A Role for Hydroxy-Methylglutaryl Coenzyme A Reductase in Pulmonary Inflammation and Host Defense

• DOI: 10.1164/rccm.200406-729oc
• Publication Date: 2005-03-07T23:38:14Z
• Authors: Michael B. Fessler; Scott K. Young; Samithamby Jeyase...; Jonathan G. Lieber; Patrick G. Arndt; Jerry A. Nick; G. Scott Worthen
• Keywords: Lovastatin; Mevalonic acid; Proinflammatory cytokine

Rationale: A growing literature indicates that hydroxy-methylglutaryl coenzyme reductase inhibitors (statins) modulate proinflammatory cellular signaling and functions. No studies to date, however, have addressed whether statins pulmonary inflammation triggered by aerogenic stimuli or they affect host defense. Objectives: To test lovastatin modulates LPS-induced antibacterial Methods: address these questions, confirm any effect of as dependent on inhibition reductase, we treated C57Bl/6 mice with three oral doses 10 mg/kg (or vehicle) intraperitoneal mevalonic acid saline), then exposed them the following: (1) aerosolized LPS, (2) intratracheal keratinocyte-derived chemokine (KC), (3) Klebsiella pneumoniae. Measurements main results: LPS- KC-induced airspace neutrophils were reduced lovastatin, an was blocked cotreatment. Lovastatin also associated parenchymal myeloperoxidase microvascular permeability, altered serum cytokines after LPS. Native clearance K. pneumoniae inhibited extrapulmonary dissemination enhanced, both reversibly acid. Ex vivo isolated from lovastatin-treated confirmed inhibitory effects Rac activation, actin polymerization, chemotaxis, bacterial killing. Conclusion: attenuates induced LPS impairs