/EBPβ-mediated transcriptional suppression

Arensdorf

Rutkowski

2013

Journal of Cell Science

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SummaryActivation of the unfolded protein response (UPR) by endoplasmic reticulum (ER) stress culminates in extensive gene regulation, with transcriptional upregulation of genes that improve the protein folding capacity of the organelle. However, a substantial number of genes are downregulated by ER stress, and the mechanisms that lead to this downregulation and its consequences on cellular function are poorly understood. We found that ER stress led to coordinated transcriptional suppression of diverse cellular processes, including those involved in cytokine signaling. Using expression of the IL-4/IL-13 receptor subunit Il4ra as a sentinel, we sought to understand the mechanism behind this suppression and its impact on inflammatory signaling. We found that reinitiation of global protein synthesis by GADD34-mediated dephosphorylation of eIF2a resulted in preferential expression of the inhibitory LIP isoform of the transcription factor C/EBPb. This regulation was in turn required for the suppression of Il4ra and related inflammatory genes. Suppression of Il4ra was lost in Cebpb 2/2 cells but could be induced by LIP overexpression. As a consequence of Il4ra suppression, ER stress impaired IL-4/ IL-13 signaling. Strikingly, Cebpb 2/2 cells lacking Il4ra downregulation were protected from this signaling impairment. This work identifies a novel role for C/EBPb in regulating transcriptional suppression and inflammatory signaling during ER stress.

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“…Type 2 T helper (Th2) cells and Th2 cytokines such as interleukin (IL)-4, IL-5 and IL-13 play a central role in regulating the behavior of inflammatory cells in asthmatic airways. It has been proposed that interferon-γ-producing Th1 cells inhibit the development of allergic diseases by counterbalancing the proliferation and development of Th2 cells in some stages of inflammation [1,2,3,4]. CD4 + CD25 + regulatory T (Treg) cells play a critical role in the balance of the immune network by suppressing or limiting effector immune responses against internal and external insults.…”

Section: Introductionmentioning

confidence: 99%

The Involvement of Glucocorticoids in Psychological Stress-Induced Exacerbations of Experimental Allergic Asthma

Okuyama

Dobashi

Miyasaka

et al. 2014

Int Arch Allergy Immunol

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Background: Psychological stress is associated with the aggravation of asthma symptoms. Glucocorticoids (GC), which are stress hormones released upon exposure to stress, have the potential to shift immune responses towards a predominant Th2 response by priming antigen-presenting cells to produce lower levels of IL-12 as well as reducing the development of regulatory T cells. However, the involvement of GC in psychological stress-induced exacerbations of allergic asthma has not yet been clarified. Methods: Sensitized mice were exposed to restraint stress followed by forced swimming stress, during which a GC receptor antagonist or a GC synthesis inhibitor was administered, and then antigen was inhaled. Corticosterone levels in the blood were measured in stressed and nonstressed mice. After antigen inhalation, the airway responses to aerosolized methacholine, epithelial mucus secretion and airway inflammation were evaluated, and the IL-13 contents in bronchoalveolar lavage fluid were measured. Results: The exposure to stress significantly increased corticosterone levels. Allergic airway responses and the increase of IL-13 contents evoked by antigen inhalation were significantly higher in stressed mice than in nonstressed mice. The administration of a GC receptor antagonist and a GC synthesis inhibitor during stress exposure significantly reduced the exacerbation of the airway responses and the increase of IL-13 contents in stressed mice challenged with antigen. Conclusions: These results indicate that the increased release of GC upon exposure to stress has a priming effect on the aggravation of allergic airway responses following the exposure, suggesting a pathophysiological role for the neuroendocrine axis in linking psychological stress to asthma exacerbations.

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Pathophysiology of asthma: What has our current understanding taught us about new therapeutic approaches?

Cited by 125 publications

References 133 publications

Mast Cell-Deficient KitW-sh Mice Develop House Dust Mite-Induced Lung Inflammation despite Impaired Eosinophil Recruitment

Mast Cell-Deficient KitW-sh Mice Develop House Dust Mite-Induced Lung Inflammation despite Impaired Eosinophil Recruitment

Endoplasmic reticulum stress impairs IL-4/IL-13 signaling through C/EBPβ-mediated transcriptional suppression

The Involvement of Glucocorticoids in Psychological Stress-Induced Exacerbations of Experimental Allergic Asthma

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