title: Matrix metalloproteinase-9 inhibition reduces inflammation and improves motility in murine models of postoperative ileus.
abstract: OBJECTIVE
  Matrix metalloproteinase (MMP)-9, a member of the gelatinase family of MMPs, mediates leukocyte migration during inflammation. Inflammation contributes to development of postoperative ileus (POI), which is caused by physical disturbances to the bowel during abdominal surgery. We evaluated the role of MMP-9 in POI and investigated whether disruption of MMP-9 or administration of an inhibitor of MMP-9 activity reduced cellular inflammation and bowel dysmotility in rat and mouse models of POI.
  
  
  METHODS
  Mice and rats underwent laparotomy and bowel manipulation; bowel tissues were collected 3 to 24 hours later and analyzed by real-time reverse-transcriptase polymerase chain reaction, immunoblot, in situ zymography, and functional analyses.
  
  
  RESULTS
  Bowel manipulation resulted in a time-dependent increase in MMP-9 expression within the intestinal muscularis; increases in MMP-9 messenger RNA were inducible nitric oxide synthase dependent. Immunoblot analyses confirmed the presence of the proenzyme and the catalytically active form of MMP-9. Administration of MMP-2/MMP-9 II, a dual active-site inhibitor, reduced the number of myeloperoxidase-positive immune cells that infiltrated the muscularis and prevented the surgically induced reduction in bowel smooth muscle contractility. Zymography analysis, performed in muscularis whole mounts in situ, indicated that MMP-9 and not MMP-2 mediated the gelatinase activity observed in infiltrating cells. MMP-9 knockout mice were protected from the inflammation and dysmotility associated with POI.
  
  
  CONCLUSIONS
  MMP-9 mediates cellular inflammatory responses within the intestinal muscularis in mouse and rat models of POI. Inhibition of MMP-9 activity reduced recruitment of immune cells to the intestinal muscularis, preventing loss of smooth muscle contractility. Induction of MMP-9 expression requires inducible nitric oxide synthase.
authors.affiliation: Johnson & Johnson Pharmaceutical Research Division, Spring House, Pennsylvania, USA.
authors.forename: Beverley A
authors.initials: BA
authors.lastname: Moore
authors.forename: Carl L
authors.initials: CL
authors.lastname: Manthey
authors.forename: Dana L
authors.initials: DL
authors.lastname: Johnson
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Bauer
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology / Q000601:surgery; D004195:Disease Models, Animal; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D045823:Ileus / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D007421:Intestine, Small / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology / Q000601:surgery; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D011183:Postoperative Complications / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D011480:Protease Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D005765:Gastrointestinal Agents; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9