Matrix Metalloproteinases 2 and 9 in Indomethacin-Induced Rat Gastric Ulcer

Abstract

The restoration of functional connective tissue is a major goal of the wound healing process. The 72- and 92-kD gelatinases (MMP-2 and MMP-9) are extracellular matrix metalloproteinases (MMPs), which are known to degrade type IV and V collagens and gelatin, and have a potential role in wound healing. The spatial and temporal gelatinolytic activities of MMP-2 and MMP-9 were analyzed as a function of ulcer age, in homogenates of rat, indomethacin-induced, chronic gastric ulcers. The rats were sacrificed on 1, 3, 7, 12, 18, 24 and 28 days after subcutaneous indomethacin injections. Zymographic analyses revealed elevated activation of MMP-9 and latent and active MMP-2 in gastric ulcers, when compared to gastric tissue from non-indomethacin-treated rats. The intact tissue and tissue from ulcerous lesions contained MMP-2. The highest activity of MMP-2 was found in 3 day gastric ulcers and returned to the control level by day 24. MMP-9 was not present in the intact tissue and the highest gelatinolytic activity of MMP-9 was also observed on the 3rd day after administration of indomethacin. The activity thereafter decreased and returned to the control level by day 24. In situ hybridization was used to evaluate which cells synthesize MMP-2 and MMP-9. MMP-2 was seen mostly in fibroblast-like cells in the submucosa and MMP-9 in macrophage-like cells in the mucosa on the margins of the ulcers. Thus, we conclude that these two MMPs seem to have different functions during the gastric ulcer injury/healing process. MMP-2 may participate in the physiological turnover of the gastric extracellular matrix, whereas MMP-9 may be important in the early phase of gastric ulcer formation and also in the healing process.

Curcumin Regulates Expression and Activity of Matrix Metalloproteinases 9 and 2 during Prevention and Healing of Indomethacin-induced Gastric Ulcer

“…In addition, gastric lesions caused by indomethacin are due to overexpression of MMP-9 protein in damaged tissue. Lempinen et al (13) showed that indomethacin causes enhancement of MMP-9 as well as MMP-2 activity in chronic gastric ulcers in the rat model. In contrast we have consistently seen decreased MMP-2 activity and increased MMP-9 activity by indomethacin in a time-and dose-dependent manner in the acute ulcer model.…”

“…Increased lipid peroxidation, protein oxidation, and depletion of glutathione are the major indications of the oxidative damage of the gastric mucosal cells by indomethacin (8,11). However, very little is known about the involvement of MMP and TIMP expression in NSAID-induced gastric ulcer (12)(13)(14)(15). MMP-1 concentration is found to be significantly higher in H. pylori-induced ulcer compared with that of NSAIDs ulcer (12).…”

“…MMPs) in gastric ulceration have been implicated in few reports during the last few years (15,16), but the mechanistic basis is not very clear today. MMP-2 has been suggested to participate in the physiological turnover of the gastric ECM, whereas MMP-9 may be important in the early phase of indomethacin-induced chronic gastric ulcers (13). Very recently, Mori et al (17) reported MMP-9 induction through activation of NF-B in H. pylori-infected cultured gastric mucosal cells.…”

Protective Effects of Acetaminophen on Ibuprofen-Induced Gastric Mucosal Damage in Rats with Associated Suppression of Matrix Metalloproteinase

“…However, MMPs play a critical role in ECM degradation and remodeling during inflammation and wound-healing processes (Egeblad and Werb, 2002). Several studies describe the involvement of MMPs in degradation and remodeling of ECM during pathogenesis and healing of gastric ulcers (Lempinen et al, 2000;Shahin et al, 2001;Swarnakar et al, 2005;Sengupta and MacDonald, 2007). In particular, MMP-1, -8, -13, and -14 are responsible for cleavage of both collagen I and III, the major types of collagen in the stomach wall (Chakraborti et al, 2003;Yan and Boyd, 2007;Fanjul-Fernandez et al, 2010).…”

Cag Pathogenicity Island-independent Up-regulation of Matrix Metalloproteinases-9 and -2 Secretion and Expression in Mice by Helicobacter pylori Infection

“…MMPs, specifically gelatinase A (MMP-2, 72 kDa) and gelatinase B (MMP-9, 92 kDa) are responsible for degradation of type IV and V collagen, elastin, and fibronectin (23,24). MMP-2 is constitutively expressed and may participate in the remodeling of the ECM (23), while MMP-9 is important in degradation of ECM and basement membrane barriers during gastric ulcer and gastric cancer (25)(26)(27). In several inflammatory diseases such as rheu-matoid arthritis (28) and inflammatory bowel disease (29), MMPs substantially contribute to remodeling of connective tissues and stromal tissue destruction.…”