Agonist of peroxisome proliferator-activated receptor gamma (PPAR-gamma): a new compound with potent gastroprotective and ulcer healing properties.
Pioglitazone, a specific ligand for peroxisome proliferator-activated receptor gamma (PPAR-gamma), was recently implicated in the control of inflammatory processes and in the modulation of the expression of various cytokines such as tumor necrosis factor alpha (TNF-alpha), but its role in the mechanism of gastric mucosal integrity has not been studied extensively. This study was designed to determine the effect of pioglitazone on gastric mucosal lesions induced in rats by topical application of 100% ethanol and by 3.5 h of water immersion and restraint stress (WRS) with or without pretreatment with indomethacin (5 mg/kg i.p.) to inhibit cyclooxygenase-1 (COX-1) and COX-2 enzyme activities and L-NNA (20 mg/kg i.p.) to suppress nitric oxide (NO)-synthase. In addition, the effect of pioglitazone on ulcer healing in rats with chronic acetic acid ulcers (ulcer area 28 mm2) was determined. Rats were killed 1 h and 3.5 h after ethanol administration or WRS exposure or at day 9 upon ulcer induction, and the number and area of gastric lesions were measured by planimetry, the gastric blood flow (GBF) was determined by H2-gas clearance technique and the mucosal PGE2 generation and gene expression and plasma concentration of TNF-alpha and IL-1beta were also evaluated. Pre-treatment with pioglitazone dose-dependently attenuated gastric lesions induced by 100% ethanol and WRS; the dose reducing these lesions by 50% (ID50) being 10 mg/kg and 7 mg/kg, respectively. The protective effect of pioglitazone was accompanied by the significant rise in the GBF, an increase in PGE2 generation and the significant fall in the plasma TNF-alpha and IL-1beta levels. Strong signals for IL-1beta- and TNF-alpha mRNA were recorded in gastric mucosa exposed to ethanol or WRS, and these effects were significantly decreased by pioglitazone. Indomethacin which suppressed PG generation by about 90%, while augmenting WRS damage, and L-NNA, that suppressed NO-synthase activity, significantly attenuated the protective and hyperaemic activity of this PPAR-gamma ligand. In the chronic study, pioglitazone significantly reduced the area of gastric ulcers on day 9 and significantly raised the GBF at the ulcer margin. The acceleration of ulcer healing by PPAR-gamma ligand was accompanied by a significant increase in the expression of PECAM-1 protein, a marker of angiogenesis. We conclude that (1) pioglitazone exerts a potent gastroprotective and hyperaemic actions on the stomach involving endogenous PG and NO and attenuation of the expression and release of proinflammatory cytokines TNF-alpha and IL-1beta, and (2) PPAR-gamma ligand accelerates ulcer healing, possibly due to the enhancement in angiogenesis at ulcer margin.
Brzozowski
Tomasz
T
Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland. mpbrzozo@cyf-kr.edu.pl
Konturek
Peter C
PC
Pajdo
Robert
R
Kwiecień
Slawomir N
SN
Konturek
Stanislaw
S
Targosz
Aneta
A
Burnat
Grzegorz
G
Cieszkowski
Jakub
J
Pawlik
Wieslaw W
WW
Hahn
Eckhart G
EG
D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001783:Blood Flow Velocity / Q000187:drug effects; D015153:Blotting, Western; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects / Q000293:injuries; D015870:Gene Expression / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000097:blood / Q000235:genetics; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012149:Restraint, Physical / Q000009:adverse effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013276:Stomach Ulcer / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects
D000897:Anti-Ulcer Agents; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D047495:PPAR gamma; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D019335:Nitroarginine; D000431:Ethanol; D019001:Nitric Oxide Synthase; D015232:Dinoprostone; D000077205:Pioglitazone; D007213:Indomethacin