4F, apolipoprotein AI mimetic peptide, attenuates acute lung injury and improves survival in endotoxemic rats.
BACKGROUND
4F, apolipoprotein AI mimetic peptide, mimics anti-inflammatory properties of high-density lipoprotein (HDL). The aim of this study was to investigate whether 4F attenuates acute lung injury and improves survival in endotoxemic rats and to determine whether the therapeutic benefits of 4F are associated with the stimulation of sphingosine-1-phosphate receptor 1 (S1P1), the activation of Akt, the down-regulation of the nuclear factor-κB (NF-κB) pathway, and the suppression of cell adhesion molecules.


METHODS
To induce endotoxemia in rats, lipopolysaccharide (LPS, 10 mg/kg) was injected into a tail vein and 10 minutes later, vehicle or 4F (10 mg/kg) was administered intraperitoneally, respectively. We observed the survival of subjects for 72 hours. At 6-hour post-LPS, we killed animals and measured S1P1 expression, phosphorylated Akt/Akt ratio, cytoplasmic phosphorylated inhibitor κB-α/inhibitor κB-α ratio, nuclear NF-κB p65 expression and DNA-binding activity, endothelial leukocyte adhesion molecule-1 (E-selectin) and intercellular adhesion molecule-1 expression, myeloperoxidase activity, and histologic damages in lung tissues. We also measured serum HDL cholesterol level.


RESULTS
4F improved survival in endotoxemic rats. 4F restored LPS-induced diminution of serum HDL cholesterol level and increased lung S1P1 expression and phosphorylated Akt/Akt ratio in LPS-treated rats. Furthermore, 4F suppressed inhibitor κB-α degradation, NF-κB activation, E-selectin and intercellular adhesion molecule-1 expression, and myeloperoxidase activity, and attenuated histologic damages in lung tissues.


CONCLUSIONS
4F attenuated acute lung injury and improved survival in endotoxemic rats. The therapeutic benefits of 4F were found to be associated with the stimulation of S1P1, the activation of Akt, the down-regulation of the NF-κB pathway, and the suppression of cell adhesion molecules.
Department of Emergency Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
Woon Yong
WY
Kwon
Gil Joon
GJ
Suh
Kyung Su
KS
Kim
Young Ho
YH
Kwak
Kyuseok
K
Kim
D055371:Acute Lung Injury / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism / Q000627:therapeutic use*; D001665:Binding Sites; D015153:Blotting, Western; D008076:Cholesterol, HDL / Q000097:blood; D004195:Disease Models, Animal; D015536:Down-Regulation; D019040:E-Selectin / Q000032:analysis / Q000378:metabolism; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009195:Peroxidase / Q000032:analysis / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D018709:Statistics, Nonparametric; D015996:Survival Rate; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D019040:E-Selectin; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018799:Intercellular Adhesion Molecule-1; D009195:Peroxidase; D019892:eIF-2 Kinase