Role of leptin in ulcer healing.
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 gastric 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 (TGFalpha). Gastric ulcers were produced in rats by the acetic acid method. Rats with ulcers were divided in following treatment groups: (1) vehicle; (2) leptin (10 microg/kg i.p.); (3) CCK (10 microg/kg s.c.); and (4) leptin or CCK with or without tyrphostin A46 (200 microg/kg i.p.), an inhibitor of epidermal growth factor (EGF)-receptor tyrosine kinase or NG-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 determined. In addition, mucosal biopsy samples were taken from the ulcer area for histological evaluation as well as for the determination of mRNA and protein expression for leptin and constitutive nitric oxide synthase (cNOS) and inducibile nitric oxide synthase (iNOS) by reverse-transcriptase polymerase chain reaction (RT-PCR) and Western blot, respectively. In addition, the gene expression for TGFalpha was analyzed by RT-PCR. Both leptin and CCK reduced significantly the ulcer area as compared to vehicle-treated group by approximately 50%. The treatment with tyrphostin or N(G)-nitro-L-arginine reversed in part the acceleration of ulcer healing by leptin and CCK. The expression of leptin mRNA and protein was significantly increased at the ulcer edge. The leptin-induced acceleration of ulcer healing was associated with increased expression of transcripts for TGFalpha 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 TGFalpha and increased production of nitric oxide due to up-regulation of cNOS and iNOS in the ulcer area.
Konturek
P C
PC
Department of Medicine I, University Erlangen-Nuremberg, Krankenhausstr. 12, D-91054, Erlangen, Germany. PKonturek@aol.com
Brzozowski
T
T
Sulekova
Z
Z
Brzozowska
I
I
Duda
A
A
Meixner
H
H
Hahn
E G
EG
Konturek
S J
SJ
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D005765:Gastrointestinal Agents / Q000627:therapeutic use; D020738:Leptin / Q000378:metabolism* / Q000627:therapeutic use; D008297:Male; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D019335:Nitroarginine / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012844:Sincalide / Q000627:therapeutic use; D013276:Stomach Ulcer / Q000188:drug therapy / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000187:drug effects / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology
D004791:Enzyme Inhibitors; D005765:Gastrointestinal Agents; D020738:Leptin; D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D020032:Tyrphostins; C086599:tyrphostin A46; D019335:Nitroarginine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; C496322:Nos1 protein, rat; C496316:Nos3 protein, rat; D012844:Sincalide