Inhibition of Inflammatory Mediators

Le, Wei; Ahuja, Rahul; Cho, Do‐Yeon; Hwang, Peter H.; Upadhyay, Daya

doi:10.1177/0194599811400367

Cited by 26 publications

(13 citation statements)

References 24 publications

(92 reference statements)

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“…However, the basic mechanisms related to mevalonate and HMGR biology are generally conserved across eukaryotes which suggest that the statin effects should also be similar. Although not studied directly in asthmatic airways or under allergic conditions, the few published papers evaluating the effects of statins on human bronchial epithelial cells show inhibition of pro-inflammatory cytokine/chemokine expression [15,16,21]. This leads us to believe that our results may be extrapolated to human epithelial cells, although more research is needed to further test this hypothesis and the underlying mechanisms of action.…”

Section: Discussionmentioning

confidence: 88%

Differential effects of simvastatin on IL-13-induced cytokine gene expression in primary mouse tracheal epithelial cells

et al. 2012

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BackgroundAsthma causes significant morbidity worldwide in adults and children alike, and incurs large healthcare costs. The statin drugs, which treat hyperlipidemia and cardiovascular diseases, have pleiotropic effects beyond lowering cholesterol, including immunomodulatory, anti-inflammatory, and anti-fibrotic properties which may benefit lung health. Using an allergic mouse model of asthma, we previously demonstrated a benefit of statins in reducing peribronchiolar eosinophilic inflammation, airway hyperreactivity, goblet cell hyperplasia, and lung IL-4 and IL-13 production.ObjectivesIn this study, we evaluated whether simvastatin inhibits IL-13-induced pro-inflammatory gene expression of asthma-related cytokines in well-differentiated primary mouse tracheal epithelial (MTE) cell cultures. We hypothesized that simvastatin reduces the expression of IL-13-inducible genes in MTE cells.MethodsWe harvested tracheal epithelial cells from naïve BALB/c mice, grew them under air-liquid interface (ALI) cell culture conditions, then assessed IL-13-induced gene expression in MTE cells using a quantitative real-time PCR mouse gene array kit.ResultsWe found that simvastatin had differential effects on IL-13-mediated gene expression (inhibited eotaxin-1; MCP-1,-2,-3; and osteopontin (SPP1), while it induced caspase-1 and CCL20 (MIP-3α)) in MTE cells. For other asthma-relevant genes such as TNF, IL-4, IL-10, CCL12 (MCP-5), CCL5 (RANTES), and CCR3, there were no significant IL-13-inducible or statin effects on gene expression.ConclusionsSimvastatin modulates the gene expression of selected IL-13-inducible pro-inflammatory cytokines and chemokines in primary mouse tracheal epithelial cells. The airway epithelium may be a viable target tissue for the statin drugs. Further research is needed to assess the mechanisms of how statins modulate epithelial gene expression.

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Section: Discussionmentioning

confidence: 88%

Differential effects of simvastatin on IL-13-induced cytokine gene expression in primary mouse tracheal epithelial cells

et al. 2012

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“…We speculate that preconditioning could be due to the a priori modulation of immune cell responses [52, 53], decreased pro-inflammatory cytokine/chemokine gene expression at the level of the airway epithelium [54, 55] or mesenchyme, or reduced vascular recruitment of leukocytes into lung tissue [56–58], amongst other mechanisms. Statins have been shown to inhibit lymphocyte function-associated antigen (LFA)-1 by binding to it and preventing high affinity binding of leukocytes to vascular endothelium to facilitate transmigration into inflamed tissues.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin inhibits smoke-induced airway epithelial injury: implications for COPD therapy

Davis¹,

Zeki

Bratt³

et al. 2012

Eur Respir J

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Chronic obstructive pulmonary disease (COPD) is the third leading cause of death. The statin drugs may have therapeutic potential in respiratory diseases such as COPD, but whether they prevent bronchial epithelial injury is unknown. We hypothesised that simvastatin attenuates acute tobacco smoke-induced neutrophilic lung inflammation and airway epithelial injury. Spontaneously hypertensive rats were given simvastatin (20 mg·kg−1 i.p.) daily for either 7 days prior to tobacco smoke exposure and during 3 days of smoke exposure, or only during tobacco smoke exposure. Pre-treatment with simvastatin prior to and continued throughout smoke exposure reduced the total influx of leukocytes, neutrophils and macrophages into the lung and airways. Simvastatin attenuated tobacco smoke-induced cellular infiltration into lung parenchymal and airway subepithelial and interstitial spaces. 1 week of simvastatin pre-treatment almost completely prevented smoke-induced denudation of the airway epithelial layer, while simvastatin given only concurrently with the smoke exposure had no effect. Simvastatin may be a novel adjunctive therapy for smoke-induced lung diseases, such as COPD. Given the need for statin pre-treatment there may be a critical process of conditioning that is necessary for statins’ anti-inflammatory effects. Future work is needed to elucidate the mechanisms of this statin protective effect.

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“…Chen, Pendyala, Natarajan, Garcia, & Jacobson, 2008; Jacobson, et al, 2005), smooth muscle cell proliferation (Takeda, et al, 2006; Vigano, et al, 1995), extracellular matrix deposition (Schaafsma, et al, 2011), epithelial cell cytokine production (Iwata, et al, 2012; Murphy, et al, 2008; Sakoda, et al, 2006; W. Wang, et al, 2011; Zeki, Thai, Kenyon, & Wu, 2012), and cell fate phenomena such as endoplasmic reticulum (ER) stress, autophagy, and apoptosis (J.…”

Section: Pulmonary Diseasementioning

confidence: 99%

Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease

Yeganeh

Wiechec

Ande

et al. 2014

Pharmacology & Therapeutics

137

129

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The cholesterol biosynthesis pathway, also known as the mevalonate (MVA) pathway, is an essential cellular pathway that is involved in diverse cell functions. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) is the rate-limiting step in cholesterol biosynthesis and catalyzes the conversion of HMG-CoA to MVA. Given its role in cholesterol and isoprenoid biosynthesis, the regulation of HMGCR has been intensely investigated. Because all cells require a steady supply of MVA, both the sterol (i.e. cholesterol) and non-sterol (i.e. isoprenoid) products of MVA metabolism exert coordinated feedback regulation on HMGCR through different mechanisms. The proper functioning of HMGCR as the proximal enzyme in the MVA pathway is essential under both normal physiologic conditions and in many diseases given its role in cell cycle pathways and cell proliferation, cholesterol biosynthesis and metabolism, cell cytoskeletal dynamics and stability, cell membrane structure and fluidity, mitochondrial function, proliferation, and cell fate. The blockbuster statin drugs (‘statins’) directly bind to and inhibit HMGCR, and their use for the past thirty years has revolutionized the treatment of hypercholesterolemia and cardiovascular diseases, in particular coronary heart disease. Initially thought to exert their effects through cholesterol reduction, recent evidence indicates that statins also have pleiotropic immunomodulatory properties independent of cholesterol lowering. In this review we will focus on the therapeutic applications and mechanisms involved in the MVA cascade including Rho GTPase and Rho kinase (ROCK) signaling, statin inhibition of HMGCR, geranylgeranyltransferase (GGTase) inhibition, and farnesyltransferase (FTase) inhibition in cardiovascular disease, pulmonary diseases (e.g. asthma and chronic obstructive pulmonary disease (COPD), and cancer.

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Inhibition of Inflammatory Mediators

Abstract: Statins induce anti-inflammatory effects in human airway epithelial inflammation. Statins may play a role in the treatment and prevention of chronic rhinosinusitis and pulmonary exacerbation of obstructive airway diseases.

Cited by 26 publications

References 24 publications

Differential effects of simvastatin on IL-13-induced cytokine gene expression in primary mouse tracheal epithelial cells

Differential effects of simvastatin on IL-13-induced cytokine gene expression in primary mouse tracheal epithelial cells

Simvastatin inhibits smoke-induced airway epithelial injury: implications for COPD therapy

Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease

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