Heparanase Mediates Intestinal Inflammation and Injury in a Mouse Model of Sepsis

Abstract

SummaryHeparanase, a heparan sulfate (HS)-specific endoglycosidase, plays an important role in inflammation and mediates acute pulmonary and renal injuries during sepsis. To explore its role in septic intestinal injury, a non-anticoagulant heparanase inhibitor, N-desulfated/re-N-acetylated heparin (NAH), was administrated to a mouse sepsis model induced by cecal ligation and puncture (CLP). Immunohistochemical staining revealed massive shedding of HS from the intestinal mucosal surfaces after CLP, and effective inhibition of heparanase by NAH was confirmed by markedly reduced HS shedding. Following CLP, intestinal expression of heparanase was increased, whereas pretreatment with NAH reduced the sepsisinduced upregulation of heparanase expression. Meanwhile, CLP led to shedding of syndecan-1 and upregulated expression of proteases such as matrix metalloprotease-9 and urokinase-type plasminogen activator in the intestine, whereas NAH markedly suppressed syndecan-1 shedding and protease upregulation following CLP. In addition, pretreatment with NAH attenuated intestinal injury, inhibited neutrophil infiltration and suppressed the production of inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6) in the intestine during sepsis, and it also significantly reduced the elevation of inflammatory cytokines in the serum 24 hr after CLP. Our findings demonstrate that the activation of intestinal heparanase contributes to intestinal injury during early sepsis by facilitating the destruction of mucosal epithelial glycocalyx and promoting inflammatory responses. (J Histochem Cytochem 65:241-249, 2017)

Modulation of Intestinal Epithelial Glycocalyx Development by Human Milk Oligosaccharides and Non‐Digestible Carbohydrates

“…HS and HA are the major components of glycosaminoglycan in the glycocalyx . Both of them can regulate mechanotransduction and maintain gut barrier integrity . Interestingly, just like with HS also HA in the glycocalyx was increased by 3‐FL and not by 2′‐FL after 1 day of stimulation.…”

“…The different glycocalyx molecules can contribute in different ways to gut homeostasis. HS can mediate cell signaling by binding numerous extracellular ligands such as fibroblast growth factor and contributes to homeostasis of innate immunity . HA is highly viscous and forms a physical barrier on top of the gut epithelium .…”

Both UFH and NAH alleviate shedding of endothelial glycocalyx and coagulopathy in LPS‑induced sepsis

“…LPS, lipopolysaccharide; HS, heparan sulphate; SDC-1, syndecan-1; UFH, unfractionated heparin; NAH, N-acetylheparin; BDCA-3, thrombomodulin. injuries during sepsis (14,26). Heparan sulfates are the most common endothelial cell surface GAG, comprising 50-90% of the GAG pool.…”

­­The Effects of Vagus Nerve Stimulation Mediated Protection of Intestinal Epithelial Glycocalyx on Acute Lung Injury Associated With Traumatic Hemorrhagic Shock/Resuscitation

“…Glycocalyx could be damaged by in ammation factors and ischemia-reperfusion injury, the change of wall shear stress , the increase of cholesterol and decrease of high-density lipoprotein (27,(30)(31)(32).Previous studies showed that in ammation factors, such as matrix metalloproteinase-1 (MMP-1), MMP-7, MMP-15 and MMP-9, are capable of cleaving GCX components (9,30,(33)(34)(35)(36). Recently, many clinical trials demonstrated that the increase of other in ammatory factors, like IL-6, TNF-α, and the decrease of antiin ammatory, such as IL-10, also could damage glycocalyx (37,38).In this study, we found that there were extensive damage of glycocalyx on IECs after THS/R, and the level of IL-6, TNF-α and NF-κB in gut were increased.…”