Corticosteroids prevent myofibroblast accumulation and airway remodeling in mice

At present there are conflicting results from studies investigating the role of corticosteroids in inhibiting airway remodeling in asthma. We have used a mouse model to determine whether administration of corticosteroids prevents the development of allergen-induced structural features of airway remodeling. Mice treated with corticosteroids were subjected to repetitive ovalbumin (OVA) challenge for 3 mo, at which time levels of peribronchial fibrosis and the thickness of the peribronchial smooth muscle layer were assessed by immunohistology, levels of transforming growth factor (TGF)-β1 by ELISA, and the number of α-smooth muscle actin+/Col-1+ peribronchial myofibroblasts by immunohistochemistry. Corticosteroids significantly reduced allergen-induced increases in peribronchial collagen deposition and levels of total lung collagen but did not reduce allergen-induced increases in the thickness of the peribronchial smooth muscle layer. Levels of lung TGF-β1 were significantly reduced in mice treated with systemic corticosteroids, and this was associated with a significant decrease in the number of peribronchial inflammatory cells that expressed TGF-β1, including eosinophils and mononuclear cells. Corticosteroids also significantly reduced the number of peribronchial myofibroblasts. Overall, these studies demonstrate that administration of corticosteroids significantly reduces levels of allergen-induced peribronchial fibrosis. The reduction in peribronchial fibrosis mediated by corticosteroids is likely to be due to several mechanisms including inhibition of expression of TGF-β1, a reduction in the number of peribronchial inflammatory cells expressing TGF-β1 (eosinophils, macrophages), as well as by corticosteroids reducing the accumulation of peribronchial myofibroblasts that contribute to collagen expression.

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The Improvement Effect of Sodium Ferulate on the Formation of Pulmonary Fibrosis in Silicosis Mice Through the Neutrophil Alkaline Phosphatase 3 (NALP3)/Transforming Growth Factor-β1 (TGF-β1)/α-Smooth Muscle Actin (α-SMA) Pathway

Medical Science Monitor ◽

10.12659/msm.927978 ◽

2021 ◽

Vol 27 ◽

Author(s):

Jingyin Han ◽

Yangmin Jia ◽

Shujuan Wang ◽

Xiaoyu Gan

Keyword(s):

Alkaline Phosphatase ◽

Smooth Muscle ◽

Growth Factor ◽

Transforming Growth Factor ◽

Smooth Muscle Actin ◽

Transforming Growth Factor Β1 ◽

Muscle Actin ◽

Improvement Effect ◽

Neutrophil Alkaline Phosphatase ◽

Tgf Β1

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MKL1 mediates TGF-β1-induced α-smooth muscle actin expression in human renal epithelial cells

AJP Renal Physiology ◽

10.1152/ajprenal.00142.2007 ◽

2008 ◽

Vol 294 (5) ◽

pp. F1116-F1128 ◽

Cited By ~ 52

Author(s):

Gerard Elberg ◽

Lijuan Chen ◽

Dorit Elberg ◽

Michael D. Chan ◽

Charlotte J. Logan ◽

...

Keyword(s):

Smooth Muscle ◽

Epithelial Cells ◽

Transforming Growth Factor ◽

Smooth Muscle Actin ◽

Primary Cultures ◽

Muscle Actin ◽

Mesenchymal Transition ◽

Endogenous Expression ◽

Tgf Β1 ◽

Stimulation Of

Transforming growth factor-β1 (TGF-β1) is known to induce epithelial-mesenchymal transition in the kidney, a process involved in tubulointerstitial fibrosis. We hypothesized that a coactivator of the serum response factor (SRF), megakaryoblastic leukemia factor-1 (MKL1), stimulates α-smooth muscle actin (α-SMA) transcription in primary cultures of renal tubular epithelial cells (RTC), which convert into myofibroblasts on treatment with TGF-β1. Herein, we study the effect of MKL1 expression on α-SMA in these cells. We demonstrate that TGF-β1 stimulation of α-SMA transcription is mediated through CC(A/T)6-rich GG elements known to bind to SRF. These elements also mediate the MKL1 effect that dramatically activates α-SMA transcription in serum-free media. MKL1 fused to green fluorescent protein localizes to the nucleus and induces α-SMA expression regardless of treatment with TGF-β1. Using proteasome inhibitors, we also demonstrate that the proteolytic ubiquitin pathway regulates MKL1 expression. These data indicate that MKL1 overexpression is sufficient to induce α-SMA expression. Inhibition of endogenous expression of MKL1 by small interfering RNA abolishes TGF-β1 stimulation of α-SMA expression. Therefore, MKL1 is also absolutely required for TGF-β1 stimulation of α-SMA expression. Western blot and immunofluorescence analysis show that overexpressed and endogenous MKL1 are located in the nucleus in non-stimulated RTC. Chromatin immunoprecipitation assay demonstrates that TGF-β1 induces binding of endogenous SRF and MKL1 to the α-SMA promoter in chromatin. Since MKL1 constitutes a potent factor regulating α-SMA expression, modulation of endogenous MKL1 expression or activity may have a profound effect on myofibroblast formation and function in the kidney.

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Regulation of IL-17A and implications for TGF-β1 comodulation of airway smooth muscle remodeling in severe asthma

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00416.2018 ◽

2019 ◽

Vol 316 (5) ◽

pp. L843-L868 ◽

Cited By ~ 3

Author(s):

Jon M. Evasovic ◽

Cherie A. Singer

Keyword(s):

Smooth Muscle ◽

Airway Inflammation ◽

Severe Asthma ◽

Airway Smooth Muscle ◽

Transforming Growth Factor ◽

Airway Remodeling ◽

High Dose ◽

Persistent Symptoms ◽

Immune Factors ◽

Tgf Β1

Severe asthma develops as a result of heightened, persistent symptoms that generally coincide with pronounced neutrophilic airway inflammation. In individuals with severe asthma, symptoms are poorly controlled by high-dose inhaled glucocorticoids and often lead to elevated morbidity and mortality rates that underscore the necessity for novel drug target identification that overcomes limitations in disease management. Many incidences of severe asthma are mechanistically associated with T helper 17 (TH17) cell-derived cytokines and immune factors that mediate neutrophilic influx to the airways. TH17-secreted interleukin-17A (IL-17A) is an independent risk factor for severe asthma that impacts airway smooth muscle (ASM) remodeling. TH17-derived cytokines and diverse immune mediators further interact with structural cells of the airway to induce pathophysiological processes that impact ASM functionality. Transforming growth factor-β1 (TGF-β1) is a pivotal mediator involved in airway remodeling that correlates with enhanced TH17 activity in individuals with severe asthma and is essential to TH17 differentiation and IL-17A production. IL-17A can also reciprocally enhance activation of TGF-β1 signaling pathways, whereas combined TH1/TH17 or TH2/TH17 immune responses may additively impact asthma severity. This review seeks to provide a comprehensive summary of cytokine-driven T cell fate determination and TH17-mediated airway inflammation. It will further review the evidence demonstrating the extent to which IL-17A interacts with various immune factors, specifically TGF-β1, to contribute to ASM remodeling and altered function in TH17-driven endotypes of severe asthma.

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Latent adenoviral infection induces production of growth factors relevant to airway remodeling in COPD

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00315.2002 ◽

2004 ◽

Vol 286 (1) ◽

pp. L189-L197 ◽

Cited By ~ 22

Author(s):

Emiko Ogawa ◽

W. Mark Elliott ◽

Fiona Hughes ◽

Thomas J. Eichholtz ◽

James C. Hogg ◽

...

Keyword(s):

Growth Factors ◽

Growth Factor ◽

Transforming Growth Factor ◽

Airway Remodeling ◽

Smooth Muscle Actin ◽

Tissue Growth ◽

Chronic Obstructive ◽

Adenoviral Infection ◽

E1a Gene ◽

Tgf Β1

Previous studies showed an association between latent adenoviral infection with expression of the adenoviral E1A gene and chronic obstructive pulmonary disease (COPD). The present study focuses on how the adenoviral E1A gene could alter expression of growth factors by human bronchial epithelial (HBE) cells. The data show that connective tissue growth factor (CTGF) and transforming growth factor (TGF)-β1 mRNA and protein expression were upregulated in E1A-positive HBE cells. Upregulation of CTGF in this in vitro model was independent of TGF-β secreted into the growth medium. Comparison of E1A-positive with E1A-negative HBE cells showed that both expressed cytokeratin but only E1A-positive cells expressed the mesenchymal markers vimentin and α-smooth muscle actin. We conclude that latent infection of epithelial cells by adenovirus E1A could contribute to airway remodeling in COPD by the viral E1A gene, inducing TGF-β1 and CTGF expression and shifting cells to a more mesenchymal phenotype.

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Airway fibrosis in rats induced by vanadium pentoxide

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2000.278.1.l209 ◽

2000 ◽

Vol 278 (1) ◽

pp. L209-L216 ◽

Cited By ~ 36

Author(s):

James C. Bonner ◽

Annette B. Rice ◽

Cindy R. Moomaw ◽

Daniel L. Morgan

Keyword(s):

Smooth Muscle ◽

Airway Smooth Muscle ◽

Vanadium Pentoxide ◽

Airway Remodeling ◽

Mucous Cell ◽

Intratracheal Instillation ◽

Muscle Layer ◽

Airway Smooth Muscle Cell ◽

Smooth Muscle Layer ◽

Airway Fibrosis

Vanadium pentoxide (V2O5) is a cause of occupational asthma and bronchitis. We previously reported that intratracheal instillation of rats with V2O5causes fibrosis of the lung parenchyma (J. C. Bonner, P. M. Lindroos, A. B. Rice, C. R. Moomaw, and D. L. Morgan. Am. J. Physiol. Lung Cell. Mol. Physiol. 274: L72–L80, 1998). In this report, we show that intratracheal instillation of V2O5induces airway remodeling similar to that observed in individuals with asthma. These changes include airway smooth muscle cell thickening, mucous cell metaplasia, and airway fibrosis. The transient appearance of peribronchiolar myofibroblasts, which were desmin and vimentin positive, coincided with a twofold increase in the thickness of the airway smooth muscle layer at day 6after instillation and preceded the development of airway fibrosis by day 15. The number of nuclear profiles within the smooth muscle layer also increased twofold after V2O5instillation, suggesting that hyperplasia accounted for thickening of the smooth muscle layer. The majority of cells incorporating bromodeoxyuridine at day 3 were located in the connective tissue surrounding the airway smooth muscle wall that was positive for vimentin and desmin. These data suggest that myofibroblasts are the principal proliferating cell type that contributes to the progression of airway fibrosis after V2O5injury.

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l-Thyroxine promotes a proliferative airway smooth muscle phenotype in the presence of TGF-β1

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00071.2014 ◽

2015 ◽

Vol 308 (3) ◽

pp. L301-L306 ◽

Cited By ~ 9

Author(s):

Bart G. J. Dekkers ◽

Saeideh Naeimi ◽

I. Sophie T. Bos ◽

Mark H. Menzen ◽

Andrew J. Halayko ◽

...

Keyword(s):

Smooth Muscle ◽

Thyroid Hormones ◽

Protein Expression ◽

Airway Smooth Muscle ◽

Transforming Growth Factor ◽

Airway Remodeling ◽

Contractile Protein ◽

Cell Phenotype ◽

Minor Effect ◽

Tgf Β1

Hypothyroidism may reduce, whereas hyperthyroidism may aggravate, asthma symptoms. The mechanisms underlying this relationship are largely unknown. Since thyroid hormones have central roles in cell growth and differentiation, we hypothesized that airway remodeling, in particular increased airway smooth muscle (ASM) mass, may be involved. To address this hypothesis, we investigated the effects of triiodothyronine (T3) and l-thyroxine (T4) in the absence and presence of the profibrotic transforming growth factor (TGF)-β1 on human ASM cell phenotype switching. T3 (1–100 nM) and T4 (1–100 nM) did not affect basal ASM proliferation. However, when combined with TGF-β1 (2 ng/ml), T4 synergistically increased the proliferative response, whereas only a minor effect was observed for T3. In line with a switch from a contractile to a proliferative ASM phenotype, T4 reduced the TGF-β1-induced contractile protein expression by ∼50%. Cotreatment with T3 reduced TGF-β1-induced contractile protein expression by ∼25%. The synergistic increase in proliferation was almost fully inhibited by the integrin αvβ3 antagonist tetrac (100 nM), whereas no significant effects of the thyroid receptor antagonist 1–850 (3 μM) were observed. Inhibition of MEK1/2, downstream of the integrin αvβ3, also inhibited the T4- and TGF-β1-induced proliferative responses. Collectively, the results indicate that T4, and to a lesser extent T3, promotes a proliferative ASM phenotype in the presence of TGF-β1, which is predominantly mediated by the membrane-bound T4 receptor αvβ3. These results indicate that thyroid hormones may enhance ASM remodeling in asthma, which could be of relevance for hyperthyroid patients with this disease.

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Contribution of intestinal smooth muscle to Crohn's disease fibrogenesis

European Journal of Histochemistry ◽

10.4081/ejh.2014.2457 ◽

2014 ◽

Cited By ~ 11

Author(s):

C. Severi ◽

R. Sferra ◽

A. Scirocco ◽

A. Vetuschi ◽

N. Pallotta ◽

...

Keyword(s):

Smooth Muscle ◽

Growth Factor ◽

Transforming Growth Factor ◽

Smooth Muscle Actin ◽

Muscularis Propria ◽

Muscle Layer ◽

Stricture Formation ◽

Matrix Deposition ◽

Fibrotic Process ◽

Collagen Iii

Mesenchymal cells transdifferentiation and extracellular matrix deposition are involved in the fibrotic process of Crohnâ€™s disease (CD). Mesenchymal smooth muscle cells (SMCs) de-differentiation, driven by Platelet-derived growth factor (PDGF) that counteracts Transforming growth factor (TGF-Î²) has been studied in vascular muscle. The role of SMCs in intestinal fibrogenesis is still not clearly elucidated. Aim of the study was to evaluate the possible myogenic contribution to CD fibrotic process through the comparative analysis of histological, morphometric and molecular alterations occurring in human smooth muscle. Full thickness specimens were obtained from CD (non-involved and stenotic tracts) and healthy (control) ileum. Tissues were processed for histological and immunohistochemical (IHC) analyses and SMCs were isolated from the muscularis propria for morphofunctional and molecular (qPCR) analyses. CD stenotic ileum showed a significant increased thickness of all layers compared to CD non-involved and control ileum. IHC revealed an overexpression of Î±-smooth muscle actin and collagens I-III throughout all intestinal layers only in stenotic tracts. The two growth factors, PDGF and TGF-Î², showed a progressive increase in expression in the muscle layer from CD non-involved to stenotic tracts. Freshly isolated SMCs presented alterations in CD non-involved tracts that progressively increased in the stenotic tracts consisting in a statistical increase in mRNA encoding for PDGF-Î² and collagen III, paralleled to a decrease in TGF-Î² and Tribbles-like protein-3 mRNA, and altered morphofunctional parameters consisting in progressive decreases in cell length and contraction to acetylcholine. These findings indicate that intrinsic myogenic alterations occur in CD ileum, that they likely precede stricture formation, and might represent suitable new targets for anti-fibrotic interventions.

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