This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 200406-729OCv1 171/6/606    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fessler, M. B. Articles by Worthen, G. S. Search for Related Content PubMed PubMed Citation Articles by Fessler, M. B. Articles by Worthen, G. S.

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

Department of Medicine, National Jewish Medical and Research Center; and Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to Michael B. Fessler, M.D., Department of Medicine, National Jewish Medical and Research Center, 1400 Jackson Street, D403 Neustadt, Denver, CO 80206. E-mail: michael.fessler{at}uchsc.edu

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

Key Words: acute respiratory distress syndrome • lipopolysaccharide • pneumonia • rho • statins

This article has been cited by other articles:

				K. Smoak, J. Madenspacher, S. Jeyaseelan, B. Williams, D. Dixon, K. R. Poch, J. A. Nick, G. S. Worthen, and M. B. Fessler Effects of Liver X Receptor Agonist Treatment on Pulmonary Inflammation and Host Defense J. Immunol., March 1, 2008; 180(5): 3305 - 3312. [Abstract] [Full Text] [PDF]

				A. Baldan, A. V. Gomes, P. Ping, and P. A. Edwards Loss of ABCG1 Results in Chronic Pulmonary Inflammation J. Immunol., March 1, 2008; 180(5): 3560 - 3568. [Abstract] [Full Text] [PDF]

				S. E. Alexeeff, A. A. Litonjua, D. Sparrow, P. S. Vokonas, and J. Schwartz Statin Use Reduces Decline in Lung Function: VA Normative Aging Study Am. J. Respir. Crit. Care Med., October 15, 2007; 176(8): 742 - 747. [Abstract] [Full Text] [PDF]

				G. B. J. Mancini Clarion Call for Trials Assessing "Cardiopulmonary" Agents To Reduce Morbidity and Mortality in Inflammatory Lung Diseases Chest, April 1, 2007; 131(4): 950 - 951. [Full Text] [PDF]

				F. J. Frost, H. Petersen, K. Tollestrup, and B. Skipper Influenza and COPD Mortality Protection as Pleiotropic, Dose-Dependent Effects of Statins Chest, April 1, 2007; 131(4): 1006 - 1012. [Abstract] [Full Text] [PDF]

				S. Jeyaseelan, S. K. Young, M. B. Fessler, Y. Liu, K. C. Malcolm, M. Yamamoto, S. Akira, and G. S. Worthen Toll/IL-1 Receptor Domain-Containing Adaptor Inducing IFN-beta (TRIF)-Mediated Signaling Contributes to Innate Immune Responses in the Lung during Escherichia coli Pneumonia J. Immunol., March 1, 2007; 178(5): 3153 - 3160. [Abstract] [Full Text] [PDF]

				M. B. Fessler, P. G. Arndt, I. Just, J. A. Nick, K. C. Malcolm, and G. Scott Worthen Dual role for RhoA in suppression and induction of cytokines in the human neutrophil Blood, February 1, 2007; 109(3): 1248 - 1256. [Abstract] [Full Text] [PDF]

				P. G. Arndt, S. K. Young, K. R. Poch, J. A. Nick, S. Falk, R. W. Schrier, and G. S. Worthen Systemic Inhibition of the Angiotensin-Converting Enzyme Limits Lipopolysaccharide-Induced Lung Neutrophil Recruitment through Both Bradykinin and Angiotensin II-Regulated Pathways J. Immunol., November 15, 2006; 177(10): 7233 - 7241. [Abstract] [Full Text] [PDF]

				E M W van de Garde, E Hak, P C Souverein, A W Hoes, J M M van den Bosch, and H G M Leufkens Statin treatment and reduced risk of pneumonia in patients with diabetes Thorax, November 1, 2006; 61(11): 957 - 961. [Abstract] [Full Text] [PDF]

				P. M. Henson, G. P. Cosgrove, and R. W. Vandivier State of the Art. Apoptosis and Cell Homeostasis in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, August 1, 2006; 3(6): 512 - 516. [Full Text] [PDF]

				E Hothersall, C McSharry, and N C Thomson Potential therapeutic role for statins in respiratory disease. Thorax, August 1, 2006; 61(8): 729 - 734. [Abstract] [Full Text] [PDF]

				S. Jeyaseelan, S. K. Young, M. Yamamoto, P. G. Arndt, S. Akira, J. K. Kolls, and G. S. Worthen Toll/IL-1R Domain-Containing Adaptor Protein (TIRAP) Is a Critical Mediator of Antibacterial Defense in the Lung against Klebsiella pneumoniae but Not Pseudomonas aeruginosa J. Immunol., July 1, 2006; 177(1): 538 - 547. [Abstract] [Full Text] [PDF]

				G.B. J. Mancini, M. Etminan, B. Zhang, L. E. Levesque, J. M. FitzGerald, and J. M. Brophy Reduction of Morbidity and Mortality by Statins, Angiotensin-Converting Enzyme Inhibitors, and Angiotensin Receptor Blockers in Patients With Chronic Obstructive Pulmonary Disease J. Am. Coll. Cardiol., June 20, 2006; 47(12): 2554 - 2560. [Abstract] [Full Text] [PDF]

				K. Morimoto, W. J. Janssen, M. B. Fessler, K. A. McPhillips, V. M. Borges, R. P. Bowler, Y.-Q. Xiao, J. A. Kench, P. M. Henson, and R. W. Vandivier Lovastatin enhances clearance of apoptotic cells (efferocytosis) with implications for chronic obstructive pulmonary disease. J. Immunol., June 15, 2006; 176(12): 7657 - 7665. [Abstract] [Full Text] [PDF]

				E. P. van de Visse, M. van der Heijden, J. Verheij, G. P. van Nieuw Amerongen, V. W. M. van Hinsbergh, A. R. J. Girbes, and A. B. J. Groeneveld Effect of prior statin therapy on capillary permeability in the lungs after cardiac or vascular surgery. Eur. Respir. J., May 1, 2006; 27(5): 1026 - 1032. [Abstract] [Full Text] [PDF]

				T. Nawrot, A. Nemmar, and B. Nemery Update in environmental and occupational medicine 2005. Am. J. Respir. Crit. Care Med., May 1, 2006; 173(9): 948 - 952. [Full Text] [PDF]

				E. B. Milbrandt, A. Ishizaka, and D. C. Angus Update in critical care 2005. Am. J. Respir. Crit. Care Med., April 15, 2006; 173(8): 833 - 841. [Full Text] [PDF]

				S. Jeyaseelan, R. Manzer, S. K. Young, M. Yamamoto, S. Akira, R. J. Mason, and G. S. Worthen Induction of CXCL5 During Inflammation in the Rodent Lung Involves Activation of Alveolar Epithelium Am. J. Respir. Cell Mol. Biol., June 1, 2005; 32(6): 531 - 539. [Abstract] [Full Text] [PDF]