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Matrix metalloproteinase-9 modulates intestinal injury in rats with transmural colitis
Carlos Medina1, Alfredo Santana, Maria Cristina Paz
1Servicios de Gastroenterología y, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain.
Abstract:
Proteolysis and degradation of extracellular matrix by metalloproteinases (MMPs) may contribute to intestinal injury in inflammatory bowel disease. In the present study, we investigated the pathogenic role of gelatinases (MMP-9 and MMP-2) on transmural colonic injury in a rat model of chronic colitis, which was induced by intracolonic instillation of trinitrobenzene sulfonic acid (TNBS). The activity and expression of MMP-2 and MMP-9 were measured in colonic tissue and peripheral neutrophils by fluorescence, zymography, Western blot, or immunohistochemistry at different time-points. Furthermore, myeloperoxidase content in colonic homogenates was analyzed to evaluate inflammation. Finally, morphological changes were assessed following early or delayed administration of CGS-27023-A, a synthetic inhibitor of MMPs. We found that the induction of colitis led to a significant up-regulation in tissue gelatinase concentration, whereas no changes in collagenase activity were observed. In addition, up-regulation of pro-MMP-9, but not of pro-MMP-2, was found on Days 7 and 10 following the induction of colitis. Furthermore, transmural MMP-9 was detected by immunofluorescent staining in the inflamed tissue. Consistent with tissue samples, neutrophils from colitic rats showed a significantly increased activity of pro-MMP-9. Finally, early but not delayed treatment with CGS-27023-A attenuated colonic mucosal injury in rats with TNBS-induced colitis. In conclusion, up-regulation of MMP-9 in peripheral and colonic neutrophils modulates transmural colonic injury in rats with TNBS-induced colitis.
Insights
Matrix metalloproteinases (MMPs) contribute to inflammatory bowel disease. This study shows matrix metalloproteinase-9 (MMP-9) up-regulation in neutrophils exacerbates colonic injury in a rat colitis model, suggesting MMP-9 inhibition as a therapeutic target.
Area of Science:
- Gastroenterology
- Molecular Biology
- Immunology
Background:
- Extracellular matrix degradation by matrix metalloproteinases (MMPs) is implicated in inflammatory bowel disease (IBD) pathogenesis.
- Gelatinases, specifically MMP-9 and MMP-2, are key MMPs involved in tissue remodeling and inflammation.
Purpose of the Study:
- To investigate the role of gelatinases (MMP-9 and MMP-2) in transmural colonic injury in a rat model of chronic colitis induced by trinitrobenzene sulfonic acid (TNBS).
- To evaluate the therapeutic potential of a synthetic MMP inhibitor, CGS-27023-A.
Main Methods:
- Induction of chronic colitis in rats using TNBS.
- Measurement of MMP-2 and MMP-9 activity and expression in colonic tissue and peripheral neutrophils using zymography, Western blot, and immunohistochemistry.
- Assessment of myeloperoxidase content for inflammation and morphological changes.
- Administration of CGS-27023-A at early or delayed time points.
Main Results:
- Colitis induction led to significant up-regulation of gelatinase concentration in colonic tissue.
- Pro-MMP-9, but not pro-MMP-2, was significantly up-regulated in colonic tissue and neutrophils from colitic rats.
- Transmural MMP-9 was detected in inflamed tissue, and neutrophils showed increased pro-MMP-9 activity.
- Early administration of CGS-27023-A attenuated colonic mucosal injury, while delayed treatment did not.
Conclusions:
- Up-regulation of MMP-9 in peripheral and colonic neutrophils plays a significant role in modulating transmural colonic injury in TNBS-induced colitis.
- Targeting MMP-9, particularly with early intervention, may be a promising therapeutic strategy for inflammatory bowel disease.
