Lovastatin-induced decrease of intracellular cholesterol level attenuates fibroblast-to-myofibroblast transition in bronchial fibroblasts derived from asthmatic patients

Michalik, Marta; Soczek, Ewelina; Kosińska, Milena; Rak, Monika; Wójcik, Katarzyna; Lasota, Sławomir; Pierzchalska, Małgorzata; Czyż, Jarosław; Madeja, Zbigniew

doi:10.1016/j.ejphar.2013.02.023

Cited by 34 publications

(42 citation statements)

References 61 publications

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“…T cell activation, proliferation, and migration are also suppressed by statin treatment (24). In addition to their effects on immune cells, statins have been shown to suppress bronchial wall remodeling (28). …”

Section: Discussionmentioning

confidence: 99%

Fluvastatin Suppresses Mast Cell and Basophil IgE Responses: Genotype-Dependent Effects

Kolawole

McLeod

Ndaw

et al. 2016

The Journal of Immunology

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Mast cell- and basophil-associated inflammatory diseases are a considerable burden to society. A significant portion of patients have symptoms despite standard-of-care therapy. Statins, used to lower serum cholesterol, have immune modulating activities. We tested the in vitro and in vivo effects of statins on IgE-mediated mast cell and basophil activation. Fluvastatin showed the most significant inhibitory effects of the six statins tested, suppressing IgE-induced cytokine secretion among mouse mast cells and basophils. Fluvastatin's effects were reversed by mevalonic acid or geranylgeranyl pyrophosphatase, and mimicked by geranylgeranyl transferase inhibition. Fluvastatin selectively suppressed key FcεRI signaling pathways, including Syk, Akt, and ERK. While mast cells and basophils from the C57BL/6J mouse strain were responsive to fluvastatin, those from 129/SvImJ mice were completely resistant. Resistance correlated with fluvastatin-induced upregulation of the statin target HMG-CoA reductase. Human mast cell cultures from eight donors showed a wide range of fluvastatin responsiveness. These data demonstrate that fluvastatin is a potent suppressor of IgE-mediated mast cell activation, acting at least partly via blockade of geranyl lipid production downstream of HMG-CoA reductase. Importantly, consideration of statin use for treating mast cell-associated disease needs to incorporate genetic background effects, which can yield drug resistance.

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Section: Discussionmentioning

confidence: 99%

Fluvastatin Suppresses Mast Cell and Basophil IgE Responses: Genotype-Dependent Effects

Kolawole

McLeod

Ndaw

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

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“…Such inhibitory effects on acute versus chronic asthma are dependent on differential expression of muscarinic receptor subtypes [153]. Evidence by Schaafsma et al highlights that simvastatin may inhibit TGF-b1-induced fibronectin expression in airway fibroblasts [154] which in turn attenuates fibroblast-to-myofibroblast transition in asthmatic settings [155].…”

Section: Tgf-ß Targeted Therapymentioning

confidence: 99%

Transforming growth factor β and severe asthma: A perfect storm

Al‐Alawi

Hassan

Chotirmall

2014

Respiratory Medicine

131

108

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Asthma is a chronic inflammatory airway disease involving complex interplay between resident and infiltrative cells, which in turn are regulated by a wide range of host mediators. Identifying useful biomarkers correlating with clinical symptoms and degree of airway obstruction remain important to effective future asthma treatments. Transforming growth factor β (TGF-β) is a major mediator involved in pro-inflammatory responses and fibrotic tissue remodeling within the asthmatic lung. Its role however, as a therapeutic target remains controversial. The aim of this review is to highlight its role in severe asthma including interactions with adaptive T-helper cells, cytokines and differentiation through regulatory T-cells. Associations between TGF-β and eosinophils will be addressed and the effects of genetic polymorphisms of the TGF-β1 gene explored in the context of asthma. We highlight TGF-β1 as a potential future therapeutic target in severe asthma including its importance in identifying emerging clinical phenotypes in asthmatic subjects who may be suitable for individualized therapy through TGF-β modulation.

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“…However, it seems that statins do not to have any additional benefit in asthma control or steroid-sparing effect in asthma treatment [40]. Nevertheless, most recent in vitro study shown that lovastatin attenuates both TGF-b1-induced phenotypic transdifferentiation of asthmatic bronchial fibroblasts into myofibroblasts in culture and human bronchial fibroblasts proliferation [41]. Also, rosuvastatin is a potent inhibitor of human airway smooth muscle cells growth induced by different mitogenic stimuli [42].…”

Section: Discussionmentioning

confidence: 99%