title: Anti-inflammatory mechanisms of apolipoprotein A-I mimetic peptide in acute respiratory distress syndrome secondary to sepsis.
abstract: Acute respiratory distress syndrome (ARDS) due to sepsis has a high mortality rate with limited treatment options. High density lipoprotein (HDL) exerts innate protective effects in systemic inflammation. However, its role in ARDS has not been well studied. Peptides such as L-4F mimic the secondary structural features and functions of apolipoprotein (apo)A-I, the major protein component of HDL. We set out to measure changes in HDL in sepsis-mediated ARDS patients, and to study the potential of L-4F to prevent sepsis-mediated ARDS in a rodent model of lipopolysaccharide (LPS)-mediated acute lung injury, and a combination of primary human leukocytes and human ARDS serum. We also analyzed serum from non-lung disease intubated patients (controls) and sepsis-mediated ARDS patients. Compared to controls, ARDS demonstrates increased serum endotoxin and IL-6 levels, and decreased HDL, apoA-I and activity of anti-oxidant HDL-associated paraoxanase-1. L-4F inhibits the activation of isolated human leukocytes and neutrophils by ARDS serum and LPS in vitro. Further, L-4F decreased endotoxin activity and preserved anti-oxidant properties of HDL both in vitro and in vivo. In a rat model of severe endotoxemia, L-4F significantly decreased mortality and reduces lung and liver injury, even when administered 1 hour post LPS. Our study suggests the protective role of the apoA-I mimetic peptide L-4F in ARDS and gram-negative endotoxemia and warrant further clinical evaluation. The main protective mechanisms of L-4F are due to direct inhibition of endotoxin activity and preservation of HDL anti-oxidant activity.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Oleg F
authors.initials: OF
authors.lastname: Sharifov
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Amit
authors.initials: A
authors.lastname: Gaggar
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.forename: Vinod K
authors.initials: VK
authors.lastname: Mishra
authors.forename: Jaideep
authors.initials: J
authors.lastname: Honavar
authors.forename: Silvio H
authors.initials: SH
authors.lastname: Litovsky
authors.forename: Mayakonda N
authors.initials: MN
authors.lastname: Palgunachari
authors.forename: C Roger
authors.initials: CR
authors.lastname: White
authors.forename: G M
authors.initials: GM
authors.lastname: Anantharamaiah
authors.forename: Himanshu
authors.initials: H
authors.lastname: Gupta
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016632:Apolipoprotein A-I / Q000737:chemistry*; D015415:Biomarkers / Q000378:metabolism; D019446:Endotoxemia / Q000150:complications*; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D057786:Peptidomimetics / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000150:complications* / Q000188:drug therapy* / Q000276:immunology; D013481:Superoxides / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D000893:Anti-Inflammatory Agents; D016632:Apolipoprotein A-I; D015415:Biomarkers; D008070:Lipopolysaccharides; D057786:Peptidomimetics; D013481:Superoxides