The HDL from septic-ARDS patients with composition changes exacerbates pulmonary endothelial dysfunction and acute lung injury induced by cecal ligation and puncture (CLP) in mice
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.
Methods: To 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.
Results: Septic-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.
Conclusions: Our 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.
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Posted 18 Sep, 2020
On 04 Nov, 2020
On 19 Oct, 2020
Received 18 Oct, 2020
On 07 Oct, 2020
Received 07 Oct, 2020
Invitations sent on 02 Oct, 2020
On 02 Oct, 2020
On 16 Sep, 2020
On 15 Sep, 2020
On 15 Sep, 2020
Posted 15 May, 2020
On 20 Aug, 2020
Received 19 Aug, 2020
Received 17 Jul, 2020
On 16 Jul, 2020
Invitations sent on 15 Jul, 2020
On 15 Jul, 2020
On 17 May, 2020
On 16 May, 2020
On 16 May, 2020
On 11 May, 2020
On 10 May, 2020
On 10 May, 2020
On 09 May, 2020
The HDL from septic-ARDS patients with composition changes exacerbates pulmonary endothelial dysfunction and acute lung injury induced by cecal ligation and puncture (CLP) in mice
Posted 18 Sep, 2020
On 04 Nov, 2020
On 19 Oct, 2020
Received 18 Oct, 2020
On 07 Oct, 2020
Received 07 Oct, 2020
Invitations sent on 02 Oct, 2020
On 02 Oct, 2020
On 16 Sep, 2020
On 15 Sep, 2020
On 15 Sep, 2020
Posted 15 May, 2020
On 20 Aug, 2020
Received 19 Aug, 2020
Received 17 Jul, 2020
On 16 Jul, 2020
Invitations sent on 15 Jul, 2020
On 15 Jul, 2020
On 17 May, 2020
On 16 May, 2020
On 16 May, 2020
On 11 May, 2020
On 10 May, 2020
On 10 May, 2020
On 09 May, 2020
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.
Methods: To 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.
Results: Septic-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.
Conclusions: Our 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.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5