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Effects of ApoA-I Mimetic Peptide L-4F in LPS-Mediated Inflammation

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Apolipoprotein Mimetics in the Management of Human Disease

Abstract

Despite recent advances in antimicrobial and anti-inflammatory therapy, sepsis continues to be a major cause of death in hospitalized patients. To date few interventions have been successful in treating sepsis. Microbes, via their unique molecular patterns, activate a cascade of events that leads to the clinical manifestation of sepsis. Lipopolysaccharide (LPS), a component of the outer membrane of gram-negative bacteria, mediates many of the toxic effects associated with sepsis. The innate immune response is activated during sepsis to protect the host. Circulating lipoproteins especially high-density lipoproteins (HDL) are important components of this immune response. Low concentrations of cholesterol and HDL are associated with oxidative stress and elevated inflammatory mediators in response to LPS. This is associated with poorer outcomes in septic patients. Apolipoprotein (apo) A-I is the principle protein component of HDL that is responsible for many of the anti-inflammatory properties of HDL. Results of studies indicate that HDL/apoA-I administration may be effective in treating sepsis. However obtaining therapeutic quantities of the HDL/apoA-I is impractical. Peptide 18A and its structural variant 4F are only 18 amino acid residues in length (compared to 243 amino acids present in human apoA-I). They have no sequence similarity with apoA-I, but they mimic the class A amphipathic helixes contained in apoA-I with lipid-binding properties. Recent in vitro and in vivo studies indicate that 4F efficiently inhibits LPS-mediated inflammatory responses and could be considered as an effective alternative to HDL/apoA-I therapy in conditions mediated by gram-negative infection. Major mechanisms of anti-inflammatory properties of 4F might include a direct binding and neutralization of LPS, strong antioxidant properties, effects on HDL function, and effects on cell membranes.

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Abbreviations

apoA-I:

Apolipoprotein A-I

apoB:

Apolipoprotein B

apoE:

Apolipoprotein E

CD14:

Membrane (m) or soluble (s) pattern recognition receptor (cluster of differentiation 14)

HDL:

High-density lipoproteins

IL:

Interleukin

LAL:

Limulus amebocyte lysate

LBP:

Lipopolysaccharide-binding protein

LDL:

Low-density lipoproteins

LPS:

Lipopolysaccharide

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

PON 1:

Paraoxonase 1

rHDL:

Reconstituted HDL

TNF-α:

Tumor necrosis factor alpha

TLR:

Toll-like receptor

VCAM-1:

Vascular cell adhesion protein 1

VLDL:

Very low-density lipoproteins

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Authors and Affiliations

  1. Department of Medicine, University of Alabama at Birmingham, ZRB-334, 703 19th Street South, Birmingham, AL, 35294, USA

    Oleg F. Sharifov MD, PhD

  2. Department of Medicine, University of Alabama at Birmingham, BDB-668, 1808 7th Avenue South, Birmingham, AL, 35294, USA

    G. M. Anantharamaiah PhD

  3. Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, BDB-668, 1808 7th Avenue South, Birmingham, AL, 35294, USA

    G. M. Anantharamaiah PhD

  4. Department of Medicine, University of Alabama at Birmingham, Birmingham Veterans Affairs Medical Center, BDB-101, 1808 7th Avenue South, Birmingham, AL, 35294, USA

    Himanshu Gupta MD, FACC

Authors
  1. Oleg F. Sharifov MD, PhD
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  2. G. M. Anantharamaiah PhD
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  3. Himanshu Gupta MD, FACC
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Correspondence to Himanshu Gupta MD, FACC .

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Editors and Affiliations

  1. Department of Medicine, University of Alabama School of Medicine, Birmingham, Alabama, USA

    G.M. Anantharamaiah

  2. LipimetiX Development, LLC, Natick, Massachusetts, USA

    Dennis Goldberg

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Sharifov, O.F., Anantharamaiah, G.M., Gupta, H. (2015). Effects of ApoA-I Mimetic Peptide L-4F in LPS-Mediated Inflammation. In: Anantharamaiah, G., Goldberg, D. (eds) Apolipoprotein Mimetics in the Management of Human Disease. Adis, Cham. https://doi.org/10.1007/978-3-319-17350-4_6

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  • DOI: https://doi.org/10.1007/978-3-319-17350-4_6

  • Publisher Name: Adis, Cham

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