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Airway Remodeling

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David H Broide – 1st expert on this subject based on the ideXlab platform

  • Genes and Pathways Regulating Decline in Lung Function and Airway Remodeling in Asthma.
    Allergy Asthma and Immunology Research, 2019
    Co-Authors: David H Broide

    Abstract:

    Asthma is a common disorder of the Airways characterized by Airway inflammation and by decline in lung function and Airway Remodeling in a subset of asthmatics. Airway Remodeling is characterized by structural changes which include Airway smooth muscle hypertrophy/hyperplasia, subepithelial fibrosis due to thickening of the reticular basement membrane, mucus metaplasia of the epithelium, and angiogenesis. Epidemiologic studies suggest that both genetic and environmental factors may contribute to decline in lung function and Airway Remodeling in a subset of asthmatics. Environmental factors include respiratory viral infection-triggered asthma exacerbations, and tobacco smoke. There is also evidence that several asthma candidate genes may contribute to decline in lung function, including ADAM33, PLAUR, VEGF, IL13, CHI3L1, TSLP, GSDMB, TGFB1, POSTN, ESR1 and ARG2. In addition, mediators or cytokines, including cysteinyl leukotrienes, matrix metallopeptidase-9, interleukin-33 and eosinophil expression of transforming growth factor-β, may contribute to Airway Remodeling in asthma. Although increased Airway smooth muscle is associated with reduced lung function (i.e. forced expiratory volume in 1 second) in asthma, there have been few long-term studies to determine how individual pathologic features of Airway Remodeling contribute to decline in lung function in asthma. Clinical studies with inhibitors of individual gene products, cytokines or mediators are needed in asthmatic patients to identify their individual role in decline in lung function and/or Airway Remodeling.

  • autophagy plays a role in fstl1 induced epithelial mesenchymal transition and Airway Remodeling in asthma
    American Journal of Physiology-lung Cellular and Molecular Physiology, 2017
    Co-Authors: Marina Miller, Jinxiang Wu, Junfei Wang, Jiping Zhao, David H Broide, Shuo Li, Jiawei Xu, Liang Dong

    Abstract:

    Asthma is a chronic disease related to Airway hyperresponsiveness and Airway Remodeling. Airway Remodeling is the important reason of refractory asthma and is associated with differentiation of air…

  • anti siglec f antibody reduces allergen induced eosinophilic inflammation and Airway Remodeling
    Journal of Immunology, 2009
    Co-Authors: Dae Jin Song, Marina Miller, Peter Rosenthal, Michael Croft, Pejman Soroosh, Mai Zhang, Ajit Varki, David H Broide

    Abstract:

    Siglec-F is a sialic acid-binding Ig superfamily receptor that is highly expressed on eosinophils. We have investigated whether administration of an anti-Siglec-F Ab to OVA-challenged wild-type mice would reduce levels of eosinophilic inflammation and levels of Airway Remodeling. Mice sensitized to OVA and challenged repetitively with OVA for 1 mo who were administered an anti-Siglec-F Ab had significantly reduced levels of peribronchial eosinophilic inflammation and significantly reduced levels of subepithelial fibrosis as assessed by either trichrome staining or lung collagen levels. The anti-Siglec-F Ab reduced the number of bone marrow, blood, and tissue eosinophils, suggesting that the anti-Siglec-F Ab was reducing the production of eosinophils. Administration of a F(ab′)2 fragment of an anti-Siglec-F Ab also significantly reduced levels of eosinophilic inflammation in the lung and blood. FACS analysis demonstrated increased numbers of apoptotic cells (annexin V+/CCR3+ bronchoalveolar lavage and bone marrow cells) in anti-Siglec-F Ab-treated mice challenged with OVA. The anti-Siglec-F Ab significantly reduced the number of peribronchial major basic protein+/TGF-β+ cells, suggesting that reduced levels of eosinophil-derived TGF-β in anti-Siglec-F Ab-treated mice contributed to reduced levels of peribronchial fibrosis. Administration of the anti-Siglec-F Ab modestly reduced levels of periodic acid-Schiff-positive mucus cells and the thickness of the smooth muscle layer. Overall, these studies suggest that administration of an anti-Siglec-F Ab can significantly reduce levels of allergen-induced eosinophilic Airway inflammation and features of Airway Remodeling, in particular subepithelial fibrosis, by reducing the production of eosinophils and increasing the number of apoptotic eosinophils in lung and bone marrow.

Qutayba Hamid – 2nd expert on this subject based on the ideXlab platform

  • role of transforming growth factor β in Airway Remodeling in asthma
    American Journal of Respiratory Cell and Molecular Biology, 2011
    Co-Authors: Rabih Halwani, Saleh Almuhsen, Hamdan Aljahdali, Qutayba Hamid

    Abstract:

    TGF-β is one of the main mediators involved in tissue Remodeling in the asthmatic lung. This profibrotic cytokine is produced by a number of cells, including macrophages, epithelial cells, fibroblasts, and eosinophils. High expression of TGF-β in patients with asthma was reported by many investigators. However, controversy remains whether the concentration of TGF-β correlates with disease severity. TGF-β is believed to play an important role in most of the cellular biological processes leading to Airway Remodeling. It was shown to be involved in epithelial changes, subepithelial fibrosis, Airway smooth muscle Remodeling, and microvascular changes. Here, sources of TGF-β, as well as its role in the development of Airway Remodeling, will be reviewed. Therapeutic strategies that modulate TGF-β will also be discussed.

  • Airway Remodeling in asthma
    Current Opinion in Pharmacology, 2010
    Co-Authors: Rabih Halwani, Qutayba Hamid, Saleh Almuhsen

    Abstract:

    Asthmatic Airway Remodeling is the pathophysiological modifications of the normal Airway wall structure which include changes in the composition and organization of its cellular and molecular constituents. These modifications are the major cause of the symptoms associated with decreased pulmonary function. Airway Remodeling is partially reversible in mild asthma but mostly irreversible in chronic severe asthma. It is initiated as a repair process in response to Airway wall injuries caused by inflammation; however, dysregulation of this process leads to Airway Remodeling. In this review, we will summarize the most recent findings about the different structural changes in Airways of asthmatics as well as mediators involved in this process.

  • Airway Remodeling in asthma
    Allergology International, 2007
    Co-Authors: Yuki Sumi, Qutayba Hamid

    Abstract:

    ABSTRACT Airway Remodeling can be defined as changes in the composition, content, and organization of the cellular and molecular constituents of the Airway wall. Airway Remodeling is a characteristic feature of asthma, and has important functional implications. These structural changes include epithelial detachment, subepithelial fibrosis, increased Airway smooth muscle (ASM) mass, decreased distance between epithelium and ASM cells, goblet cell hyperplasia, mucus gland hyperplasia, proliferation of blood vessels and Airway edema and changes in the cartilage. Each can contribute to Airway hyperreactivity (AHR), and may eventually lead to irreversible airflow obstruction with disease progression. Structural changes can be observed from early onset of the disease and thus Remodeling is thought to be characteristic of asthma. Some aspects of Airway Remodeling can be explained as a consequence of TH2 inflammation, although it has also been suggested that the exaggerated inflammation and Remodeling seen in asthmatic Airways is the consequence of abnormal injury and repair responses stemming from the susceptibility of bronchial epithelia to components of the inhaled environment. According to this view, Remodeling occurs by way of a noninflammatory mechanism, where inflammation of Airways and altered structure and function of the Airways are parallel and interacting factors. Airway Remodeling in established asthma is poorly responsive to current therapies, such as inhalation of corticosteroids and administration of β2-agonists, antileukotrienes, and theophylline.

Marina Miller – 3rd expert on this subject based on the ideXlab platform

  • autophagy plays a role in fstl1 induced epithelial mesenchymal transition and Airway Remodeling in asthma
    American Journal of Physiology-lung Cellular and Molecular Physiology, 2017
    Co-Authors: Marina Miller, Jinxiang Wu, Junfei Wang, Jiping Zhao, David H Broide, Shuo Li, Jiawei Xu, Liang Dong

    Abstract:

    Asthma is a chronic disease related to Airway hyperresponsiveness and Airway Remodeling. Airway Remodeling is the important reason of refractory asthma and is associated with differentiation of air…

  • fstl1 promotes asthmatic Airway Remodeling by inducing oncostatin m
    Journal of Immunology, 2015
    Co-Authors: Marina Miller, Andrew Beppu, Peter Rosenthal, Alexa Pham, Maya R Karta, Dae In J Song, Christine Vuong, Taylor A Doherty, Michael Croft, Bruce L Zuraw

    Abstract:

    Chronic asthma is associated with Airway Remodeling and decline in lung function. In this article, we show that follistatin-like 1 (Fstl1), a mediator not previously associated with asthma, is highly expressed by macrophages in the lungs of humans with severe asthma. Chronic allergen-challenged Lys-Cre(tg) /Fstl1(Delta/Delta) mice in whom Fstl1 is inactivated in macrophages/myeloid cells had significantly reduced Airway Remodeling and reduced levels of oncostatin M (OSM), a cytokine previously not known to be regulated by Fstl1. The importance of the Fstl1 induction of OSM to Airway Remodeling was demonstrated in murine studies in which administration of Fstl1 induced Airway Remodeling and increased OSM, whereas administration of an anti-OSM Ab blocked the effect of Fstl1 on inducing Airway Remodeling, eosinophilic Airway inflammation, and Airway hyperresponsiveness, all cardinal features of asthma. Overall, these studies demonstrate that the Fstl1/OSM pathway may be a novel pathway to inhibit Airway Remodeling in severe human asthma.

  • ormdl3 transgenic mice have increased Airway Remodeling and Airway responsiveness characteristic of asthma
    Journal of Immunology, 2014
    Co-Authors: Marina Miller, Andrew Beppu, Peter Rosenthal, Taylor A Doherty, James L Mueller, Hal M Hoffman, Matthew D Mcgeough, Carla A Pena, Maho Suzukawa, Maho Niwa

    Abstract:

    Orosomucoid-like (ORMDL)3 has been strongly linked with asthma in genetic association studies. Because allergen challenge induces lung ORMDL3 expression in wild-type mice, we have generated human ORMDL3 zona pellucida 3 Cre (hORMDL3zp3-Cre) mice that overexpress human ORMDL3 universally to investigate the role of ORMDL3 in regulating Airway inflammation and Remodeling. These hORMDL3zp3-Cre mice have significantly increased levels of Airway Remodeling, including increased Airway smooth muscle, subepithelial fibrosis, and mucus. hORMDL3zp3-Cre mice had spontaneously increased Airway responsiveness to methacholine compared to wild-type mice. This increased Airway Remodeling was associated with selective activation of the unfolded protein response pathway transcription factor ATF6 (but not Ire1 or PERK). The ATF6 target gene SERCA2b, implicated in Airway Remodeling in asthma, was strongly induced in the lungs of hORMDL3zp3-Cre mice. Additionally, increased levels of expression of genes associated with Airway Remodeling (TGF-β1, ADAM8) were detected in Airway epithelium of these mice. Increased levels of Airway Remodeling preceded increased levels of Airway inflammation in hORMDL3zp3-Cre mice. hORMDL3zp3-Cre mice had increased levels of IgE, with no change in levels of IgG, IgM, and IgA. These studies provide evidence that ORMDL3 plays an important role in vivo in Airway Remodeling potentially through ATF6 target genes such as SERCA2b and/or through ATF6-independent genes (TGF-β1, ADAM8).

    This article is featured in In This Issue , p.[3453][1]

    [1]: /lookup/volpage/192/3453