Effect of Simvastatin on CF Airway Inflammation

Cystic Fibrosis (CF) lung disease is characterized by chronic bacterial infection and excessive inflammation. The airways of patients with CF contain large amounts of neutrophils, neutrophil products, and pro-inflammatory mediators. This inflammatory response may be linked to the loss of CFTR function. It is unknown, however, what signaling mechanisms link a loss of CFTR function to the excessive inflammatory response. Several signaling pathways are dysregulated in CF epithelial cells. Among these is the pathway that leads to the production of nitric oxide (NO). Reduced production of NO, which has important antibacterial and anti-inflammatory effects in the airway, may contribute to the establishment of the chronic bacterial infection and the development of the subsequent overzealous inflammatory response in CF.

NO synthesis in the airway epithelium is regulated by nitric oxide synthase 2 (NOS2). NOS2 expression is negatively regulated by the Rho GTPases, which are over-expressed in CF and may also play a role in the inflammatory dysregulation characteristic of the lung disease. Inhibition of the Rho GTPases with 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR) inhibitors, such as simvastatin (Zocor®), increases NOS2 protein expression in CF airway epithelial cells. The statins have also been shown to have potent systemic anti-inflammatory effects, many of which may be pertinent to CF. We propose to test the hypothesis that HMG-CoAR inhibitors, such as simvastatin, have the potential to correct abnormalities in NO production and decrease inflammation in the airways of patients with CF. The following specific aims will be pursued in this application: 1) To determine the effect of simvastatin treatment on exhaled nitric oxide (eNO) concentrations in subjects with CF; 2) To determine the effect of simvastatin treatment on inflammation and NOS2 production in the airway of subjects with CF, as determined by quantitative RT-PCR for IL-6, IL-8, and NOS2 mRNA in nasal epithelial cells; 3) To determine if quantitative RT-PCR measurements on nasal epithelial cells might be used as a surrogate marker of lower airway inflammation by comparing the measures obtained from nasal epithelial scrapes with inflammatory measurements obtained from induced sputum.

This study has the potential to identify a new agent that targets a signaling pathway (Rho GTPase) that appears to be dysregulated in CF, and thus, may exert multiple beneficial effects in the CF airway including increasing airway NO concentrations, decreasing neutrophil influx and reducing production of inflammatory mediators. In addition to evaluating the anti-inflammatory effects of statins in CF, this study presents an opportunity to evaluate alternative outcome measures of CF airway inflammation. The results of this study will provide important information regarding the feasibility of using nasal epithelial sampling as a relatively non-invasive measure of airway inflammation in CF.