Heparanase Mediates Intestinal Inflammation and Injury in a Mouse Model of Sepsis
Heparanase Mediates Intestinal Inflammation and Injury in a Mouse Model of Sepsis
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DOI：
10.1369/0022155417692536
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发表时间：
2017-04-01
影响因子：
3.2
通讯作者：
Jin, Guiyun
中科院分区：
文献类型：
--
作者：
Chen, Song;He, Ying;Jin, Guiyun
乙酰肝素酶是一种硫酸乙酰肝素 (HS) 特异性内切糖苷酶，在炎症中发挥重要作用，并介导脓毒症期间的急性肺和肾损伤。为了探讨其在脓毒性肠损伤中的作用，将一种非抗凝乙酰肝素酶抑制剂 N-脱硫/再-N-乙酰化肝素 (NAH) 给予盲肠结扎穿刺 (CLP) 诱导的小鼠脓毒症模型。免疫组织化学染色显示，CLP 后肠粘膜表面大量 HS 脱落，并且 NAH 有效抑制乙酰肝素酶，HS 脱落明显减少。 CLP后，肠道乙酰肝素酶表达增加，而NAH预处理减少了败血症诱导的乙酰肝素酶表达上调。同时，CLP导致肠道中syndecan-1的脱落并上调基质金属蛋白酶9和尿激酶型纤溶酶原激活剂等蛋白酶的表达，而NAH则显着抑制CLP后syndecan-1的脱落和蛋白酶的上调。此外，NAH预处理可减轻脓毒症期间肠道损伤，抑制中性粒细胞浸润并抑制肠道炎症细胞因子（肿瘤坏死因子-α、白细胞介素1β和白细胞介素6）的产生，并且还显着降低CLP后24小时血清中炎症细胞因子的升高。我们的研究结果表明，肠道乙酰肝素酶的激活通过促进粘膜上皮糖萼的破坏和促进炎症反应而导致早期脓毒症期间的肠道损伤。
Heparanase, 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-alpha, interleukin-1 beta, 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.