Ultrastructure of the bronchial epithelium in three children with asthma

Konrádová, V; Čopová, C.; Suková, B; Houštěk, J

doi:10.1002/ppul.1950010403

Cited by 32 publications

(22 citation statements)

References 2 publications

(1 reference statement)

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“…Superoxide radicals increase TGF-b transcription in alveolar epithelial cells (14) and promote TGF-b activity and collagen deposition from human lung fibroblasts (15). Mitochondrial ROS have recently been shown to be required for downstream TGFb 16 signaling, and mitochondrial dysfunction is a feature of asthmatic airway cells (17)(18)(19). Given that IL-13 and allergens both induce ROS, which have been shown to increase transcription, activation, and downstream TGF-b signaling, we hypothesized that mitochondrial ROS are a critical signaling intermediary between IL-13 stimulation and TGF-b-dependent airway remodeling.…”

mentioning

confidence: 99%

Mitochondrial-Targeted Antioxidant Therapy Decreases Transforming Growth Factor-β–Mediated Collagen Production in a Murine Asthma Model

Jaffer¹,

Carter

Sanders³

et al. 2015

Am J Respir Cell Mol Biol

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Asthma is a disease of acute and chronic inflammation in which cytokines play a critical role in orchestrating the allergic inflammatory response. IL-13 and transforming growth factor (TGF)-b promote fibrotic airway remodeling, a major contributor to disease severity. Improved understanding is needed, because current therapies are inadequate for suppressing development of airway fibrosis. IL-13 is known to stimulate respiratory epithelial cells to produce TGF-b, but the mechanism through which this occurs is unknown. Here, we tested the hypothesis that reactive oxygen species (ROS) are a critical signaling intermediary between IL-13 or allergen stimulation and TGF-b-dependent airway remodeling. We used cultured human bronchial epithelial cells and an in vivo mouse model of allergic asthma to map a pathway where allergens enhanced mitochondrial ROS, which is an essential upstream signal for TGF-b activation and enhanced collagen production and deposition in airway fibroblasts. We show that mitochondria in airway epithelium are an essential source of ROS that activate TGF-b expression and activity. TGF-b from airway epithelium stimulates collagen expression in fibroblasts, contributing to an early fibrotic response to allergen exposure in cultured human airway cells and in ovalbumin-challenged mice. Treatment with the mitochondrialtargeted antioxidant, (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (mitoTEMPO), significantly attenuated mitochondrial ROS, TGF-b, and collagen deposition in OVA-challenged mice and in cultured human epithelial cells. Our findings suggest that mitochondria are a critical source of ROS for promoting TGF-b activity that contributes to airway remodeling in allergic asthma. Mitochondrial-targeted antioxidants may be a novel approach for future asthma therapies.

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mentioning

confidence: 99%

Mitochondrial-Targeted Antioxidant Therapy Decreases Transforming Growth Factor-β–Mediated Collagen Production in a Murine Asthma Model

Jaffer¹,

Carter

Sanders³

et al. 2015

Am J Respir Cell Mol Biol

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“…In addition, increased numbers of mitochondria and altered mitochondria have been observed in bronchial epithelium in murine model of asthma and asthmatic children (6,7). Also, oxidative-free radicals relevant to asthma pathogenesis, such as peroxynitrite, primarily affect cytochrome c oxidase by degrading its heme centers and damaging its copper center.…”

mentioning

confidence: 99%

Mitochondrial Structural Changes and Dysfunction Are Associated with Experimental Allergic Asthma

Mabalirajan

Dinda

Kumar

et al. 2008

The Journal of Immunology

195

234

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An imbalance between Th1 and Th2 immune response is crucial for the development of pathophysiological features of asthma. A Th2-dominant response produces oxidative stress in the airways, and it is thought to be one of the crucial components of asthma pathogenesis. Although mitochondrion is a crucial organelle to produce endogenous reactive oxygen species, its involvement in this process remains unexplored as yet. We demonstrate in this study that OVA-induced experimental allergic asthma in BALB/c mice is associated with mitochondrial dysfunction, such as reduction of cytochrome c oxidase activity in lung mitochondria, reduction in the expression of subunit III of cytochrome c oxidase in bronchial epithelium, appearance of cytochrome c in the lung cytosol, decreased lung ATP levels, reduction in the expression of 17 kDa of complex I in bronchial epithelium, and mitochondrial ultrastructural changes such as loss of cristae and swelling. However, there was no change in the expression of subunits II and III of cytochrome c oxidase. Interestingly, administration of IL-4 mAb reversed these mitochondrial dysfunction and structural changes. In contrast, IFN-γ mAb administration neither reversed nor further deteriorated the mitochondrial dysfunction and structural changes compared with control asthmatic mice administered with isotypic control Ab, although airway hyperresponsiveness deteriorated further. These results suggest that mitochondrial structural changes and dysfunction are associated with allergic asthma. These findings may help in the development of novel drug molecules targeting mitochondria for the treatment of asthma.

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“…As far back as 1985, it had been described that human bronchial epithelial cells of asthmatics showed swollen mitochondria [32]. Mabalirajan and colleagues dissected this further in experimental mouse models of allergic airway inflammation and found this to be an integral part of the asthma phenotype [33] [34].…”

Section: Pathophysiologymentioning

confidence: 99%

Obesity, Metabolic Syndrome, and Airway Disease

Agrawal

Prakash

2014

Immunology and Allergy Clinics of North America

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SYNOPSIS Common pathophysiological mechanisms are increasingly being recognized between obesity, metabolic dysfunction, and airway disease. Obesity increases asthma risk or severity, in multiple studies across the globe. Metabolic changes of obesity such as diabetes or insulin resistance are associated with asthma as well as poorer lung function. Insulin resistance has also been found to increase asthma risk independent of body mass. Conversely, asthma has been associated with abnormal glucose and lipid metabolism, insulin resistance, and obesity. These bidirectional and dose-dependent associations suggest common unifying molecular processes that contribute to these seemingly disparate diseases. Reduced mitochondrial mass and/or function is increasingly recognized as one such mechanism that has been causally associated with insulin resistance, obesity and asthma, while conversely, restoration of mitochondrial numbers and function can lead to recovery of normal bioenergetics with reversal of disease features. Here, we review current understanding of how dietary and lifestyle factors lead to changes in mitochondrial metabolism and cellular bioenergetics, inducing various components of the cardiometabolic syndrome as well as airway disease. We provide an overview of and evidence for potentially useful mitochondria-targeted therapies, and discuss the emerging use of mesenchymal stem cells as mitochondrial donors, in the context of asthma.

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Ultrastructure of the bronchial epithelium in three children with asthma

Cited by 32 publications

References 2 publications

Mitochondrial-Targeted Antioxidant Therapy Decreases Transforming Growth Factor-β–Mediated Collagen Production in a Murine Asthma Model

Mitochondrial-Targeted Antioxidant Therapy Decreases Transforming Growth Factor-β–Mediated Collagen Production in a Murine Asthma Model

Mitochondrial Structural Changes and Dysfunction Are Associated with Experimental Allergic Asthma

Obesity, Metabolic Syndrome, and Airway Disease

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