Gastroenterology

Gastroenterology

Volume 120, Issue 4, March 2001, Pages 925-937
Gastroenterology

Alimentary Tract
Enhanced survival and mucosal repair after dextran sodium sulfate–induced colitis in transgenic mice that overexpress growth hormone,☆☆

https://doi.org/10.1053/gast.2001.22470Get rights and content

Abstract

Background & Aims: Growth hormone (GH) is used as therapy for inflammatory bowel disease (IBD), but the specific effects on intestine are unknown. Transgenic mice overexpressing GH (MT1-bGH-TG) were used to test whether increased plasma GH levels alter inflammation or crypt damage during dextran sodium sulfate (DSS)-induced colitis. Methods: MT1-bGH-TG and wild-type (WT) littermates were given 3% DSS for 5 days followed by up to 10 days of recovery. Colitis and epithelial cell proliferation were evaluated histologically. Plasma insulin-like growth factor (IGF)-I and colonic IGF-I, interleukin (IL)-1β, and intestinal trefoil factor (ITF) messenger RNAs (mRNAs) were measured. Results: DSS induced similar disease onset in MT1-bGH-TG and WT. More MT1-bGH-TG survived than WT. By recovery day 7, MT1-bGH-TG had less inflammation and crypt damage, elevated plasma IGF-I, and increased colonic ITF expression relative to WT. Colonic IL-1β was elevated in DSS-treated MT1-bGH-TG and WT, but IL-1β mRNA abundance correlated with disease only in WT. MT1-bGH-TG showed earlier increases in epithelial cell proliferation than WT during recovery but only WT showed atypical repair. Conclusions: GH does not alter susceptibility to acute DSS-induced colitis but enhances survival, remission of inflammation, and mucosal repair during recovery. GH therapy may be beneficial during active IBD by improving mucosal repair.

GASTROENTEROLOGY 2001;120:925-937

Section snippets

Transgenic mice

MT1-bGH-TG breeder pairs on a C57BL6/SJL genetic background were provided by Drs. Richard Palmiter, Ralph Brinster, and Richard Behringer.32 Hemizygous MT1-bGH-TG males were mated with WT C57BL6/SJL females (Jackson Laboratories, Bar Harbor, ME) to provide MT1-bGH-TG and WT littermates for the experiments. MT1-bGH-TG mice are readily distinguished from WT by increased body weight, which is evident by postnatal day 28. Genotype was verified on selected mice by polymerase chain reaction (PCR) on

GH excess enhances survival during DSS-induced colitis and recovery

All MT1-bGH-TG and WT mice survived 5 days of treatment with 4% DSS, but there was 25% mortality of MT1-bGH-TG mice and 50% mortality of WT mice during the 10 days after cessation of 4% DSS. Therefore, this dose of DSS was not used further. With a 3% dose of DSS, 100% of MT1-bGH-TG and WT mice survived the 5-day treatment with DSS. During recovery, 100% of MT1-bGH-TG (30 animals) survived the entire recovery phase, whereas 6 of 30 WT did not survive until the designated study time. MT1-bGH-TG

Discussion

This study shows that chronic elevation of plasma GH did not have a significant protective effect on the onset or severity of acute colitis induced by DSS or associated mucosal damage. GH excess did, however, improve survival during recovery from colitis, promote remission of inflammation, and enhance mucosal repair. The more precipitous weight loss in the WT mice that did not survive the recovery period compared with MT1-bGH-TG supports the concept that anabolic effects of GH to maintain body

Acknowledgements

The authors thank Dr. John Woosley for assistance with pathology, Eileen Hoyt for assistance with image analyses, Evonne Bruton for assistance with radioimmunoassays, Kirk McNaughton for assistance with histology, and Deborah Carver for secretarial assistance.

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    Supported by a predoctoral fellowship from the Howard Hughes Medical Foundation (to K.L.W.), a grant from the Crohn's and Colitis Foundation of America, and National Institutes of Health grant DK47709 (to P.K.L. and R.B.S.). The study was facilitated by the molecular histopathology core of the Center for Gastrointestinal Biology and Disease (NIH P30-DK-34987) and mouse pathology, tissue culture, and DNA synthesis cores of the Lineberger Cancer Center (NIH CA16086).

    ☆☆

    Address requests for reprints to: Kristen L. Williams, B.S., Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7545. e-mail: [email protected]; fax: (919) 966-6927.

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