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Updated: May 10, 2026
Functional Assessment of Intestinal Motility and Gut Wall Inflammation in Rodents: Analyses in a Standardized Model of Intestinal Manipulation
Published on: September 11, 2012
Matrix metalloproteinase-9 inhibition reduces inflammation and improves motility in murine models of postoperative
Beverley A Moore1, Carl L Manthey, Dana L Johnson
1Johnson & Johnson Pharmaceutical Research Division, Spring House, Pennsylvania, USA.
Background & Aims:
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.
Insights
Matrix metalloproteinase-9 (MMP-9) drives inflammation and bowel dysfunction in postoperative ileus (POI). Inhibiting MMP-9 reduces immune cell infiltration and restores smooth muscle function in animal models.
Area of Science:
- Gastroenterology
- Immunology
- Surgical Research
Background:
- Postoperative ileus (POI) is a common complication following abdominal surgery.
- Inflammation, mediated by matrix metalloproteinase-9 (MMP-9), plays a key role in POI development.
- MMP-9 is a gelatinase involved in leukocyte migration during inflammatory processes.
Purpose of the Study:
- To evaluate the role of MMP-9 in the pathogenesis of POI.
- To investigate if inhibiting MMP-9 activity or disrupting MMP-9 can reduce inflammation and bowel dysmotility in POI models.
- To determine the relationship between MMP-9 induction and inducible nitric oxide synthase (iNOS).
Main Methods:
- Animal models (rats and mice) of POI were established using laparotomy and bowel manipulation.
- Bowel tissues were analyzed for MMP-9 expression and activity using molecular and biochemical techniques (RT-PCR, immunoblot, in situ zymography).
- Functional analyses assessed smooth muscle contractility and immune cell infiltration (myeloperoxidase staining).
Main Results:
- Bowel manipulation significantly increased MMP-9 expression in the intestinal muscularis, dependent on iNOS.
- Administration of an MMP-2/MMP-9 inhibitor reduced immune cell infiltration and preserved smooth muscle contractility.
- Mice lacking MMP-9 (knockout) were protected from POI-induced inflammation and dysmotility.
- In situ zymography confirmed MMP-9, not MMP-2, as the primary mediator of gelatinase activity in infiltrating cells.
Conclusions:
- MMP-9 is a critical mediator of inflammation and smooth muscle dysfunction in POI.
- Inhibiting MMP-9 activity effectively reduces immune cell recruitment and prevents loss of intestinal contractility.
- Inducible nitric oxide synthase is required for the induction of MMP-9 expression in POI.
