Heparanase Mediates Intestinal Inflammation and Injury in a Mouse Model of Sepsis.
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 sepsis-induced 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.
Department of Emergency Medicine (SC, CL), The First Affiliated Hospital of Hainan Medical College, Haikou, People's Republic of China.
Song
S
Chen
Department of Geratology (YH), The First Affiliated Hospital of Hainan Medical College, Haikou, People's Republic of China.
Ying
Y
He
Department of Critical Care Medicine, The First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China (ZH, XY, XM).
Ziwei
Z
Hu
Department of Critical Care Medicine, Peking University Cancer Hospital, Beijing, People's Republic of China (SL).
Siyu
S
Lu
Department of Critical Care Medicine, The First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China (ZH, XY, XM).
Xiaohan
X
Yin
Department of Critical Care Medicine, The First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China (ZH, XY, XM).
Xiaochun
X
Ma
Department of Emergency Medicine (SC, CL), The First Affiliated Hospital of Hainan Medical College, Haikou, People's Republic of China.
Chuanzhu
C
Lv
Department of Intervention Therapy (GJ), The First Affiliated Hospital of Hainan Medical College, Haikou, People's Republic of China.
Guiyun
G
Jin
D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006493:Heparin / Q000031:analogs & derivatives / Q000494:pharmacology; D006497:Heparan Sulfate / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D007422:Intestines / Q000276:immunology / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D018805:Sepsis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D053668:Syndecan-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D000099175:Heparanase
D016207:Cytokines; D005966:Glucuronidase; D006493:Heparin; D006497:Heparan Sulfate; D053583:Interleukin-1beta; D015850:Interleukin-6; D053668:Syndecan-1; D014409:Tumor Necrosis Factor-alpha; D000099175:Heparanase; C044153:heparin, N-desulfated
heparan sulfate; heparanase; intestinal injury; mucosal epithelial glycocalyx; sepsis; syndecan-1