Novel role of famotidine in downregulation of matrix metalloproteinase-9 during protection of ethanol-induced acute gastric ulcer.
Gastric ulcer is a multifaceted process including acid secretion, reactive oxygen species generation, prostaglandin inhibition, and extracellular matrix (ECM) degradation. Matrix metalloproteinases (MMPs) have the ability to cleave and remodel the ECM. We investigated the activity and expression of MMP-9 and -2 in ethanol-induced acute gastric ulceration in rats. We found that severity of gastric ulcer was strongly correlated with increasing doses of ethanol and increased secretion of proMMP-9. ProMMP-9 was upregulated approximately 25-fold at maximum ulcer index. Increased secretion of proMMP-9 was associated with increased expression of tumor necrosis factor-alpha and interleukin-6. We examined the effect of H(2)-receptor antagonists and antioxidants on proMMP-9 secretion and synthesis during prevention of ethanol-induced gastric ulcer. Our data reveal that famotidine dose dependently blocked increased secretion and synthesis of proMMP-9 during gastroprotection and arrested infiltration of inflammatory cells as well as oxidative stress in rat gastric tissues. Similar to H(2)-receptor antagonists, N-acetylcysteine and dimethyl sulfoxide, well-known antioxidants, inhibited proMMP-9 upregulation to the control level. In conclusion, ethanol-induced gastric ulceration is associated with increased expression of proMMP-9 that can be attenuated by H(2)-receptor antagonists and antioxidants. These findings furnish a novel MMP-9-mediated pathway and its inhibition via proinflammatory cytokines by famotidine in ethanol-induced gastric ulceration.
Pradeepkumar Singh
Laishram
L
Department of Physiology, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India.
Kundu
Parag
P
Ganguly
Krishnendu
K
Mishra
Amartya
A
Swarnakar
Snehasikta
S
D000208:Acute Disease; D000818:Animals; D000897:Anti-Ulcer Agents / Q000627:therapeutic use*; D016207:Cytokines / Q000502:physiology; D004195:Disease Models, Animal; D000431:Ethanol / Q000633:toxicity*; D015738:Famotidine / Q000627:therapeutic use*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D007249:Inflammation / Q000517:prevention & control; D007700:Kinetics; D015227:Lipid Peroxidation / Q000187:drug effects; D008666:Metalloendopeptidases / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D000096122:Mitochondrial Processing Peptidase
D000897:Anti-Ulcer Agents; D016207:Cytokines; D000431:Ethanol; D015738:Famotidine; D008666:Metalloendopeptidases; D000096122:Mitochondrial Processing Peptidase