Acute Allergen-Induced Airway Remodeling in Atopic Asthma

Phipps, Simon; Benyahia, F.; Ou, Tsan‐Teng; Barkans, J.; Robinson, Douglas S.; Kay, A. B.

doi:10.1165/rcmb.2004-0193oc

Cited by 115 publications

(100 citation statements)

References 28 publications

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“…*P , 0.05. studies, TGF-b1, CTGF, and PAI-1 mRNA levels were all specifically enriched in the epithelial layer and not in the underlying smooth muscle. In addition, recent studies have shown activation of signaling pathways downstream of TGF-b receptor engagement in the bronchial epithelium in both animal models and biopsies from humans with asthma (15,(26)(27)(28)(29). Specifically, phospho-Smad 2, the activated receptor Smad, colocalizes with the epithelium in both antigen-challenged mice (including in this study) and humans with asthma.…”

Section: Discussionsupporting

confidence: 55%

Transforming Growth Factor-β1 Suppresses Airway Hyperresponsiveness in Allergic Airway Disease

Alcorn¹,

Rinaldi²,

Jaffe³

et al. 2007

Am J Respir Crit Care Med

109

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Rationale: Asthma is characterized by increases in airway resistance, pulmonary remodeling, and lung inflammation. The cytokine transforming growth factor (TGF)-b has been shown to have a central role in asthma pathogenesis and in mouse models of allergic airway disease. Objectives: To determine the contribution of TGF-b to airway hyperresponsiveness (AHR), we examined the time course, source, and isoform specificity of TGF-b production in an in vivo mouse asthma model. To then elucidate the function of TGF-b in AHR, inflammation, and pulmonary fibrosis, we examined the effects of blocking TGF-b signaling with neutralizing antibody. Methods: Mice were sensitized and challenged with ovalbumin (OVA) to establish allergic airway disease. TGF-b activity was neutralized by intranasal administration of monoclonal antibody. Measurements and Main Results: TGF-b1 protein levels were increased in OVA-challenged lungs versus naive controls, and airway epithelial cells were shown to be a likely source of TGF-b1. In addition, TGF-b1 levels were elevated in OVA-exposed IL-5-null mice, which fail to recruit eosinophils into the airways. Neutralization of TGF-b1 with specific antibody had no significant effect on airway inflammation and eosinophilia, although anti-TGF-b1 antibody enhanced OVAinduced AHR and suppressed pulmonary fibrosis. Conclusions: These data show that TGF-b1 is the main TGF-b isoform produced after OVA challenge, with a likely cellular source being the airway epithelium. The effects of blocking TGF-b1 signaling had differential effects on AHR, fibrosis, and inflammation. While TGF-b neutralization may be beneficial to abrogating airway remodeling, it may be detrimental to lung function by increasing AHR.

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Section: Discussionsupporting

confidence: 55%

Transforming Growth Factor-β1 Suppresses Airway Hyperresponsiveness in Allergic Airway Disease

Alcorn¹,

Rinaldi²,

Jaffe³

et al. 2007

Am J Respir Crit Care Med

109

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“…The level of P-Smad2 has been used as an indicator for TGF-␤ responsiveness (Smad2/3 dependent) in aortas and other tissues (Phipps et al, 2004;Liao and Laufs, 2005). The upregulation of VCAM-1 has been employed as a marker for early atherosclerotic lesions (Nakashima et al, 1998).…”

Section: Tgf-␤-induced Growth Inhibition Is Reversed By Cholesterolmentioning

confidence: 99%

Cholesterol suppresses cellular TGF-β responsiveness: implications in atherogenesis

Chen

Liu

Fliesler

et al. 2007

Journal of Cell Science

166

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Hypercholesterolemia is a major causative factor for atherosclerotic cardiovascular disease. The molecular mechanisms by which cholesterol initiates and facilitates the process of atherosclerosis are not well understood. Here, we demonstrate that cholesterol treatment suppresses or attenuates TGF-β responsiveness in all cell types studied as determined by measuring TGF-β-induced Smad2 phosphorylation and nuclear translocation, TGF-β-induced PAI-1 expression, TGF-β-induced luciferase reporter gene expression and TGF-β-induced growth inhibition. Cholesterol, alone or complexed in lipoproteins (LDL, VLDL), suppresses TGF-β responsiveness by increasing lipid raft and/or caveolae accumulation of TGF-β receptors and facilitating rapid degradation of TGF-β and thus suppressing TGF-β-induced signaling. Conversely, cholesterol-lowering agents (fluvastatin and lovastatin) and cholesterol-depleting agents (β-cyclodextrin and nystatin) enhance TGF-β responsiveness by increasing non-lipid raft microdomain accumulation of TGF-β receptors and facilitating TGF-β-induced signaling. Furthermore, the effects of cholesterol on the cultured cells are also found in the aortic endothelium of ApoE-null mice fed a high-cholesterol diet. These results suggest that high cholesterol contributes to atherogenesis, at least in part, by suppressing TGF-β responsiveness in vascular cells.

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“…26,27 Previous studies have shown that epithelial damage results in epithelial cells releasing pro-inflammatory factors such as IL-1 and tumor necrosis factor-a. 28 These factors in turn recruit and stimulate mast cells to release various factors including IL-10.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a novel model incorporating airway epithelial damage and related fibrosis to the pathogenesis of asthma

Royce

Patel

Samuel

2014

Laboratory Investigation

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Asthma develops from injury to the airways/lungs, stemming from airway inflammation (AI) and airway remodeling (AWR), both contributing to airway hyperresponsiveness (AHR). Airway epithelial damage has been identified as a new etiology of asthma but is not targeted by current treatments. Furthermore, it is poorly studied in currently used animal models of AI and AWR. Therefore, this study aimed to incorporate epithelial damage/repair with the well-established ovalbumin (OVA)-induced model of chronic allergic airway disease (AAD), which presents with AI, AWR, and AHR, mimicking several features of human asthma. A 3-day naphthalene (NA)-induced model of epithelial damage/repair was superimposed onto the 9-week OVA-induced model of chronic AAD, before 6 weeks of OVA nebulization (NA þ OVA group), during the second last OVA nebulization period (OVA/NA group) or 1 day after the 6-week OVA nebulization period (OVA þ NA group), using 6-8-week-old female Balb/c mice (n ¼ 6-12/group). Mice subjected to the 9-week OVA model, 3-day NA model or respective vehicle treatments (saline and corn oil) were used as appropriate controls. OVA alone significantly increased epithelial thickness and apoptosis, goblet cell metaplasia, TGF-b1, subepithelial collagen (assessed by morphometric analyses of various histological stains), total lung collagen (hydroxyproline analysis), and AHR (invasive plethysmography) compared with that in saline-treated mice (all Po0.05 vs saline treatment). NA alone caused a significant increase in epithelial denudation and apoptosis, TGF-b1, subepithelial, and total lung collagen compared with respective measurements from corn oil-treated controls (all Po0.01 vs corn oil treatment). All three combined models underwent varying degrees of epithelial damage and AWR, with the OVA þ NA model demonstrating the greatest increase in subepithelial/total lung collagen and AHR (all Po0.05 vs OVA alone or NA alone). These combined models of airway epithelial damage/AAD demonstrated that epithelial damage is a key contributor to AWR, fibrosis and related AHR, and augments the effects of AI on these parameters.

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Acute Allergen-Induced Airway Remodeling in Atopic Asthma

Cited by 115 publications

References 28 publications

Transforming Growth Factor-β1 Suppresses Airway Hyperresponsiveness in Allergic Airway Disease

Transforming Growth Factor-β1 Suppresses Airway Hyperresponsiveness in Allergic Airway Disease

Cholesterol suppresses cellular TGF-β responsiveness: implications in atherogenesis

Characterization of a novel model incorporating airway epithelial damage and related fibrosis to the pathogenesis of asthma

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