The Experts below are selected from a list of 13512 Experts worldwide ranked by ideXlab platform
David H Broide - One of the best experts on this subject based on the ideXlab platform.
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Genes and Pathways Regulating Decline in Lung Function and Airway Remodeling in Asthma.
Allergy Asthma and Immunology Research, 2019Co-Authors: David H BroideAbstract: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.
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autophagy plays a role in fstl1 induced epithelial mesenchymal transition and Airway Remodeling in asthma
American Journal of Physiology-lung Cellular and Molecular Physiology, 2017Co-Authors: Marina Miller, Jiping Zhao, Jinxiang Wu, Junfei Wang, David H Broide, Shuo Li, Jiawei Xu, Liang DongAbstract: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...
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anti siglec f antibody reduces allergen induced eosinophilic inflammation and Airway Remodeling
Journal of Immunology, 2009Co-Authors: Dae Jin Song, Marina Miller, Peter Rosenthal, Michael Croft, Pejman Soroosh, Mai Zhang, Ajit Varki, David H BroideAbstract: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.
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cytokines and growth factors in Airway Remodeling in asthma
Current Opinion in Immunology, 2007Co-Authors: Taylor A Doherty, David H BroideAbstract:Airway Remodeling in asthma is defined by several structural changes including epithelial cell mucus metaplasia, an increase in peribronchial smooth muscle mass, subepithelial fibrosis, and angiogenesis. Cytokines, chemokines, and growth factors released from inflammatory and structural cells in the Airway are considered to play a pivotal role in the development of Remodeling. Studies of allergen induced Airway Remodeling in transgenic mice suggest an important role for TGF-β, VEGF, Th2 cytokines (IL-5, IL-9, IL-13), and epithelial derived NF-κB regulated chemokines in Airway Remodeling. Although studies of bronchial biopsies from human asthmatics also demonstrate expression of TGF-β, VEGF, IL-5, IL-9, IL-13, and NF-κB regulated chemokines, further human intervention studies are required in which individual cytokines or chemokines are neutralized to define their role in Airway Remodeling.
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inhibition of allergen induced Airway Remodeling in smad 3 deficient mice
Journal of Immunology, 2007Co-Authors: Marina Miller, Shauna Mcelwain, Annie V Le, Kirsti Golgotiu, David H BroideAbstract:Intracellular signaling pathways that converge on Smad 3 are used by both TGF-β and activin A, key cytokines implicated in the process of fibrogenesis. To determine the role of Smad 3 in allergen-induced Airway Remodeling, Smad 3-deficient and wild-type (WT) mice were sensitized to OVA and challenged by repetitive administration of OVA for 1 mo. Increased levels of activin A and increased numbers of peribronchial TGF-β1+ cells were detected in WT and Smad 3-deficient mice following repetitive OVA challenge. Smad 3-deficient mice challenged with OVA had significantly less peribronchial fibrosis (total lung collagen content and trichrome staining), reduced thickness of the peribronchial smooth muscle layer, and reduced epithelial mucus production compared with WT mice. As TGF-β and Smad 3 signaling are hypothesized to mediate differentiation of fibroblasts to myofibroblasts in vivo, we determined the number of peribronchial myofibroblasts (Col-1+ and α-smooth muscle actin+) as assessed by double-label immunofluorescence microscopy. Although the number of peribronchial myofibroblasts increased significantly in WT mice following OVA challenge, there was a significant reduction in the number of peribronchial myofibroblasts in OVA-challenged Smad 3-deficient mice. There was no difference in levels of eosinophilic Airway inflammation or Airway responsiveness in Smad 3-deficient compared with WT mice. These results suggest that Smad 3 signaling is required for allergen-induced Airway Remodeling, as well as allergen-induced accumulation of myofibroblasts in the Airway. However, Smad 3 signaling does not contribute significantly to Airway responsiveness.
Qutayba Hamid - One of the best experts on this subject based on the ideXlab platform.
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role of transforming growth factor β in Airway Remodeling in asthma
American Journal of Respiratory Cell and Molecular Biology, 2011Co-Authors: Rabih Halwani, Saleh Almuhsen, Hamdan Aljahdali, Qutayba HamidAbstract: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.
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Airway Remodeling in asthma
Current Opinion in Pharmacology, 2010Co-Authors: Rabih Halwani, Saleh Almuhsen, Qutayba HamidAbstract: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.
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Airway Remodeling in asthma
Allergology International, 2007Co-Authors: Yuki Sumi, Qutayba HamidAbstract: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 - One of the best experts on this subject based on the ideXlab platform.
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autophagy plays a role in fstl1 induced epithelial mesenchymal transition and Airway Remodeling in asthma
American Journal of Physiology-lung Cellular and Molecular Physiology, 2017Co-Authors: Marina Miller, Jiping Zhao, Jinxiang Wu, Junfei Wang, David H Broide, Shuo Li, Jiawei Xu, Liang DongAbstract: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...
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fstl1 promotes asthmatic Airway Remodeling by inducing oncostatin m
Journal of Immunology, 2015Co-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 ZurawAbstract: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.
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ormdl3 transgenic mice have increased Airway Remodeling and Airway responsiveness characteristic of asthma
Journal of Immunology, 2014Co-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 NiwaAbstract: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
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anti siglec f antibody reduces allergen induced eosinophilic inflammation and Airway Remodeling
Journal of Immunology, 2009Co-Authors: Dae Jin Song, Marina Miller, Peter Rosenthal, Michael Croft, Pejman Soroosh, Mai Zhang, Ajit Varki, David H BroideAbstract: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.
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inhibition of allergen induced Airway Remodeling in smad 3 deficient mice
Journal of Immunology, 2007Co-Authors: Marina Miller, Shauna Mcelwain, Annie V Le, Kirsti Golgotiu, David H BroideAbstract:Intracellular signaling pathways that converge on Smad 3 are used by both TGF-β and activin A, key cytokines implicated in the process of fibrogenesis. To determine the role of Smad 3 in allergen-induced Airway Remodeling, Smad 3-deficient and wild-type (WT) mice were sensitized to OVA and challenged by repetitive administration of OVA for 1 mo. Increased levels of activin A and increased numbers of peribronchial TGF-β1+ cells were detected in WT and Smad 3-deficient mice following repetitive OVA challenge. Smad 3-deficient mice challenged with OVA had significantly less peribronchial fibrosis (total lung collagen content and trichrome staining), reduced thickness of the peribronchial smooth muscle layer, and reduced epithelial mucus production compared with WT mice. As TGF-β and Smad 3 signaling are hypothesized to mediate differentiation of fibroblasts to myofibroblasts in vivo, we determined the number of peribronchial myofibroblasts (Col-1+ and α-smooth muscle actin+) as assessed by double-label immunofluorescence microscopy. Although the number of peribronchial myofibroblasts increased significantly in WT mice following OVA challenge, there was a significant reduction in the number of peribronchial myofibroblasts in OVA-challenged Smad 3-deficient mice. There was no difference in levels of eosinophilic Airway inflammation or Airway responsiveness in Smad 3-deficient compared with WT mice. These results suggest that Smad 3 signaling is required for allergen-induced Airway Remodeling, as well as allergen-induced accumulation of myofibroblasts in the Airway. However, Smad 3 signaling does not contribute significantly to Airway responsiveness.
Reynold A. Panettieri - One of the best experts on this subject based on the ideXlab platform.
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Airway smooth muscle cell hyperplasia: a therapeutic target in Airway Remodeling in asthma?
Progress in cell cycle research, 2020Co-Authors: Alaina J. Ammit, Reynold A. PanettieriAbstract:: Severe asthma is characterized by Airway Remodeling due, in part, to increases in Airway smooth muscle (ASM) mass. Regulation of ASM hyperplasia is considered an attractive therapeutic target for the potential treatment of Airway Remodeling in asthma. In order to develop anti-Remodeling drugs, researchers have utilized cell culture techniques to elucidate the cellular and molecular mechanisms underlying ASM cell proliferation and to identify the critical cell cycle events that regulate ASM cell growth. Attractive lead compounds that have emerged from in vitro studies can now be examined in new animal models of Airway Remodeling, thus providing tools to design novel therapies to prevent or abrogate Airway Remodeling.
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transforming growth factor β1 function in Airway Remodeling and hyperresponsiveness the missing link
American Journal of Respiratory Cell and Molecular Biology, 2017Co-Authors: Christie A Ojiaku, Reynold A. PanettieriAbstract:The pathogenesis of asthma includes a complex interplay among Airway inflammation, hyperresponsiveness, and Remodeling. Current evidence suggests that Airway structural cells, including bronchial smooth muscle cells, myofibroblasts, fibroblasts, and epithelial cells, mediate all three aspects of asthma pathogenesis. Although studies show a connection between Airway Remodeling and changes in bronchomotor tone, the relationship between the two remains unclear. Transforming growth factor β1 (TGF-β1), a growth factor elevated in the Airway of patients with asthma, plays a role in Airway Remodeling and in the shortening of various Airway structural cells. However, the role of TGF-β1 in mediating Airway hyperresponsiveness remains unclear. In this review, we summarize the literature addressing the role of TGF-β1 in Airway Remodeling and shortening. Through our review, we aim to further elucidate the role of TGF-β1 in asthma pathogenesis and the link between Airway Remodeling and Airway hyperresponsiveness in as...
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Is Airway Remodeling clinically relevant in asthma
The American Journal of Medicine, 2003Co-Authors: Aili L. Lazaar, Reynold A. PanettieriAbstract:The social and economic impact of asthma is substantial worldwide. Although current therapies targeting both Airway inflammation and Airway hyperreactivity effectively relieve and prevent symptoms in the majority of patients, some patients experience persistent symptoms and a progressive decline in lung function, described as irreversible or refractory asthma. Indeed, there are many unanswered questions about the role of Airway Remodeling in asthma. This review addresses several topics of controversy, including whether all patients with asthma demonstrate Airway Remodeling; the contribution of distinct Airway resident cells to the development of Remodeling; the role of biomarkers or noninvasive measurements in predicting Airway Remodeling; and the effectiveness of current therapies on Airway Remodeling and disease progression.
Mingji Yi - One of the best experts on this subject based on the ideXlab platform.
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inhibition Airway Remodeling and transforming growth factor β1 smad signaling pathway by astragalus extract in asthmatic mice
International Journal of Molecular Medicine, 2012Co-Authors: Zhenghai Qu, Zhaochuan Yang, Lei Chen, Zhidong Lv, Mingji YiAbstract:Airway Remodeling is characterized by Airway wall thickening, subepithelial fibrosis, increased smooth muscle mass, angiogenesis and increased mucous glands, which can lead to a chronic and obstinate asthma with pulmonary function depression. In the present study, we investigated whether the astragalus extract inhibits Airway Remodeling in a mouse asthma model and observed the effects of astragalus extract on the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway in ovalbumin-sensitized mice. Mice were sensitized and challenged by ovalbumin to establish a model of asthma. Treatments included the astragalus extract and budesonide. Lung tissues were obtained for hematoxylin and eosin staining and Periodic acid-Schiff staining after the final ovalbumin challenge. Levels of TGF-β1 were assessed by immunohistology and ELISA, levels of TGF-β1 mRNA were measured by RT-PCR, and levels of P-Smad2/3 and T-Smad2/3 were assessed by western blotting. Astragalus extract and budesonide reduced allergen-induced increases in the thickness of bronchial Airway and mucous gland hypertrophy, goblet cell hyperplasia and collagen deposition. Levels of lung TGF-β1, TGF-β1 mRNA and P-Smad2/3 were significantly reduced in mice treated with astragalus extract and budesonide. Astragalus extract improved asthma Airway Remodeling by inhibiting the expression of the TGF-β1/Smad signaling pathway, and may be a potential drug for the treatment of patients with a severe asthma Airway.
