title: The Mevalonate Pathway and Innate Immune Hyper-Responsiveness in the Pathogenesis of COPD and Lung Cancer: Potential for Chemoprevention.
abstract: Current evidence suggests that persisting and/or exaggerated inflammation in the lungs initiated by smoking, and up-regulated through genetic susceptibility, may result in lung remodelling and impaired repair. The mevalonate pathway, through its modifying effects on innate immune responsiveness, may be involved in these processes providing a plausible pathogenic link between the development of chronic obstructive pulmonary disease (COPD) and lung cancer. The mevalonate pathway, mediates these effects through important intra-cellular signalling molecules called guanine phosphate transferases (GTPases) such as Rho-A. Smoke exposure activates cell surface proteins which, through the mediating influence of GTPases, then modify the activation of NFkB and its downstream effects on genes underlying innate immunity, neutrophilic inflammation and carcinogenesis. The mevalonate pathway is readily and substantially modified by inhibition of the enzyme 3-hydroxy-3-methyl-glutaryl-Coenzyme A (HMGCo-A) reductase. This enzyme controls the rate limiting step of the mevalonate pathway and is subject to inhibition by statin drugs and small chain fatty acids derived from high dietary fibre intake. Thus inhibiting the mevelonate pathway, and dampening the innate immune response to smoking, may play a critical role in modifying pulmonary inflammation and lung remodelling. Such an action might slow the progression of COPD and reduce the tendency to the development of lung cancer. This review examines the pre-clinical and clinical data suggesting that HMGCoA-reductase inhibition and it's modification of the mevalonate pathway, may have a chemo-preventive effect on lung cancer, particularly in patients with COPD where pulmonary inflammation is increased and the risk of lung cancer is greatest.
authors.affiliation: Respiratory Genetics Group; PO Box 26161, Epsom, Auckland 1344, New Zealand.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Young
authors.forename: Raewyn J
authors.initials: RJ
authors.lastname: Hopkins
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D018890:Chemoprevention / Q000379:methods*; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008175:Lung Neoplasms / Q000517:prevention & control*; D008798:Mevalonic Acid / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000517:prevention & control*
chemical_list: D000214:Acyl Coenzyme A; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; C015901:glutaryl-coenzyme A; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid
keywords: COPD; innate immunity; lung cancer and statins; mevalonate pathway.