Comparative effects of glucagon-like peptide-2 (GLP-2), growth hormone (GH), and keratinocyte growth factor (KGF) on markers of gut adaptation after massive small bowel resection in rats

被引:53
作者
Washizawa, N
Gu, LH
Gu, L
Openo, KP
Jones, DP
Ziegler, TR
机构
[1] Toho Univ, Sch Med, Dept Surg, Tokyo, Japan
[2] Emory Univ, Sch Med, Dept Med, Atlanta, GA 30322 USA
[3] Emory Univ, Sch Med, Ctr Clin & Mol Nutr, Atlanta, GA 30322 USA
关键词
D O I
10.1177/0148607104028006399
中图分类号
R15 [营养卫生、食品卫生]; TS201 [基础科学];
学科分类号
100403 ;
摘要
Background: Administration of specific growth factors exert gut-trophic effects in animal models of massive small bowel resection (SBR); however, little comparative data are available. Our aim was to compare effects of a human glucagon-like peptide-2 (GLP-2) analog, recombinant growth hormone (GH) and recombinant keratinocyte growth factor (KGF) on jejunal, ileal, and colonic growth and functional indices after 80% SBR in rats. Methods: Thirty-seven male rats underwent small bowel transection (sham operation) with s.c. saline administration (control; Tx-S; n = 7) or 80% midjejuno-ileal resection (Rx) and treatment with either s.c. saline (Rx-S, n = 7), GLP-2 at 0.2 mg/kg/d (Rx-GLP-2; n = 8), GH at 3.0 mg/kg/d (Rx-GH; n = 8), or KGF at 3.0 (Rx-KGF; n = 7) for 7 days. All groups were pair-fed to intake of Rx-S rats. Gut mucosal cell growth indices (wet weight, DNA and protein content, villus height, crypt depth, and total mucosal height) were measured. Expression of the cytoprotective trefoil peptide TFF3 was determined by Western blot. Gut mucosal concentrations of the tripeptide glutathione (L-glutamyl-L-cysteinyl-glycine) and glutathione disulfide (GSSG) were measured by high-performance liquid chromatography and the glutathione/GSSG ratio calculated. Results: SBR increased adaptive growth indices in jejunal, ileal, and colonic mucosa. GLP-2 treatment increased jejunal villus height and jejunal total mucosal height compared with effects of resection alone or resection with GH or KGF treatment. Both GH and KGF modestly increased colonic crypt depth after SBR. SBR did not affect small bowel or colonic goblet cell number or TFF3 expression; however, goblet cell number and TFF3 expression in both small bowel and colon were markedly up-regulated by KGF treatment and unaffected by GLP-2 and GH. SBR oxidized the ileal and colonic mucosal glutathione/GSSG redox pools. GLP-2 treatment after SBR increased the glutathione/GSSG ratio in jejunum, whereas KGF had an intermediate effect. In addition, GLP-2 (but not GH or KGF) prevented the SBR-induced oxidation of the glutathione/GSSG pools in both ileum and colon. Conclusions: GLP-2 exerts superior trophic effects on jejunal growth and also improves mucosal glutathione redox status throughout the bowel after massive SBR in rats. Both GH and KGF increase colonic mucosal growth in this model. KGF alone potently increases gut mucosal goblet cell number and expression of the cytoprotective trefoil peptide TFF3. The differential effects of GLP-2, GH and KGF administration in this model of short bowel syndrome suggest that individual therapy with these growth factors may not be an adequate strategy to maximally improve adaptive gut mucosal growth and cytoprotection after massive small intestinal resection. Future research should address the use of these agents in combination in short bowel syndrome.
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页码:399 / 409
页数:11
相关论文
共 65 条
  • [1] Growth factors regulation of rabbit sodium-dependent neutral amino acid transporter ATB0 and oligopeptide transporter 1 mRNAs expression after enterectomy
    Avissar, NE
    Ziegler, TR
    Wang, HT
    Gu, LH
    Miller, JNH
    Iannoli, P
    Leibach, FH
    Ganapathy, V
    Sax, HC
    [J]. JOURNAL OF PARENTERAL AND ENTERAL NUTRITION, 2001, 25 (02) : 65 - 72
  • [2] STIMULATION BY RECOMBINANT HUMAN GROWTH-HORMONE OF GROWTH AND DEVELOPMENT OF REMAINING BOWEL AFTER SUBTOTAL ILEOJEJUNECTOMY IN RATS
    BENHAMOU, PH
    CANARELLI, JP
    LEROY, C
    DEBOISSIEU, D
    DUPONT, C
    [J]. JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION, 1994, 18 (04) : 446 - 452
  • [3] Human recombinant growth hormone increases small bowel lengthening after massive small bowel resection in piglets
    Benhamou, PH
    Canarelli, JP
    Richard, S
    Cordonnier, C
    Postel, JP
    Grenier, E
    Leke, A
    Dupont, C
    [J]. JOURNAL OF PEDIATRIC SURGERY, 1997, 32 (09) : 1332 - 1336
  • [4] Glucagon-like peptide-2 enhances intestinal epithelial barrier function of both transcellular and paracellular pathways in the mouse
    Benjamin, MA
    McKay, DM
    Yang, PC
    Cameron, H
    Perdue, MH
    [J]. GUT, 2000, 47 (01) : 112 - 119
  • [5] BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
  • [6] AGA technical review on short bowel syndrome and intestinal transplantation
    Buchman, AL
    Scolapio, J
    Fryer, J
    [J]. GASTROENTEROLOGY, 2003, 124 (04) : 1111 - 1134
  • [7] GLP-2 stimulates intestinal growth in premature TPN-fed pigs by suppressing proteolysis and apoptosis
    Burrin, DG
    Stoll, B
    Jiang, R
    Petersen, Y
    Elnif, J
    Buddington, RK
    Schmidt, M
    Holst, JJ
    Hartmann, B
    Sangild, PT
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 2000, 279 (06): : G1249 - G1256
  • [8] A NEW TREATMENT FOR PATIENTS WITH SHORT-BOWEL SYNDROME - GROWTH-HORMONE, GLUTAMINE, AND A MODIFIED DIET
    BYRNE, TA
    PERSINGER, RL
    YOUNG, LS
    ZIEGLER, TR
    WILMORE, DW
    [J]. ANNALS OF SURGERY, 1995, 222 (03) : 243 - 255
  • [9] Prevention of parenteral nutrition-induced gut hypoplasia by coinfusion of glucagon-like peptide-2
    Chance, WT
    FoleyNelson, T
    Thomas, I
    Balasubramaniam, A
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 1997, 273 (02): : G559 - G563
  • [10] IGF-I augments resection-induced mucosal hyperplasia by altering enterocyte kinetics
    Dahly, EM
    Guo, ZW
    Ney, DM
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 2003, 285 (04) : R800 - R808