Abstract
BackgroundSeptic-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.MethodsTo investigate HDL remodeling in septic-ARDS, we analyzed the changes of HDL composition 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.ResultsSeptic-ARDS patients showed significant changes of HDL composition, accompanied with significantly decreased HDL-C. We further indicated that A-HDL treatment aggravated CLP induced ALI. Intriguingly, these deleterious effects of A-HDL were associated with pulmonary endothelial dysfunction, rather than the increased plasma lipopolysaccharide (LPS). Further in vitro results demonstrated the direct effects of A-HDL on MLECs, including increased endothelial permeability, enhanced expressions of adhesion proteins and pro-inflammatory cytokines via activating NF-κB signaling and decreased junction protein expression.ConclusionsOur results depicted the remodeling of HDL composition in sepsis, which predisposes lung to ARDS via inducing ECs dysfunction. These results also demonstrated the importance of circulating HDL in regulating alveolar homeostasis.
Highlights
Septic-acute respiratory distress syndrome (ARDS), characterized by the acute lung injury (ALI) secondary to aberrant systemic inflammatory response, has high morbidity and mortality
The dysregulation of high density lipoprotein (HDL) in ARDS patients To determine the changes of HDL in septic-ARDS, the plasma samples were collected from 40 ARDS patients and 40 matched healthy controls (Table 1 for the clinical characteristics)
The ratios of apoE, apoC-III and serum amyloid A (SAA) to apoA-I increased in A-HDL, while the fractions of MPO, PON1, apoA-Acute physiology and chronic health evaluation II (II) and apoA-IV were comparable between N-HDL and A-HDL (Fig. 1a)
Summary
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. Acute respiratory distress syndrome (ARDS) is presented as noncardiogenic pulmonary edema-induced hypoxia caused by acute lung injury (ALI) secondary to lung excessive inflammation [1]. Owing to the vast surface area of pulmonary microvascular endothelium for effective gas exchange, the pulmonary vascular endothelial cells (ECs) are vulnerable to circulating stimuli during sepsis [3]. Excessive inflammation further impairs pulmonary microvascular integrity due to the decrease in endothelial cell–cell junction proteins (e.g. cadherin) and ECs apoptosis, resulting in pulmonary vascular permeability disruption, alveolar edema, additional immunocytes trafficking and uncontrolled alveolar inflammation [7]. Inflammation-mediated pulmonary endothelial dysfunction is considered to be the main pathogenesis of septic-ARDS. Understanding the mechanism of circulating inflammatory imbalance in pulmonary endothelial dysfunction is of crucial importance
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