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The adverse alterations of HDL in quality promote septic ARDS via exacerbated pulmonary endothelial dysfunction


 Background

Septic acute respiratory distress syndrome (ARDS), characterized by the acute lung injury (ALI) secondary to aberrant systemic inflammatory response, has high morbidity and mortality. Despite increased understanding of ALI pathogenesis, the therapies to prevent lung dysfunction underlying systemic inflammatory disorder remain elusive. The high density lipoprotein (HDL) has critical protective effects in sepsis and its dysfunction has a manifested contribution to septic organ failure. However, the adverse changes in HDL composition and function in septic ARDS patients are large unknown.

Method

To investigate HDL remodeling in septic ARDS, we analyzed composition changes of plasma HDL from 40 patients with septic ARDS (A-HDL) and 40 matched normal controls (N-HDL). To determine the deleterious functional remodeling of HDL, A-HDL or N-HDL was administrated to C57BL/6 and apoA-I knock-out (KO) mice after cecal ligation and puncture (CLP) procedure. Mouse lung microvascular endothelial cells (MLECs) were further treated by these HDLs to investigate whether the adverse effects of A-HDL were associated with endothelial dysfunction.

Results

ARDS patients showed significant changes of HDL composition, accompanied with the dramatic decrease in plasma HDL-C. We further indicated that A-HDL treatment aggravated CLP induced ALI. Intriguingly, this deleterious effects of A-HDL were associated with pulmonary endothelial dysfunction, rather than the deregulation of plasma lipopolysaccharide (LPS). Further in vitro results demonstrated the direct effects of A-HDL on MLECs, including increased expressions of adhesion proteins and pro-inflammatory cytokines via activating NF-κB signaling and decreased junction protein expression.

Conclusions

Our results depicted a sepsis induced remodeling in HDL quality, which predisposes lung to ARDS via inducing ECs dysfunction. These results also demonstrated the importance of circulating HDL in regulating alveolar homeostasis.