Parabromophenacyl Bromide Inhibits Subepithelial Fibrosis by Reducing TGF-β&lt;sub&gt;1&lt;/sub&gt; in a Chronic Mouse Model of Allergic Asthma

Ram, Arjun; Mabalirajan, Ulaganathan; Jaiswal, Ashish; Rehman, Rakhshinda; Singh, V.R.; Ghosh, Balaram

doi:10.1159/000434679

Cited by 7 publications

(10 citation statements)

References 34 publications

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“…In Th cells, GCs may restore Th1/Th2 balance by altering the secretion of various cytokines, which induce Th cell differentiation [5]. In our study, we confirmed that DEX decreased airway responsiveness and inflammation [25], and we also found that DEX could inhibit Th2 cytokine production and increase Th1 cytokine production in OVA-sensitized mice. A novel finding in our study is that DEX enhanced T-bet expression but inhibited GATA3 expression through the Notch1 (NICD1)-RBPj pathway, which in turn induced changes in the Th1 and Th2 phenotype.…”

Section: Discussionsupporting

confidence: 82%

Glucocorticoids Modulate Th1 and Th2 Responses in Asthmatic Mouse Models by Inhibition of Notch1 Signaling

Feng

et al. 2018

Int Arch Allergy Immunol

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Background: Notch1 has been linked to the pathogenesis of asthma due to its contribution on Th1/Th2 imbalance. γ-Secretase inhibitor (GSI) acts as an effective blocker of Notch1 signaling. Glucocorticoids (GCs) are the most effective anti-inflammatory drugs for asthma. The present study investigated the involvement of the Notch1 pathway in the anti-inflammatory effect of GCs and its association with Th1/Th2 balance. Methods: The asthma model was established in BALB/c mice by sensitization with ovalbumin (OVA). Dexamethasone (DEX; 1 mg/kg) and/or GSI (0.03 mg/kg) was orally or intranasally administrated. Results: Compared to the OVA-sensitized mice, the administration of DEX and/or GSI significantly ameliorated the airway inflammation infiltration, goblet cell metaplasia, and airway hyper-responsiveness. The expression of IL-4 and IL-13, as well as the ratios of eosinophils and lymphocytes, were significantly decreased, whereas IFN-γ and IL-2 levels were significantly increased in bronchoalveolar lavage fluid after the administration of DEX and GSI. The expressions of the Notch1/NICD1 pathway were decreased after DEX and/or GSI administration in lung tissues, especially in CD4+ T cells. Also, a reduction of GATA3 and elevation of T-bet levels were correlated with the upregulation of Th1/Th2 ratios in lung tissues. Conclusions: Through the inhibition of Notch1 signaling, both GSI and GCs could regulate Th1/Th2 balance involved in allergic airway inflammation in OVA-induced asthma.

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Section: Discussionsupporting

confidence: 82%

Glucocorticoids Modulate Th1 and Th2 Responses in Asthmatic Mouse Models by Inhibition of Notch1 Signaling

Feng

et al. 2018

Int Arch Allergy Immunol

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“…Indeed, it has been shown in a mouse model of P. aeruginosa infection that AZ increases arginase-1 expression as well as the activation of latent TGFβ 1 , consistent with polarisation to M2 macrophages. Consequently, the fibronectin concentration has been increased, and a fibrotic process is intensified [32,33] . This fact may partially explain the relatively short period of beneficial effect of AZ in the treatment of CF lung disease.…”

Section: Discussionmentioning

confidence: 99%

Steady-State Therapy with Azithromycin or Low-Dose Prednisolone in Paediatric Cystic Fibrosis Patients: Inflammatory Markers and Disease Progression

Shmarina

Pukhalsky²,

Avakian³

et al. 2017

Int Arch Allergy Immunol

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Background: Anti-inflammatory therapy is a logical approach to slowing the inevitable lung function deterioration in cystic fibrosis (CF) patients. This study's aim was to evaluate inflammatory markers and disease progression in paediatric CF patients chronically treated with azithromycin or low-dose prednisolone. Methods: The study included 204 patients with CF and 100 healthy controls; 102 CF patients were treated with basic therapy only (without anti-inflammatory treatment; WAT), and 102 individuals received basic therapy along with azithromycin (n = 59) or low-dose prednisolone (n = 43). The median duration of therapy was 24 months (range 12-82) with azithromycin and 31 months (range 12-180) with prednisolone. A cross-sectional analysis of plasma and sputum biomarkers was performed. Results: Compared with the healthy controls, the WAT group showed elevated IFN-γ, IL-10 (total), and TGFβ₁ concentrations, and decreased TNFα (total) and adrenocorticotropic hormone (ACTH) levels (all p < 0.05). Plasma TNFα (total) concentrations in azithromycin/prednisolone patients were significantly higher than those in WAT patients and similar to those of healthy children. In contrast, IL-10 (total) levels were significantly decreased in azithromycin/prednisolone-treated patients compared with WAT patients. Children from the azithromycin group demonstrated ACTH levels similar to those of healthy controls. Azithromycin-treated patients showed a significantly reduced rate of CF-related liver disease and a significantly increased incidence of glucose metabolism disturbances. Conclusions: Steady-state anti-inflammatory treatments may have a sustained immunomodulatory action at systemic and local levels in CF patients. Further investigations are needed to assess the effects of supportive azithromycin therapy on the hypothalamic-pituitary-adrenal axis and the incidence of non-pulmonary CF complications.

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“…Among all cytokines and chemokines that can be produced by bronchial epithelial cells, TGF-b1 was recognized as an important factor inducing proliferation of subepithelial fibroblasts and as a driving force of cell differentiation and activation. Increased levels of TGF-b1 have been reported in bronchoalveolar lavage fluids and biopsy specimens of asthma patients (21,22), and TGF-b1 expression correlated with the degree of subepithelial fibrosis (23,24). In healthy humans, the concentration of circulating TGF-b ranges from 0.26 to 20 ng/ml (25)(26)(27), whereas in asthma patients, the circulating TGF-b concentration ranges from 38 to 215 ng/ml (28,29).…”

Section: Discussionmentioning

confidence: 98%

TGF-β Upregulated Mitochondria Mass through the SMAD2/3→C/EBPβ→PRMT1 Signal Pathway in Primary Human Lung Fibroblasts

Sun

Fang

Tang

et al. 2019

The Journal of Immunology

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Tissue remodeling of subepithelial mesenchymal cells is a major pathologic condition of chronic obstructive pulmonary disease and asthma. Fibroblasts contribute to fibrotic events and inflammation in both airway diseases. Recent mechanistic studies established a link between mitochondrial dysfunction or aberrant biogenesis leading to tissue remodeling of the airway wall in asthma. Protein arginine methyltransferase-1 (PRMT1) participated in airway wall remodeling in pulmonary inflammation. This study investigated the mechanism by which PRMT1 regulates mitochondrial mass in primary human airway wall fibroblasts. Fibroblasts from control or asthma patients were stimulated with TGF-b for up to 48 h, and the signaling pathways controlling PRMT1 expression and mitochondrial mass were analyzed. PRMT1 activity was suppressed by the pan-PRMT inhibitor AMI-1. The SMAD2/3 pathway was blocked by SB203580 and C/EBPb by small interference RNA treatment. The data obtained from unstimulated cells showed a significantly higher basal expression of PRMT1 and mitochondrial markers in asthmatic compared with control fibroblasts. In all cells, TGF-b significantly increased the expression of PRMT1 through SMAD2/3 and C/EBPb. Subsequently, PRMT1 upregulated the expression of the mitochondria regulators PGC-1a and heat shock protein 60. Both the inhibition of the SAMD2/3 pathway or PRMT1 attenuated TGF-b-induced mitochondrial mass and C/EBPb and a-SMA expression. These findings suggest that the signaling sequence controlling mitochondria in primary human lung fibroblasts is as follows: TGF-b→SMAD2/3→C/EBPb→PRMT1→PGC-1a. Therefore, PRMT1 and C/EBPb present a novel therapeutic and diagnostic target for airway wall remodeling in chronic lung diseases.

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Parabromophenacyl Bromide Inhibits Subepithelial Fibrosis by Reducing TGF-β<sub>1</sub> in a Chronic Mouse Model of Allergic Asthma

Cited by 7 publications

References 34 publications

Glucocorticoids Modulate Th1 and Th2 Responses in Asthmatic Mouse Models by Inhibition of Notch1 Signaling

Glucocorticoids Modulate Th1 and Th2 Responses in Asthmatic Mouse Models by Inhibition of Notch1 Signaling

Steady-State Therapy with Azithromycin or Low-Dose Prednisolone in Paediatric Cystic Fibrosis Patients: Inflammatory Markers and Disease Progression

TGF-β Upregulated Mitochondria Mass through the SMAD2/3→C/EBPβ→PRMT1 Signal Pathway in Primary Human Lung Fibroblasts

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