Statin Drugs, Metabolic Pathways, and Asthma: A Therapeutic Opportunity Needing Further Research

Amir      A. Zeki; Nicholas      J. Kenyon; Tzipora      Goldkorn

Abstract

The chance discovery of hydroxymethylglutaryl (HMG)-CoA reductase inhibitors has revolutionized the care of patients with cardiovascular disease. The unexpected finding that these cholesterol-lowering drugs (or ‘statins’) also posses pleiotropic immunomodulatory properties, has opened a new area of research which investigates the anti-inflammatory and anti-proliferative properties of statins. In this brief commentary, we discuss the potential application of these drugs in asthma, where metabolic pathways pertinent to lung inflammation, in addition to the mevalonate cascade, may be targeted. We review mechanisms of action, discuss the potential therapeutic use of statins in asthma, share some preliminary data from our laboratory, discuss results from recent clinical trials in asthma, and propose a new target asthma subpopulation that could potentially benefit. We conclude our essay by highlighting the mevalonate-dependent and – independent pathways that may be modulated by statins, including the emerging area of cholesterol, sphingolipid, and lipid raft biology in lung disease. In this is an opportunity to develop new treatments for asthma, where innovative therapies are urgently needed to prevent acute exacerbations and alter disease progression.

Keywords: Statins, asthma, mevalonate, metabolic, novel therapy, HMG-CoA reductase, anti-inflammatory, immunomodulatory, eotaxin, obese asthmatic, pleiotropic immunomodulatory properties, lung inflammation, cholesterol, sphingolipid, lipid raft biology, lipid, mevastatin, homeostasis, low density lipoprotein, chronic obstructive pulmonary disease, isoprenoids, geranylgeranylpyrophosphate, guanosine triphosphatases, cel-lular proliferation, transmigration, vesicular trafficking, cytoskeletal dynamics, apoptosis, phagocytosis, antigen uptake, simvastatin, lovastatin, cytokine, chemokine, asthma mucosal immunity, forced expiratory volume in the first second, inhaled corticosteroids (ICS), inflammatory markers, leukotriene B4, eosinophils, budesonide, heterogeneous disease, novel therapies, dyslipidemia, metabolic syndrome, vitamin D, steroid hormones, Omega-3 fatty, receptor-to-ligand binding, innovative therapies