Resistance of fibrogenic responses to glucocorticoid and 2-methoxyestradiol in bleomycin-induced lung fibrosis in miceThis article is one of a selection of papers published in the Special Issue on Recent Advances in Asthma Research.

Langenbach, Shenna; Wheaton, Benjamin; Fernandes, Darren; Jones, Catherine JonesC.; Sutherland, Tara E.; Wraith, Bronwyn C. WraithB.C.; Harris, Trudi; Schuliga, Michael; McLean, Catriona; Stewart, Alastair G.

doi:10.1139/y07-065

Cited by 24 publications

(17 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All animal experiments were carried out in accordance with ethical guidelines from the University of Melbourne Animal Ethics Committee (AEEC#1513736.1). Six- to eight-week old 20–25 g C57Bl/6 mice (ARC, Perth, WA, Australia) received 35 μL of saline or bleomycin (105 mU per mouse) on day 0 by intranasal administration, as previously described ( Langenbach et al, 2007 ). Acute and chronic bleomycin mouse models were used to assess the effect of PF670462 on pulmonary fibrosis in vivo .…”

Section: Methodsmentioning

confidence: 99%

Casein Kinase 1δ/ε Inhibitor, PF670462 Attenuates the Fibrogenic Effects of Transforming Growth Factor-β in Pulmonary Fibrosis

et al. 2018

Self Cite

View full text Add to dashboard Cite

Transforming growth factor-beta (TGF-β) is a major mediator of fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). However, therapeutic global inhibition of TGF-β is limited by unwanted immunosuppression and mitral valve defects. We performed an extensive literature search to uncover a little-known connection between TGF-β signaling and casein kinase (CK) activity. We have examined the abundance of CK1 delta and epsilon (CK1δ/ε) in lung tissue from IPF patients and non-diseased controls, and investigated whether inhibition of CK1δ/ε with PF670462 inhibits pulmonary fibrosis. CK1δ/ε levels in lung tissue from IPF patients and non-diseased controls were assessed by immunohistochemistry. Anti-fibrotic effects of the CK1δ/ε inhibitor PF670462 were assessed in pre-clinical models, including acute and chronic bleomycin mouse models and in vitro experiments on spheroids made from primary human lung fibroblast cells from IPF and control donors, and human A549 alveolar-like adenocarcinoma-derived epithelial cells. Increased expression of CK1δ and ε in IPF lungs compared to non-diseased controls was accompanied by increased levels of the product, phospho-period 2. In vitro, PF670462 prevented TGF-β-induced epithelial-mesenchymal transition. The stiffness of IPF-derived spheroids was reduced by PF670462 and TGF-β-induced fibrogenic gene expression was inhibited. The CK1δ/ε inhibitor PF670462 administered systemically or locally by inhalation prevented both acute and chronic bleomycin-induced pulmonary fibrosis in mice. PF670462 administered in a ‘therapeutic’ regimen (day 7 onward) prevented bleomycin-induced lung collagen accumulation. Elevated expression and activity of CK1 δ and ε in IPF and anti-fibrogenic effects of the dual CK1δ/ε inhibitor, PF670462, support CK1δ/ε as novel therapeutic targets for IPF.

show abstract

Section: Methodsmentioning

confidence: 99%

Casein Kinase 1δ/ε Inhibitor, PF670462 Attenuates the Fibrogenic Effects of Transforming Growth Factor-β in Pulmonary Fibrosis

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…In vivo murine model. The murine model of bleomycin-induced lung injury and inflammation was conducted as previously described (25). C57Bl/6 annexin A2 Ϫ/Ϫ mice were a generous gift from Prof. Katherine Hajjar and Dr. Min Luo (Cornell University, Ithaca, NY) (29) and bred in our animal facility.…”

Section: Methodsmentioning

confidence: 99%

Annexin A2 contributes to lung injury and fibrosis by augmenting factor Xa fibrogenic activity

Schuliga

Jaffar

Berhan

et al. 2017

American Journal of Physiology-Lung Cellular and Molecular Phys

Self Cite

View full text Add to dashboard Cite

In lung injury and disease, including idiopathic pulmonary fibrosis (IPF), extravascular factor X is converted into factor Xa (FXa), a coagulant protease with fibrogenic actions. Extracellular annexin A2 binds to FXa, augmenting activation of the protease-activated receptor-1 (PAR-1). In this study, the contribution of annexin A2 in lung injury and fibrosis was investigated. Annexin A2 immunoreactivity was observed in regions of fibrosis, including those associated with fibroblasts in lung tissue of IPF patients. Furthermore, annexin A2 was detected in the conditioned media and an EGTA membrane wash of human lung fibroblast (LF) cultures. Incubation with human plasma (5% vol/vol) or purified FXa (15-50 nM) evoked fibrogenic responses in LF cultures, with FXa increasing interleukin-6 (IL-6) production and cell number by 270 and 46%, respectively ( < 0.05, = 5-8). The fibrogenic actions of plasma or FXa were attenuated by the selective FXa inhibitor apixaban (10 μM, or antibodies raised against annexin A2 or PAR-1 (2 μg/ml). FXa-stimulated LFs from IPF patients ( = 6) produced twice as much IL-6 as controls ( = 10) ( < 0.05), corresponding with increased levels of extracellular annexin A2. Annexin A2 gene deletion in mice reduced bleomycin-induced increases in bronchoalveolar lavage fluid (BALF) IL-6 levels and cell number (* < 0.05; = 4-12). Lung fibrogenic gene expression and dry weight were reduced by annexin A2 gene deletion, but lung levels of collagen were not. Our data suggest that annexin A2 contributes to lung injury and fibrotic disease by mediating the fibrogenic actions of FXa. Extracellular annexin A2 is a potential target for the treatment of IPF.

show abstract

“…There has been considerable effort to understand the molecular basis of GC resistance in severe asthma and COPD so that strategies to overcome diminished GC sensitivity can be developed [ 83 , 84 , 85 , 86 ]. Part of this phenomenon is contributed by impaired transrepression of NF-κB by GCs [ 19 ].…”

Section: Gc-insensitivity In Severe Asthma and Copdmentioning

confidence: 99%

NF-kappaB Signaling in Chronic Inflammatory Airway Disease

2015

View full text Add to dashboard Cite

Asthma and chronic obstructive pulmonary disease (COPD) are obstructive airway disorders which differ in their underlying causes and phenotypes but overlap in patterns of pharmacological treatments. In both asthma and COPD, oxidative stress contributes to airway inflammation by inducing inflammatory gene expression. The redox-sensitive transcription factor, nuclear factor (NF)-kappaB (NF-κB), is an important participant in a broad spectrum of inflammatory networks that regulate cytokine activity in airway pathology. The anti-inflammatory actions of glucocorticoids (GCs), a mainstay treatment for asthma, involve inhibition of NF-κB induced gene transcription. Ligand bound GC receptors (GRs) bind NF-κB to suppress the transcription of NF-κB responsive genes (i.e., transrepression). However, in severe asthma and COPD, the transrepression of NF-κB by GCs is negated as a consequence of post-translational changes to GR and histones involved in chromatin remodeling. Therapeutics which target NF-κB activation, including inhibitors of IκB kinases (IKKs) are potential treatments for asthma and COPD. Furthermore, reversing GR/histone acetylation shows promise as a strategy to treat steroid refractory airway disease by augmenting NF-κB transrepression. This review examines NF-κB signaling in airway inflammation and its potential as target for treatment of asthma and COPD.

show abstract

Resistance of fibrogenic responses to glucocorticoid and 2-methoxyestradiol in bleomycin-induced lung fibrosis in miceThis article is one of a selection of papers published in the Special Issue on Recent Advances in Asthma Research.

Cited by 24 publications

References 38 publications

Casein Kinase 1δ/ε Inhibitor, PF670462 Attenuates the Fibrogenic Effects of Transforming Growth Factor-β in Pulmonary Fibrosis

Casein Kinase 1δ/ε Inhibitor, PF670462 Attenuates the Fibrogenic Effects of Transforming Growth Factor-β in Pulmonary Fibrosis

Annexin A2 contributes to lung injury and fibrosis by augmenting factor Xa fibrogenic activity

NF-kappaB Signaling in Chronic Inflammatory Airway Disease

Contact Info

Product

Resources

About