Synthetic Amphipathic Helical Peptides Targeting CD36 Attenuate Lipopolysaccharide-Induced Inflammation and Acute Lung Injury.
Synthetic amphipathic helical peptides (SAHPs) designed as apolipoprotein A-I mimetics are known to bind to class B scavenger receptors (SR-Bs), SR-BI, SR-BII, and CD36, receptors that mediate lipid transport and facilitate pathogen recognition. In this study, we evaluated SAHPs, selected for targeting human CD36, by their ability to attenuate LPS-induced inflammation, endothelial barrier dysfunction, and acute lung injury (ALI). L37pA, which targets CD36 and SR-BI equally, inhibited LPS-induced IL-8 secretion and barrier dysfunction in cultured endothelial cells while reducing lung neutrophil infiltration by 40% in a mouse model of LPS-induced ALI. A panel of 20 SAHPs was tested in HEK293 cell lines stably transfected with various SR-Bs to identify SAHPs with preferential selectivity toward CD36. Among several SAHPs targeting both SR-BI/BII and CD36 receptors, ELK-B acted predominantly through CD36. Compared with L37pA, 5A, and ELK SAHPs, ELK-B was most effective in reducing the pulmonary barrier dysfunction, neutrophil migration into the lung, and lung inflammation induced by LPS. We conclude that SAHPs with relative selectivity toward CD36 are more potent at inhibiting acute pulmonary inflammation and dysfunction. These data indicate that therapeutic strategies using SAHPs targeting CD36, but not necessarily mimicking all apolipoprotein A-I functions, may be considered a possible new treatment approach for inflammation-induced ALI and pulmonary edema.
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892; National Heart, Lung, and Blood Institute, Bethesda, MD 20892; abocharov@mail.cc.nih.gov.
Alexander V
0000-0002-3482-2980
AV
Bocharov
Lung Injury Center, The University of Chicago, Chicago, IL 60637;
Tinghuai
T
Wu
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892;
Irina N
IN
Baranova
Lung Injury Center, The University of Chicago, Chicago, IL 60637;
Anna A
0000-0003-0535-7693
AA
Birukova
National Institute of Diabetes, Digestive, and Kidney Diseases, Bethesda, MD 20892; and.
Denis
D
Sviridov
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892;
Tatyana G
TG
Vishnyakova
National Heart, Lung, and Blood Institute, Bethesda, MD 20892;
Alan T
0000-0001-5839-7280
AT
Remaley
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892; National Institute of Diabetes, Digestive, and Kidney Diseases, Bethesda, MD 20892; and.
Thomas L
TL
Eggerman
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892; Office of Science Policy, Office of the Director, National Institutes of Health, Bethesda, MD 20892.
Amy P
AP
Patterson
Lung Injury Center, The University of Chicago, Chicago, IL 60637;
Konstantin G
0000-0002-0303-5394
KG
Birukov
D055371:Acute Lung Injury / Q000276:immunology* / Q000473:pathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016632:Apolipoprotein A-I / Q000276:immunology; D018955:CD36 Antigens / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D016632:Apolipoprotein A-I; D018955:CD36 Antigens; D008070:Lipopolysaccharides; D010455:Peptides