Role of Transcription Factors in the Pathogenesis of Asthma and COPD

Caramori, Gaetano; Casolari, Paolo; Adcock, Ian M.

doi:10.3109/15419061.2013.775257

Cited by 55 publications

(54 citation statements)

References 208 publications

(236 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Transcriptional regulators of inflammatory genes including those related to cytokines, adhesion molecules, enzymes and receptors, is part of the molecular signaling that drives the development and progression of lung pathologies such as asthma and COPD [45, 46]. Therefore, not surprisingly, we predicted increased activation of TFs with well-known roles in emphysema development, such as NF-κB [10, 45, 47–52], but we also revealed TFs with less described or unknown roles in the etiology of emphysema.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional profiling and targeted proteomics reveals common molecular changes associated with cigarette smoke-induced lung emphysema development in five susceptible mouse strains

et al. 2015

View full text Add to dashboard Cite

BackgroundMouse models are useful for studying cigarette smoke (CS)-induced chronic pulmonary pathologies such as lung emphysema. To enhance translation of large-scale omics data from mechanistic studies into pathophysiological changes, we have developed computational tools based on reverse causal reasoning (RCR).ObjectiveIn the present study we applied a systems biology approach leveraging RCR to identify molecular mechanistic explanations of pathophysiological changes associated with CS-induced lung emphysema in susceptible mice.Methods The lung transcriptomes of five mouse models (C57BL/6, ApoE−/−, A/J, CD1, and Nrf2−/−) were analyzed following 5–7 months of CS exposure.Results We predicted 39 molecular changes mostly related to inflammatory processes including known key emphysema drivers such as NF-κB and TLR4 signaling, and increased levels of TNF-α, CSF2, and several interleukins. More importantly, RCR predicted potential molecular mechanisms that are less well-established, including increased transcriptional activity of PU.1, STAT1, C/EBP, FOXM1, YY1, and N-COR, and reduced protein abundance of ITGB6 and CFTR. We corroborated several predictions using targeted proteomic approaches, demonstrating increased abundance of CSF2, C/EBPα, C/EBPβ, PU.1, BRCA1, and STAT1.Conclusion These systems biology-derived candidate mechanisms common to susceptible mouse models may enhance understanding of CS-induced molecular processes underlying emphysema development in mice and their relevancy for human chronic obstructive pulmonary disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s00011-015-0820-2) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 99%

Transcriptional profiling and targeted proteomics reveals common molecular changes associated with cigarette smoke-induced lung emphysema development in five susceptible mouse strains

et al. 2015

View full text Add to dashboard Cite

show abstract

“…55 Bacterial lysates are recommended in the treatment of COPD, which is characterized by increased transcription of proinflammatory factors such as cytokines, chemokines, growth factors, and enzymes that results in inflammation and tissue damage. 56 It was recently demonstrated that peripheral blood mononuclear cells from patients with COPD exposed to bacterial lysates in vitro released more IL-10. 32 The increase in immunoregulatory IL-10 secretion could regulate the production of proinflammatory mediators, thereby providing a rationale for the use of bacterial lysates to prevent acute exacerbation in patients with COPD.…”

Section: Clinical Outcomes Of Bacterial Lysate Therapy In Adult Respimentioning

confidence: 99%

Immunoregulatory and immunostimulatory responses of bacterial lysates in respiratory infections and asthma

Kearney

Dziekiewicz

Feleszko

2015

Annals of Allergy, Asthma & Immunology

100

View full text Add to dashboard Cite

“…ASM growth is promoted by growth factors, chemokines, and inflammatory cytokines and involves activation of multiple intracellular signaling cascades that ultimately induce several key transcription factors involved in regulating cell proliferation (9). Using luciferase reporter assays, we investigated activation of 10 (CRE, STAT3, E2F, C/EBP, SRE, Myc, NF-B, NFAT, Smad, and AP-1) different transcription factors to gain further insight into the mechanisms mediating the antimitogenic effects of TAS2R agonists.…”

Section: Tas2r Agonist-mediated Antimitogenic Effect Does Not Involvementioning

confidence: 99%

Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells

Sharma

Panebra

Pera

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

-Airway remodeling is a hallmark feature of asthma and chronic obstructive pulmonary disease. Clinical studies and animal models have demonstrated increased airway smooth muscle (ASM) mass, and ASM thickness is correlated with severity of the disease. Current medications control inflammation and reverse airway obstruction effectively but have limited effect on remodeling. Recently we identified the expression of bitter taste receptors (TAS2R) on ASM cells, and activation with known TAS2R agonists resulted in ASM relaxation and bronchodilation. These studies suggest that TAS2R can be used as new therapeutic targets in the treatment of obstructive lung diseases. To further establish their effectiveness, in this study we aimed to determine the effects of TAS2R agonists on ASM growth and promitogenic signaling. Pretreatment of healthy and asthmatic human ASM cells with TAS2R agonists resulted in a dose-dependent inhibition of ASM proliferation. The antimitogenic effect of TAS2R ligands was not dependent on activation of protein kinase A, protein kinase C, or high/intermediateconductance calcium-activated K ϩ channels. Immunoblot analyses revealed that TAS2R agonists inhibit growth factor-activated protein kinase B phosphorylation without affecting the availability of phosphatidylinositol 3,4,5-trisphosphate, suggesting TAS2R agonists block signaling downstream of phosphatidylinositol 3-kinase. Furthermore, the antimitogenic effect of TAS2R agonists involved inhibition of induced transcription factors (activator protein-1, signal transducer and activator of transcription-3, E2 factor, nuclear factor of activated T cells) and inhibition of expression of multiple cell cycle regulatory genes, suggesting a direct inhibition of cell cycle progression. Collectively, these findings establish the antimitogenic effect of TAS2R agonists and identify a novel class of receptors and signaling pathways that can be targeted to reduce or prevent airway remodeling as well as bronchoconstriction in obstructive airway disease. asthma; airway remodeling; G protein-coupled receptor; type 2 taste receptors G PROTEIN-COUPLED RECEPTOR (GPCR) signaling plays a vital role in the regulation of airway smooth muscle (ASM) contraction, relaxation, and proliferation (4, 12). Exaggerated presentation of procontractile GPCR agonists in the airways during allergic inflammation contributes to bronchoconstriction in obstructive airway disease such as asthma. Another salient feature of inflammatory airway diseases is airway remodeling that is characterized by excessive proliferation and accumulation of resident cells, including ASM cells. Animal models demonstrate ASM mass is increased by allergic airway inflammation, while human studies demonstrate a progressive increase in ASM mass in asthmatic subjects that increases both dynamic and fixed airway resistance, limiting the effectiveness of current rescue bronchodilators (11,21,22,26). Current antiasthma therapies, including ␤-agonists and corticosteroids, aim at alleviating bronchoconstriction and infl...

show abstract

Role of Transcription Factors in the Pathogenesis of Asthma and COPD

Cited by 55 publications

References 208 publications

Transcriptional profiling and targeted proteomics reveals common molecular changes associated with cigarette smoke-induced lung emphysema development in five susceptible mouse strains

Transcriptional profiling and targeted proteomics reveals common molecular changes associated with cigarette smoke-induced lung emphysema development in five susceptible mouse strains

Immunoregulatory and immunostimulatory responses of bacterial lysates in respiratory infections and asthma

Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells

Contact Info

Product

Resources

About