Status and prospects: personalized treatment and biomarker for airway remodeling in asthma

Zhang, Jintao; Dong, Liang

doi:10.21037/jtd-20-1024

Cited by 23 publications

(23 citation statements)

References 111 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…ASMCs reversible switching between contractile and proliferative phenotypes, is considered to contribute to proliferative diseases. Airway remodeling is one of the main features of asthma and involves structural changes of airway smooth muscle, epithelia, extracellular matrix, and blood vessels (17,18). Airway smooth muscle remodeling has important effects on airway responsiveness and severity of asthma (18).…”

Section: Discussionmentioning

confidence: 99%

Azithromycin induces apoptosis in airway smooth muscle cells through mitochondrial pathway in a rat asthma model

Wu¹,

Juan²,

Zhang³

et al. 2021

Ann Transl Med

View full text Add to dashboard Cite

Background: The proliferation of airway smooth muscle cells (ASMCs) is a key feature of airway remodeling in asthma. Azithromycin (AZM) has been shown to decrease bronchial hyperresponsiveness and airway inflammation in asthmatics; however, the role of AZM in ASMC proliferation remains unclear. Thus, we investigated the effect of AZM on ASMC proliferation in a rat model of experimental asthma.Methods: We isolated ASMCs from rats sensitized and challenged by ovabulmin (OVA), and then treated with different concentrations of AZM. Cytotoxicity of ASMC was evaluated by Cell Counting Kit-8 (CCK-8) assay, morphological change was examined with laser confocal microscope after Annexin V/propidium iodide (PI) double staining, mitochondrial membrane potential was determined with JC-1 staining, and the expression of cytochrome C was examined by western blot. Results:The relative surface areas of airway wall and smooth muscle layers in OVA-sensitized rats were significantly increased compared to those in the control group. Furthermore, in OVA-sensitized rats, the mitochondrial membrane potential of ASMC was higher, while the expression of mitochondria cytochrome C was lower compared to that in control rats. After AZM treatment, ASMC apoptosis was increased, mitochondrial membrane potential reduced, and the protein level of cytosolic cytochrome C was increased.Conclusions: This study demonstrated that AZM increased the apoptosis of ASMCs through a mitochondrial pathway, which might play an important role in ASMs proliferation during asthmatic remodeling.

show abstract

Section: Discussionmentioning

confidence: 99%

Azithromycin induces apoptosis in airway smooth muscle cells through mitochondrial pathway in a rat asthma model

Wu¹,

Juan²,

Zhang³

et al. 2021

Ann Transl Med

View full text Add to dashboard Cite

show abstract

“…Asthma is a chronic inflammatory condition of ASM, characterized by airway inflammation, airway hyper-contractility and airway remodeling (ASM proliferation) [ 69 , 70 , 71 , 72 , 73 ]. Surprisingly, very few studies on asthma have dealt with the crosstalk between mitochondrial oxidative stress and ER stress response and its impact on the inflammation in human ASM to date.…”

Section: The Homeostatic Response To Tnfα In Asthmatic Human Asmmentioning

confidence: 99%

Inflammation-Induced Protein Unfolding in Airway Smooth Muscle Triggers a Homeostatic Response in Mitochondria

Dasgupta

Delmotte

Sieck

2020

IJMS

View full text Add to dashboard Cite

The effects of airway inflammation on airway smooth muscle (ASM) are mediated by pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFα). In this review article, we will provide a unifying hypothesis for a homeostatic response to airway inflammation that mitigates oxidative stress and thereby provides resilience to ASM. Previous studies have shown that acute exposure to TNFα increases ASM force generation in response to muscarinic stimulation (hyper-reactivity) resulting in increased ATP consumption and increased tension cost. To meet this increased energetic demand, mitochondrial O2 consumption and oxidative phosphorylation increases but at the cost of increased reactive oxygen species (ROS) production (oxidative stress). TNFα-induced oxidative stress results in the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and mitochondria of ASM. In the ER, TNFα selectively phosphorylates inositol-requiring enzyme 1 alpha (pIRE1α) triggering downstream splicing of the transcription factor X-box binding protein 1 (XBP1s); thus, activating the pIRE1α/XBP1s ER stress pathway. Protein unfolding in mitochondria also triggers an unfolded protein response (mtUPR). In our conceptual framework, we hypothesize that activation of these pathways is homeostatically directed towards mitochondrial remodeling via an increase in peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α) expression, which in turn triggers: (1) mitochondrial fragmentation (increased dynamin-related protein-1 (Drp1) and reduced mitofusin-2 (Mfn2) expression) and mitophagy (activation of the Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)/Parkin mitophagy pathway) to improve mitochondrial quality; (2) reduced Mfn2 also results in a disruption of mitochondrial tethering to the ER and reduced mitochondrial Ca2+ influx; and (3) mitochondrial biogenesis and increased mitochondrial volume density. The homeostatic remodeling of mitochondria results in more efficient O2 consumption and oxidative phosphorylation and reduced ROS formation by individual mitochondrion, while still meeting the increased ATP demand. Thus, the energetic load of hyper-reactivity is shared across the mitochondrial pool within ASM cells.

show abstract

“…Published studies suggest that EMT commonly occurs in epithelial cells in asthma and may contribute to airway remodeling ( 7 , 8 ). Remodeling comprises structural alterations to the airway wall, including epithelial cell loss, goblet cell hyperplasia, hypertrophy of the airway smooth muscle, basement membrane thickening and increased angiogenesis ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

“…Inhaled or oral corticosteroids are the most common drugs used for asthma therapy in the majority of patients with asthma ( 18 ). Despite providing clinical and symptomatic improvement, existing therapies are insufficient to prevent the onset of airway remodeling ( 9 ). The influence of various therapeutic agents on epithelial barrier dysfunction, inhibition of airway remodeling and controlling adaptive immunity guide the development of further therapeutic strategies, targets and rational treatment ( 19 ).…”

Section: Introductionmentioning

confidence: 99%

Anti‑VEGF treatment suppresses remodeling factors and restores epithelial barrier function through the E‑cadherin/β‑catenin signaling axis in experimental asthma models

Türkeli¹,

Yılmaz

Karaman

et al. 2021

Exp Ther Med

View full text Add to dashboard Cite

Besides maintaining a physical barrier with adherens junctional (AJ) and tight junctional proteins, airway epithelial cells have important roles in modulating the inflammatory processes of allergic asthma. E-cadherin and β-catenin are the key AJ proteins that are involved in airway remodeling. Various mediators such as transforming growth factor-β (TGF-β), epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet derived growth factor (PDGF), insulin-like growth factor (IGF), tumor necrosis factor-α (TNF-α) and angiogenic factors, such as vascular endothelial growth factor (VEGF), are released by the airway epithelium in allergic asthma. The signaling pathways activated by these growth factors trigger epithelial-mesenchymal transition (EMT), which contributes to fibrosis and subsequent downregulation of E-cadherin. The present study used a mouse asthma model to investigate the effects of anti-VEGF, anti-TNF and corticosteroid therapies on growth factor and E-cadherin/β-catenin expression. The study used 38 male BALB/c mice, divided into 5 groups. A chronic mouse asthma model was created by treating 4 of the groups with inhaled and intraperitoneal ovalbumin (n= 8 per group). Saline, anti-TNF-α (etanercept), anti-VEGF (bevacizumab) or a corticosteroid (dexamethasone) were applied to each group by intraperitoneal injection. No medication was administered to the control group (n=6). Immunohistochemistry for E-cadherin, β-catenin and growth factors was performed on lung tissues and protein expression levels assessed using H-scores. Statistically significant differences were observed in E-cadherin, β-catenin, EGF, FG, and PFGF (P<0.001 for all) as well as the IGF H-scores between the five groups (P<0.005). Only anti-VEGF treatment caused E-cadherin and β-catenin levels to increase to the level of non-asthmatic control groups (P>0.005). All treatment groups had reduced TGF-β, PDGF and FGF H-scores in comparison with the untreated asthma group (P=0.001). The EGF and IGF levels were not significantly different between the untreated asthmatic and non-asthmatic controls. The results suggested that anti-VEGF and TNF-α inhibition treatments are effective in decreasing growth factors, in a similar manner to conventional corticosteroid treatments. Anti-VEGF and TNF inhibition therapy may be an effective treatment for remodeling in asthma while offering an alternative therapeutic option to steroid protective agents. The data suggested that anti-VEGF treatment offered greater restoration of the epithelial barrier than both anti-TNF-α and corticosteroid treatment.

show abstract

Status and prospects: personalized treatment and biomarker for airway remodeling in asthma

Cited by 23 publications

References 111 publications

Azithromycin induces apoptosis in airway smooth muscle cells through mitochondrial pathway in a rat asthma model

Azithromycin induces apoptosis in airway smooth muscle cells through mitochondrial pathway in a rat asthma model

Inflammation-Induced Protein Unfolding in Airway Smooth Muscle Triggers a Homeostatic Response in Mitochondria

Anti‑VEGF treatment suppresses remodeling factors and restores epithelial barrier function through the E‑cadherin/β‑catenin signaling axis in experimental asthma models

Contact Info

Product

Resources

About