Ulinastatin attenuates pulmonary endothelial glycocalyx damage and inhibits endothelial heparanase activity in LPS-induced ARDS

Wang, Lipeng; Huang, Xiao; Kong, Guiqing; Xu, Haixiao; Li, Jiankui; Hao, Dingjun; Wang, Tao; Han, Shasha; Han, Chunlei; Sun, Yeying; Liu, Xiangyong; Wang, Xiaozhi

doi:10.1016/j.bbrc.2016.08.005

Cited by 42 publications

(32 citation statements)

References 28 publications

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“…Ulinastatin's anti-inflammatory effects include inactivating the elastase secreted by neutrophils, decreasing inflammatory mediators and downregulating inflammatory transcription factors, including NF-κB ( 19 , 22 , 45 ). Under inflammatory conditions, ulinastatin can attenuate dysfunctions of the endothelial barrier by upregulating the expression of vascular endothelial-cadherin; it also prevents endothelial apoptosis ( 21 , 46 , 47 ). These effects against hyperpermeability may account for the protective effect of ulinastatin against heat-induced damage.…”

Section: Discussionmentioning

confidence: 99%

Cryptdin-2 predicts intestinal injury during heatstroke in mice

et al. 2017

Int J Mol Med

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Intestinal injury-induced bacterial translocation and endotoxemia are important in the pathophysiological process of heatstroke. However, the underlying mechanism remains to be fully elucidated. Previous studies using 2D-gel electrophoresis found that defensin-related cryptdin-2 (Cry-2), an intestinal α-defensin, is upregulated in intestinal tissues during heatstroke in mice, and that treatment with ulinastatin, a multivalent enzyme inhibitor, reduced heat-induced acute lung injury. To investigate the association between Cry-2 and heat stress (HS)-induced intestinal injury and the probable protective role of ulinastatin, the present study examined the intestinal expression of Cry-2 via histopathologic analysis and reverse transcription-quantitative polymerase chain reaction analysis in mice with heatstroke. The heat-stressed mice were exposed to different core temperatures and cooling treatments, and intestinal pathological changes and Chiu scores were determined. Chemical markers of intestinal injury, serum and intestinal concentrations of diamine oxidase (DAO) and D-lactic acid (D-Lac), and serum and intestinal concentrations of Cry-2 were also determined. Correlations were analyzed using Spearman's correlation analysis. It was found that HS upregulated the expression of Cry-2, and the serum and intestinal concentrations of Cry-2 were correlated with the severity of HS-induced intestinal damage, indicated by pathology scores and concentrations of DAO and D-lac. Ulinastatin protected the intestines from HS-induced injury and downregulated the expression of Cry-2, which was also correlated with the extent of intestinal injury. Therefore, ulinastatin administration may be beneficial for patients with heatstroke, and Cry-2 may be a novel predictor of HS-induced intestinal injury.

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Section: Discussionmentioning

confidence: 99%

Cryptdin-2 predicts intestinal injury during heatstroke in mice

et al. 2017

Int J Mol Med

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“…The doses and administration form of crocin were derived from the pre-experiments and previous reports [19,20]. The LPS group mice were injected intraperitoneally with the LPS (20 mg/kg) for 6 h to induce ARDS [21]. For the crocin + LPS groups, crocin at 15, 30, or 60 mg/kg was administered intraperitoneally for 7 days prior to intraperitoneal injection of the LPS for 6 h. At the same time, the control group mice were treated intraperitoneally with the same volume of normal saline.…”

Section: Animals and Groupingmentioning

confidence: 99%

Crocin alleviates lipopolysaccharide-induced acute respiratory distress syndrome by protecting against glycocalyx damage and suppressing inflammatory signaling pathways

Zhang

Zhu

et al. 2020

Inflamm. Res.

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Objective To explore the mechanisms of crocin against glycocalyx damage and inflammatory injury in lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS) mice and LPS-stimulated human umbilical vein endothelial cells (HUVECs). Methods Mice were randomly divided into control, LPS, and crocin + LPS (15, 30, and 60 mg/kg) groups. HUVECs were separated into eight groups: control, crocin, matrix metalloproteinase 9 inhibitor (MMP-9 inhib), cathepsin L inhibitor (CTL inhib), LPS, MMP-9 inhib + LPS, CTL inhib + LPS, and crocin + LPS. The potential cytotoxic effect of crocin on HUVECs was mainly evaluated through methylthiazolyldiphenyl-tetrazolium bromide assay. Histological changes were assessed via hemotoxylin and eosin staining. Lung capillary permeability was detected on the basis of wet-dry ratio and through fluorescein isothiocyanate-albumin assay. Then, protein levels were detected through Western blot analysis, immunohistochemical staining, and immunofluorescence. Results This study showed that crocin can improve the pulmonary vascular permeability in mice with LPS-induced ARDS and inhibit the inflammatory signaling pathways of high mobility group box, nuclear factor κB, and mitogen-activated protein kinase in vivo and in vitro. Crocin also protected against the degradation of endothelial glycocalyx heparan sulfate and syndecan-4 by inhibiting the expressions of CTL, heparanase, and MMP-9 in vivo and in vitro. Overall, this study revealed the protective effects of crocin on LPS-induced ARDS and elaborated their underlying mechanism. Conclusion Crocin alleviated LPS-induced ARDS by protecting against glycocalyx damage and suppressing inflammatory signaling pathways.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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“…It has been reported that DF initiates EC dysfunction, which leads to the progression of the disease . Previous reports rarely consider that DF is a contributing factor to GCX degradation . On average, components of the GCX in both humans and animals degrade and regenerate on a daily basis and in a balanced manner .…”

Section: Discussionmentioning

confidence: 99%

“…We next attempted to investigate the effects of GCX degradation in the presence of stable E‐selectin coverage. It is possible to achieve systemic GCX knockdown by pro‐inflammatory cytokines or enzymes that increase reactive oxygen species and matrix metalloproteinases activities . These agents are naturally released in certain disease settings including atherosclerosis, ischemia/reperfusion, and cancer .…”

Section: Discussionmentioning

confidence: 99%

Flow‐regulated endothelial glycocalyx determines metastatic cancer cell activity

et al. 2020

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Cancer metastasis and secondary tumor initiation largely depend on circulating tumor cell (CTC) and vascular endothelial cell (EC) interactions by incompletely understood mechanisms. Endothelial glycocalyx (GCX) dysfunction may play a significant role in this process. GCX structure depends on vascular flow patterns, which are irregular in tumor environments. This work presents evidence that disturbed flow (DF) induces GCX degradation, leading to CTC homing to the endothelium, a first step in secondary tumor formation. A 2‐fold greater attachment of CTCs to human ECs was found to occur under DF conditions, compared to uniform flow (UF) conditions. These results corresponded to an approximately 50% decrease in wheat germ agglutinin (WGA)‐labeled components of the GCX under DF conditions, vs UF conditions, with undifferentiated levels of CTC‐recruiting E‐selectin under DF vs UF conditions. Confirming the role of the GCX, neuraminidase induced the degradation of WGA‐labeled GCX under UF cell culture conditions or in Balb/C mice and led to an over 2‐fold increase in CTC attachment to ECs or Balb/C mouse lungs, respectively, compared to untreated conditions. These experiments confirm that flow‐induced GCX degradation can enable metastatic CTC arrest. This work, therefore, provides new insight into pathways of secondary tumor formation.

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Ulinastatin attenuates pulmonary endothelial glycocalyx damage and inhibits endothelial heparanase activity in LPS-induced ARDS

Cited by 42 publications

References 28 publications

Cryptdin-2 predicts intestinal injury during heatstroke in mice

Cryptdin-2 predicts intestinal injury during heatstroke in mice

Crocin alleviates lipopolysaccharide-induced acute respiratory distress syndrome by protecting against glycocalyx damage and suppressing inflammatory signaling pathways

Flow‐regulated endothelial glycocalyx determines metastatic cancer cell activity

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