Role of leptin in ulcer healing

Citation
Pc. Konturek et al., Role of leptin in ulcer healing, EUR J PHARM, 414(1), 2001, pp. 87-97
Citations number
40
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
EUROPEAN JOURNAL OF PHARMACOLOGY
ISSN journal
0014-2999 → ACNP
Volume
414
Issue
1
Year of publication
2001
Pages
87 - 97
Database
ISI
SICI code
0014-2999(20010223)414:1<87:ROLIUH>2.0.ZU;2-V
Abstract
Leptin was shown to exhibit similar to cholecystokinin (CCK) cytoprotective activity against acute gastric lesions, but its role in ulcer healing has not been examined. The aims of this study were: (1) to compare the effects of exogenous leptin to those of CCK on the course of healing of chronic gas tric ulcers; (2) to study the gene and protein expression of leptin at the ulcer margin during ulcer healing; and (3) to assess the effects of leptin administration on the mucosal gene expression of main growth factor such as transforming growth factor alpha (TGF alpha). Gastric ulcers were produced in rats by the acetic acid method. Rats with ulcers were divided in follow ing treatment groups: (1) vehicle; (2) leptin (10 mug/kg i.p.); (3) CCK (10 mug/kg s.c.); and (4) leptin or CCK with or without tyrphostin A46 (200 mu g/kg i.p.), an inhibitor of epidermal growth factor (EGF)-receptor tyrosine kinase or N-G-nitro-L-arginine (20 mg/kg i.g.), a blocker of nitric oxide synthase. Animals were euthanized 9 days after ulcer induction. The area of gastric ulcers and the gastric blood flow at the ulcer area were determine d. In addition, mucosal biopsy samples were taken from the ulcer area for h istological evaluation as well as for the determination of mRNA and protein expression for leptin and constitutive nitric oxide synthase (cNOS) and in ducibile nitric oxide synthase (iNOS) by reverse-transcriptase polymerase c hain reaction (RT-PCR) and Western blot, respectively. In addition, the gen e expression for TGF alpha was analyzed by RT-PCR. Both leptin and CCK redu ced significantly the ulcer area as compared to vehicle-treated group by si milar to 50%. The treatment with tyrphostin or N-G-nitro-L-arginine reverse d in part the acceleration of ulcer healing by leptin and CCK. The expressi on of leptin mRNA and protein was significantly increased at the ulcer edge . The leptin-induced acceleration of ulcer healing was associated with incr eased expression of transcripts for TGF alpha as well as increased mRNA and protein expression for cNOS and iNOS at the ulcer margin. We conclude that leptin accelerates ulcer healing by mechanisms involving the up-regulation of TGF alpha and increased production of nitric oxide due to up-regulation of cNOS and iNOS in the ulcer area. (C) 2001 Elsevier Science B.V. All rig hts reserved.