Dataset Information

Neferine Protects Endothelial Glycocalyx via Mitochondrial ROS in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome.

ABSTRACT: Damage to the endothelial glycocalyx is a critical factor in increased pulmonary vascular permeability, which is the basic pathological feature of acute respiratory distress syndrome (ARDS). Neferine (Nef), a bisbenzylisoquinoline alkaloid isolated from green seed embryos of Nelumbo nucifera Gaertn, has extensive pharmacological activity. In this study, we showed that Nef reduced lung-capillary permeability, down-regulated the production of cytokines (IL-1β, IL-6, TNF-α, and IL-10) and inhibited the activation of the NF-κB signaling pathway in mice with lipopolysaccharide (LPS)-induced ARDS. Further analysis indicated that Nef provided protection against endothelial glycocalyx degradation in LPS-induced ARDS mice (in vivo) and in LPS-stimulated human umbilical vein endothelial cells (in vitro). The glycocalyx-protective effect of Nef may be initiated by suppressing the production of mitochondrial ROS (mtROS) and decreasing oxidative damage. Nef was also found to promote glycocalyx restoration by accelerating the removal of mtROS in endothelial cells in LPS-induced ARDS. These results suggested the potential of Nef as a therapeutic agent for ARDS associated with Gram-negative bacterial infections and elucidated the mechanisms underlying the protection and restoration of the endothelial glycocalyx.

SUBMITTER: Liu XY

PROVIDER: S-EPMC5826949 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Neferine Protects Endothelial Glycocalyx via Mitochondrial ROS in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome.

Liu Xiang-Yong XY Xu Hai-Xiao HX Li Jian-Kui JK Zhang Dong D Ma Xiao-Hong XH Huang Li-Na LN Lü Jun-Hong JH Wang Xiao-Zhi XZ

Frontiers in physiology 20180222

Damage to the endothelial glycocalyx is a critical factor in increased pulmonary vascular permeability, which is the basic pathological feature of acute respiratory distress syndrome (ARDS). Neferine (Nef), a bisbenzylisoquinoline alkaloid isolated from green seed embryos of <i>Nelumbo nucifera Gaertn</i>, has extensive pharmacological activity. In this study, we showed that Nef reduced lung-capillary permeability, down-regulated the production of cytokines (IL-1β, IL-6, TNF-α, and IL-10) and in ...[more]

PMID: 29520236

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Project description:BackgroundSepsis-associated destruction of the pulmonary microvascular endothelial glycocalyx (EGCX) creates a vulnerable endothelial surface, contributing to the development of acute respiratory distress syndrome (ARDS). Constituents of the EGCX shed into circulation, glycosaminoglycans and proteoglycans, may serve as biomarkers of endothelial dysfunction. We sought to define the patterns of plasma EGCX degradation products in children with sepsis-associated pediatric ARDS (PARDS), and test their association with clinical outcomes.MethodsWe retrospectively analyzed a prospective cohort (2018-2020) of children (≥1 month to <18 years of age) receiving invasive mechanical ventilation for acute respiratory failure for ≥72 h. Children with and without sepsis-associated PARDS were selected from the parent cohort and compared. Blood was collected at time of enrollment. Plasma glycosaminoglycan disaccharide class (heparan sulfate, chondroitin sulfate, and hyaluronan) and sulfation subtypes (heparan sulfate and chondroitin sulfate) were quantified using liquid chromatography tandem mass spectrometry. Plasma proteoglycans (syndecan-1) were measured through an immunoassay.ResultsAmong the 39 mechanically ventilated children (29 with and 10 without sepsis-associated PARDS), sepsis-associated PARDS patients demonstrated higher levels of heparan sulfate (median 639 ng/mL [interquartile range, IQR 421-902] vs 311 [IQR 228-461]) and syndecan-1 (median 146 ng/mL [IQR 32-315] vs 8 [IQR 8-50]), both p = 0.01. Heparan sulfate subtype analysis demonstrated greater proportions of N-sulfated disaccharide levels among children with sepsis-associated PARDS (p = 0.01). Increasing N-sulfated disaccharide levels by quartile were associated with severe PARDS (n = 9/29) with the highest quartile including >60% of the severe PARDS patients (test for trend, p = 0.04). Higher total heparan sulfate and N-sulfated disaccharide levels were independently associated with fewer 28-day ventilator-free days in children with sepsis-associated PARDS (all p < 0.05).ConclusionsChildren with sepsis-associated PARDS exhibited higher plasma levels of heparan sulfate disaccharides and syndecan-1, suggesting that EGCX degradation biomarkers may provide insights into endothelial dysfunction and PARDS pathobiology.

Project description:BackgroundThe endothelial glycocalyx (EG) on the luminal surface of endothelial cells contributes to the permeability barrier of vessels and prevents activation of the coagulation cascade. Endothelial glycocalyx damage, which occurs in the shock state, results in endotheliopathy. Interleukin (IL)-22 is a cytokine with both proinflammatory and anti-inflammatory properties, and how IL-22 affects the EG has not been studied. We hypothesized that IL-22:Fc, a recombinant fusion protein with human IL-22 and the Fc portion of human immunoglobulin G1 (which extends the protein half-life), would not affect EG shedding in endothelium after injury.MethodsHuman umbilical vein endothelial cells (HUVECs) were exposed to 1 μg/mL lipopolysaccharide (LPS). Lipopolysaccharide-injured cells (n = 284) were compared with HUVECs with LPS injury plus 0.375 μg/mL of IL-22:Fc treatment (n = 293) for 12 hours. These two cohorts were compared with control HUVECs (n = 286) and HUVECs exposed to IL-22:Fc alone (n = 269). Cells were fixed and stained with fluorescein isothiocyanate-labeled wheat germ agglutinin to quantify EG. Total RNA was collected, and select messenger RNAs were quantified by real time - quantitative polymerase chain reaction (RT-qPCR) using SYBR green fluorescence.ResultsExposure of HUVECs to LPS resulted in degradation of the EG compared with control (5.86 vs. 6.09 arbitrary unit [AU], p = 0.01). Interleukin-22:Fc alone also resulted in degradation of EG (5.08 vs. 6.09 AU, p = 0.01). Treatment with IL-22:Fc after LPS injury resulted in less degradation of EG compared with LPS injury alone (5.86 vs. 5.08 AU, p = 0.002). Expression of the IL-22Ra1 receptor was not different for IL-22:Fc treated compared with LPS injury only (0.69 vs. 0.86 relative expression, p = 0.10). Treatment with IL-22:Fc after LPS injury resulted in less matrix metalloproteinase 2 (0.79 vs. 1.70 relative expression, p = 0.005) and matrix metalloproteinase 14 (0.94 vs. 2.04 relative expression, p = 0.02).ConclusionsInterleukin-22:Fc alone induces EG degradation. However, IL-22:Fc treatment after LPS injury appears to mitigate EG degradation. This protective effect appears to be mediated via reduced expression of metalloproteinases.

Dataset Information

Neferine Protects Endothelial Glycocalyx via Mitochondrial ROS in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome.

Publications

Neferine Protects Endothelial Glycocalyx via Mitochondrial ROS in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome.

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