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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
Naohiro Washizawa, MD*, ,
Li H. Gu, MD,
Liang Gu, BS,
Kyle P. Openo, MPH,
Dean P. Jones, PhD, and
Thomas R. Ziegler, MD,
From the * Department of Surgery, Toho University
School of Medicine, Tokyo, Japan; and the
Department of Medicine and
Center for Clinical and Molecular Nutrition,
Emory University School of Medicine, Atlanta, Georgia
Correspondence: Thomas R. Ziegler, MD, Suite GG-23, General Clinical Research
Center, Emory University Hospital, 1364 Clifton Rd., Atlanta, GA 30322.
Electronic mail may be sent to
tzieg01{at}emory.edu.
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
mg/kg/d (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.
Journal of Parenteral and Enteral Nutrition, Vol. 28, No. 6,
399-409 (2004)
DOI: 10.1177/0148607104028006399
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