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.
Highlights
Sepsis is frequently associated with acute respiratory distress syndrome (ARDS), which is a leading cause of morbidity and mortality in critically ill patients [1]
Since LPS mediates many of its inflammatory effects via binding to leukocytes, we measured effects of L-4F on LPS binding/ internalization by leukocytes in human blood using fluorescent Bodipy-LPS (1 mg/ml) and flow cytometry
Despite the recognition that High density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) modulate immune cell function, their role in reducing complications associated with ARDS is not clear
Summary
Sepsis is frequently associated with acute respiratory distress syndrome (ARDS), which is a leading cause of morbidity and mortality in critically ill patients [1]. TNF-a and IL-6 are important mediators of the LPS-activated inflammatory cascade leading to liver injury and acute lung injury (ALI) [7,8,9]. A high plasma IL-6 level serves as a poor prognostic indicator for sepsis-related ARDS/ALI [10,11,12,13]. Plasma levels of anti-inflammatory apolipoprotein A-I (apoA-I), the major protein constituent of HDL, and anti-oxidant enzyme paraoxonase 1 (PON1), are reduced by sepsis [18,20,21,22]. Decreased activity of PON1 in septic patients is associated with oxidative stress and inflammation progress [20,21,22]. Reconstituted HDL attenuates ALI in endotoxemic rats [25]
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