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.