3-(2,4-Dichlorophenyl)-4-(1-methyl-1<i>H</i>-indol-3-yl)-1<i>H</i>-pyrrole-2,5-dione (SB216763), a Glycogen Synthase Kinase-3 Inhibitor, Displays Therapeutic Properties in a Mouse Model of Pulmonary Inflammation and Fibrosis

Gurrieri, Carmela; Gnoato, Marianna; Montini, Barbara; Biasutto, Lucia; Gattazzo, Cristina; Brunetta, Enrico; Cabrelle, Anna; Cinetto, Francesco; Niero, Raffaele; Facco, Monica; Garbisa, Spiridione; Calabrese, Fiorella; Semenzato, Gianpietro; Agostini, Carlo

doi:10.1124/jpet.109.153049

Cited by 35 publications

(33 citation statements)

References 27 publications

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“…Glycogen synthase kinase-3 alpha/Glycogen synthase kinase-3 beta(beta (GSK3A/GSK3B) are negative regulators of glucose homeostasis, Wnt signaling and transcription factors, and this protein is positively associated with IPF. GSK3A/GSK3B inhibition in bleomycin-exposed mice has been shown to reduce alveolitis, lung fibrosis, and alveolar cell apoptosis52. GSK3A/GSK3B inhibition also decreased the production of monocyte chemoattractant protein-1 (MCP-1/CCL2) and tumor necrosis factor-α (TNF-α) by lung macrophages after bleomycin exposure in this study.…”

Section: Discussionsupporting

confidence: 62%

The peripheral blood proteome signature of idiopathic pulmonary fibrosis is distinct from normal and is associated with novel immunological processes

O’Dwyer

Norman

Xia

et al. 2017

Sci Rep

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Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial pneumonia. The disease pathophysiology is poorly understood and the etiology remains unclear. Recent advances have generated new therapies and improved knowledge of the natural history of IPF. These gains have been brokered by advances in technology and improved insight into the role of various genes in mediating disease, but gene expression and protein levels do not always correlate. Thus, in this paper we apply a novel large scale high throughput aptamer approach to identify more than 1100 proteins in the peripheral blood of well-characterized IPF patients and normal volunteers. We use systems biology approaches to identify a unique IPF proteome signature and give insight into biological processes driving IPF. We found IPF plasma to be altered and enriched for proteins involved in defense response, wound healing and protein phosphorylation when compared to normal human plasma. Analysis also revealed a minimal protein signature that differentiated IPF patients from normal controls, which may allow for accurate diagnosis of IPF based on easily-accessible peripheral blood. This report introduces large scale unbiased protein discovery analysis to IPF and describes distinct biological processes that further inform disease biology.

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Section: Discussionsupporting

confidence: 62%

The peripheral blood proteome signature of idiopathic pulmonary fibrosis is distinct from normal and is associated with novel immunological processes

O’Dwyer

Norman

Xia

et al. 2017

Sci Rep

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“…Previous studies have demonstrated an important role of ILK in regulating survival of lung fibroblasts and stimulating proliferation and migration of vascular SMC (13,16,39). Recent studies have shown that inhibition of GSK-3␤ protects bleomycin-induced lung fibrosis (20). Accumulating data indicate that CTGF can activate both ILK/GSK-3 and Wnt signaling in various pathological conditions.…”

Section: Discussionmentioning

confidence: 99%

CTGF disrupts alveolarization and induces pulmonary hypertension in neonatal mice: implication in the pathogenesis of severe bronchopulmonary dysplasia

Chen

Rong

Platteau

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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S. CTGF disrupts alveolarization and induces pulmonary hypertension in neonatal mice: implication in the pathogenesis of severe bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 300: L330 -L340, 2011. First published January 14, 2011; doi:10.1152/ajplung.00270.2010.-The pathological hallmarks of bronchopulmonary dysplasia (BPD), one of the most common long-term pulmonary complications associated with preterm birth, include arrested alveolarization, abnormal vascular growth, and variable interstitial fibrosis. Severe BPD is often complicated by pulmonary hypertension characterized by excessive pulmonary vascular remodeling and right ventricular hypertrophy that significantly contributes to the mortality and morbidity of these infants. Connective tissue growth factor (CTGF) is a multifunctional protein that coordinates complex biological processes during tissue development and remodeling. We have previously shown that conditional overexpression of CTGF in airway epithelium under the control of the Clara cell secretory protein promoter results in BPD-like architecture in neonatal mice. In this study, we have generated a doxycycline-inducible double transgenic mouse model with overexpression of CTGF in alveolar type II epithelial (AT II) cells under the control of the surfactant protein C promoter. Overexpression of CTGF in neonatal mice caused dramatic macrophage and neutrophil infiltration in alveolar air spaces and perivascular regions. Overexpression of CTGF also significantly decreased alveolarization and vascular development. Furthermore, overexpression of CTGF induced pulmonary vascular remodeling and pulmonary hypertension. Most importantly, we have also demonstrated that these pathological changes are associated with activation of integrin-linked kinase (ILK)/glucose synthesis kinase-3␤ (GSK-3␤)/␤-catenin signaling. These data indicate that overexpression of CTGF in AT II cells results in lung pathology similar to those observed in infants with severe BPD and that ILK/GSK-3␤/␤-catenin signaling may play an important role in the pathogenesis of severe BPD.

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“…Despite its inhibitory role in β-catenin signalling, GSK-3 is required for fibrosis in mice [13]. In line with this, we have shown in human pulmonary fibroblasts that GSK-3 is required for myofibroblast differentiation and matrix protein expression [14].…”

Section: Introductionmentioning

confidence: 85%

Pharmacological inhibition of GSK-3 in a guinea pig model of LPS-induced pulmonary inflammation: I. Effects on lung remodeling and pathology

et al. 2013

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BackgroundGlycogen synthase kinase-3 (GSK-3) is a constitutively active kinase that regulates multiple signalling proteins and transcription factors involved in a myriad of cellular processes. The kinase acts as a negative regulator in β-catenin signalling and is critically involved in the smad pathway. Activation of both pathways may contribute to pulmonary features of chronic obstructive pulmonary disease (COPD).MethodsIn the present study, we investigated the effect of the selective GSK-3 inhibitor SB216763 on pulmonary pathology in a guinea pig model of lipopolysaccharide (LPS)-induced COPD. Guinea pigs were instilled intranasally with LPS or saline twice weekly for 12 weeks and pre-treated with either intranasally instilled SB216763 or corresponding vehicle 30 min prior to each LPS/saline challenge.ResultsRepeated LPS exposures activated β-catenin signalling, primarily in the airway epithelium and submucosa. LPS also induced pulmonary inflammation and tissue remodelling as indicated by inflammatory cell influx, increased pulmonary fibronectin expression and enhanced small airway collagen content. Inhibition of GSK-3 by SB216763 did not affect LPS-induced inflammatory cell influx, but prevented the small airway remodelling and, unexpectedly, inhibited the activation of β-catenin in vivo. LPS or SB216763 treatment had no effect on the airway smooth muscle content and alveolar airspace size. However, GSK-3 inhibition prevented LPS-induced right ventricle hypertrophy.ConclusionsOur findings indicate that GSK-3 inhibition prevents LPS-induced pulmonary pathology in guinea pigs, and that locally reduced LPS-induced β-catenin activation appears in part to underlie this effect.

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3-(2,4-Dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763), a Glycogen Synthase Kinase-3 Inhibitor, Displays Therapeutic Properties in a Mouse Model of Pulmonary Inflammation and Fibrosis

Cited by 35 publications

References 27 publications

The peripheral blood proteome signature of idiopathic pulmonary fibrosis is distinct from normal and is associated with novel immunological processes

The peripheral blood proteome signature of idiopathic pulmonary fibrosis is distinct from normal and is associated with novel immunological processes

CTGF disrupts alveolarization and induces pulmonary hypertension in neonatal mice: implication in the pathogenesis of severe bronchopulmonary dysplasia

Pharmacological inhibition of GSK-3 in a guinea pig model of LPS-induced pulmonary inflammation: I. Effects on lung remodeling and pathology

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