Cyanidin-3-O-glucoside (C3G), an anthocyanin belonging to the flavonoid family and commonly present in food and vegetables in human diet, has exhibited anti-inflammatory and anti-oxidant effects. This study aimed to investigate the protective ability of C3G against inflammatory and oxidative injuries, as well as to clarify the possible mechanism in lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs) in vitro and acute respiratory distress syndrome mouse model in vivo. HUVECs or male Kunming mice were pretreated with C3G 1 h before LPS stimulation. C3G significantly inhibited the production of pro-inflammatory cytokines (tumor necrosis factor-α, interleukin (IL) -6, and IL-1β) in cell supernatants and bronchoalveolar lavage fluid (BALF) as determined by enzyme-linked immunosorbent assay. Histopathologic examination with hematoxylin and eosinstaining showed that C3G pretreatment substantially suppressed inflammatory cell infiltration, alveolar wall thickening, and interstitial edemain lung tissues. C3G markedly prevented LPS-induced elevation of malondialdehyde and myeloperoxidase levels in lung tissue homogenates, wet to dry ratio of lung tissues, total cells, and inflammatory cells (neutrophils and macrophages) in BALF. Moreover, C3G reduced superoxide dismutase activity in the lung tissue homogenates. Western blot assay also showed that C3G pretreatment significantly suppressed LPS-induced activation of nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways by blocking the phosphorylation of inhibitor κB-α, NF-κB/P65, extracellular signal-regulated kinase, p38, and c-Jun NH2-terminal kinase in the lung tissues. In summary, C3G may ameliorate LPS-induced injury, which results from inflammation and oxidation, by inhibiting NF-κB and MAPK pathways and playing important anti-inflammatory and anti-oxidative roles.
Sepsis commonly progresses to disseminated intravascular coagulation and induces the activation of heparanase (HPA) and the shedding of endothelial glycocalyx constituents, including syndecan-1 (SDC-1) and heparan sulphate (HS). However, the degradation of glycocalyx and its association with coagulation disorders remains undetermined. The present study aimed to evaluate the effect of unfractionated heparin (UFH) and N-acetylheparin (NAH), which is a non-anticoagulant heparin derivative, on endothelial glycocalyx and coagulation function in a lipopolysaccharide (LPS)-induced sepsis rat model, and to compare the differences observed in coagulation function between UFH and NAH. Experimental rats were randomly assigned to four groups: Control; LPS; UFH + LPS; and NAH + LPS. Rats were administered UFH or NAH and subsequently, ~1 min later, administered LPS (10 mg/kg; intravenous). The blood and lung tissues of rats were collected 0.5, 2 and 6 h after LPS injection, and were used for subsequent analysis. The results demonstrated that HPA activity and SDC-1 and HS levels increased, and this increase was associated with inflammatory cytokines and coagulation/fibrinolysis markers in the sepsis rat model. Histopathological examination was performed, and the lung injury score and lung wet/dry ratio indicated that UFH and NAH also significantly improved lung tissue injury. The results of the ELISA analysis demonstrated that UFH and NAH treatment: i) significantly decreased the levels of inflammatory cytokines including tumor necrosis factor-α and interleukin-6; ii) inhibited HPA activity and protected the integrity of the glycocalyx, which was identified by decreased HS and SDC-1 levels; and iii) decreased the levels of prothrombin fragment 1+2, thrombin-antithrombin complex, and plasminogen activator inhibitor-1 and increased the levels of fibrinogen and antithrombin-III. Preconditioning with UFH decreased the plasma activated partial thromboplastin time. These results indicated that UFH and NAH may alleviate sepsis-induced coagulopathy, and this effect may have been due to an inhibition of HPA activity and decrease in the shedding of the endothelial glycocalyx.
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