title: Enhancing apoptotic cell clearance mitigates bacterial translocation             and promotes tissue repair after gut ischemia-reperfusion injury.
abstract: A key aspect of intestinal ischemia/reperfusion (I/R) injury is the increased occurrence of apoptotic cell death in the gut. Insufficient clearance of apoptotic cells leads to increased inflammation and impaired tissue repair. Our recent studies have shown that administration of milk fat globule-epidermal growth factor-factor 8 (MFG-E8), a crucial molecule for apoptotic cell clearance, reduces apoptosis and inflammation under various disease conditions. The purpose of this study was to determine whether MFG-E8 reduces bacterial translocation and promotes tissue repair in a mouse model of gut I/R. Gut ischemia was induced by placing a microvascular clip across the superior mesenteric artery for 90 min in male adult mice. After removing the clip, recombinant murine MFG-E8 (rmMFG-E8) (0.4 µg/20 g BW) or normal saline (Vehicle) was intraperitoneally injected. At 4 h after reperfusion, apoptosis in the gut was measured by TUNEL staining. The mesenteric lymph node (MLN) complex was homogenized and plated on chocolate agar plates for bacterial culture. Neutrophil infiltration was assessed by examining myeloperoxidase (MPO) activity in the gut. Vascular endothelial growth factor (VEGF) levels in the gut, an indicator of tissue repair, were measured by western blotting. Out results showed that TUNEL-positive staining in the gut increased significantly in gut I/R vehicle-treated mice. Treatment with rmMFG-E8 markedly suppressed the number of apoptotic cells. Bacterial translocation to the MLN was minimal in sham mice, but was extensive in gut I/R vehicle-treated mice. rmMFG-E8 treatment significantly reduced bacterial translocation to the MLN. Similarly, gut I/R induced a significant increase in intestinal MPO activities in vehicle-treated mice. rmMFG-E8 treatment markedly reduced the increase in intestinal MPO activities after gut I/R. Intestinal levels of VEGF decreased significantly at 4 h after gut I/R. rmMFG-E8 treatment significantly increased intestinal VEGF levels. Thus, enhancing apoptotic cell clearance by rmMFG-E8 mitigates bacterial translocation, inhibits neutrophil infiltration and promotes tissue repair after gut I/R. Enhancing apoptotic cell clearance can be a novel concept in the treatment of gut I/R injury.
authors: Laboratory of Surgical Research, The Feinstein Institute for Medical Research and Department of Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, Manhasset, NY 11030 , USA.
authors: Rongqian
authors: R
authors: Wu
authors: Weifeng
authors: W
authors: Dong
authors: Zhimin
authors: Z
authors: Wang
authors: Asha
authors: A
authors: Jacob
authors: Tianpen
authors: T
authors: Cui
authors: Ping
authors: P
authors: Wang
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D018988:Bacterial Translocation / Q000187:drug effects; D004195:Disease Models, Animal; D007413:Intestinal Mucosa / Q000378:metabolism*; D007421:Intestine, Small / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D007422:Intestines / Q000382:microbiology* / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects / Q000382:microbiology; D008297:Male; D008643:Mesentery; D051379:Mice; D008894:Milk Proteins / Q000378:metabolism / Q000494:pharmacology; D020556:Neutrophil Infiltration / Q000187:drug effects; D015427:Reperfusion Injury / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing
chemical_list: D000954:Antigens, Surface; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D042461:Vascular Endothelial Growth Factor A