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(Circulation. 2004;110:3252-3258.)
© 2004 American Heart Association, Inc.

Molecular Cardiology

D-4F, an Apolipoprotein A-I Mimetic Peptide, Inhibits the Inflammatory Response Induced by Influenza A Infection of Human Type II Pneumocytes

Brian J. Van Lenten, PhD; Alan C. Wagner; Mohamad Navab, PhD; G.M. Anantharamaiah, PhD; Eric Ka-Wai Hui, PhD; Debi P. Nayak, PhD; Alan M. Fogelman, MD

From the Departments of Medicine (B.J.V.L., A.C.W., M.N., A.M.F.) and Microbiology, Immunology, and Molecular Genetics (E.K.H., D.P.N.), David Geffen School of Medicine at UCLA, Los Angeles, Calif, and the Departments of Medicine, Biochemistry, and Molecular Genetics and the Atherosclerosis Research Unit (G.M.A.), University of Alabama, Birmingham.

Correspondence to Brian J. Van Lenten, PhD, 47-123 CHS, Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095-1679. E-mail bvanlent{at}mednet.ucla.edu

Received December 30, 2003; de novo received February 17, 2004; accepted April 13, 2004.

Background— Evidence suggests that apolipoprotein A-I (apoA-I) and HDL play important roles in modulating inflammation. We previously reported that an apoA-I mimetic peptide, D-4F, reduced inflammatory responses to influenza virus in mice. To further define the antiinflammatory activity of D-4F, a human alveolar type II cell line, A549, was used.

Methods and Results— Cells were either uninfected or infected with influenza A in the presence or absence of D-4F. Cells treated with D-4F were more viable, and virus-induced cytokine production was suppressed by D-4F. Caspases associated with cytokine production were activated after infection but suppressed by D-4F treatment. Infected A549 cells showed dramatic increases in cellular phospholipid secretion into the media. When infected cells were incubated with D-4F, secretion of parent nonoxidized, noninflammatory phospholipids was unaltered, but production of proinflammatory oxidized phospholipids was inhibited.

Conclusions— Type II pneumocytes respond to influenza A infection by activating caspases and secreting cytokines and cellular phospholipids into the extracellular environment, including oxidized phospholipids that evoke inflammatory responses. D-4F treatment inhibited these events. Our results suggest that apoA-I and apoA-I mimetic peptides such as D-4F are antiinflammatory agents that may have therapeutic potential.

Key Words: apolipoproteins • atherosclerosis • infection • lipoproteins • epithelium

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