Progress 10/01/02 to 09/30/06
Outputs
Parenteral nutrition (PN) consists of infusion of nutrients directly into the circulatatory system bypassing the gastrointestinal (GI) tract. PN is a vital feeding technique for individuals who cannot tolerate oral nutrition. However, serious complications accompany PN because of aberrations in intestinal structure and function due to the absence of luminal nutrients. This research has enhanced understanding of how administration of growth factors, insulin-like growth factor-I (IGF-I) and growth hormone (GH), promote wound healing during intestinal injury and reduce the intestinal complications induced by PN. The three objectives of this research have been accomplished as follows. Objective one addressed the inability of GH to stimulate jejunal mucosal hyperplasia during PN. The inability of GH to stimulate mucosal hyperplasia is not due to low levels of the GH receptor and reduced GH receptor binding in intestine. Rather, the jejunal mucosa appears to be resistant to
exogenous GH between GH receptor activation and induction of immediate early genes. GH is also less potent compared to IGF-I in the stimulation of collagen synthesis in the intestine. We determined that GH, but not IGF-I, induces expression of suppressor of cytokine signaling-2 (SOC-2) protein in isolated myofibroblasts, and overexpression of SOC-2 leads to suppression of GH-induced collagen accumulation. These data suggest that GH treatment may minimize intestinal fibrosis while promoting wound healing. Objective two addressed the association between the mucosal hyperplasia induced by IGF-I and local expression of IGF binding proteins. Both the rat and mouse demonstrate mucosal hyperplasia due to PN that is reversed by infusion of IGF-I in PN solution. Jejunal atrophy due to PN and growth due to IGF-I are directly associated with expression of IGF binding protein-5 (IGFBP-5) mRNA. These data suggest that local expression of IGFBP-5 positively modulates the intestinotrophic effects of
IGF-I. Studies in knock out mice with deletion of the IGFBP-5 gene are being conducted to test the hypothesis that the ability of IGF-I to induce mucosal hyperplasia is dependent on expression of IGFBP-5 in intestine. Objective three addressed the functional significance of the mucosal hyperplasia induced by IGF-I in rats subjected to an intestinal resection that mimics human short bowel syndrome. Following a 60% jejunoileal resection plus cecectomy, rats treated with IGF-I or vehicle were maintained with PN and then transitioned to oral feeding. Treatment with IGF-I for 7 days induced mucosal hyperplasia in residual intestine that was associated with maintenance of a greater body weight 17 days after resection compared to treatment with vehicle. These data indicate successful weaning or transition from PN to oral feeding in a rat model of human short bowel syndrome due to treatment with IGF-I.
Impacts
Growth hormone and insulin-like growth factor-I (IGF-I) promote wound healing during intestinal injury. Our research has helped to elucidate the mechanisms by which these growth factors stimulate intestinal growth. Our data supports recent FDA approval for the use of growth hormone for patients with Crohn's disease and short bowel syndrome.
Publications
- Murali, S.G., Nelson, D.W., Draxler, A.K., Liu, X. and Ney, D.M. 2005. Insulin-like growth factor-I (IGF-I) attenuates jejunal atrophy in association with increased expression of IGF-I binding protein-5 in parenterally-fed mice. J. Nutr 135:2553-2559.
- Liu, X., Nelson, D.W., Holst, J.J. and Ney, D.M. 2006. Synergistic effect of supplemental enteral nutrients and glucagons-like peptide-2 (GLP-2) on intestinal adaptation in a rat model of human short bowel syndrome. Am. J. Clin. Nutr 84:1142-1150.
- Dahly, E.M. 2003. Nutritional and hormonal factors in intestinal adaptation following bowel resection. PhD Dissertation. University of Wisconsin-Madison.
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Progress 01/01/05 to 12/31/05
Outputs
Growth hormone (GH) and insulin-like growth factor-I (IGF-I) play important roles in wound healing during intestinal injury. Factors that dictate the balance between normal wound healing and excessive healing responses characterized by collagen deposition are unknown. Using RNase protection assay and in situ hybridization, we determined whether GH and/or IGF-I increase type I collagen deposition in the intestine of rats fed by total parenteral nutrition (TPN), a feeding modality used for many patients following intestinal surgery. Both GH and IGF-I stimulated collagen production but GH was less potent than IGF-I. Suppressors of cytokine signaling (SOC) are cytokine-inducible proteins that negatively feedback to inhibit the actions of cytokines; we recently reported that GH selectively upregulates SOC-2 in the intestine of TPN-fed rats. We examined whether SOC-2 could explain the reduced impact of GH compared to IGF-I on collagen production. In summary, GH, but not
IGF-I, induced SOC-2 in isolated myofibroblasts, and overexpression of SOC-2 led to a suppression of GH-induced collagen accumulation.
Impacts
These data suggest that SOC-2 induced by GH may play an important role in suppressing collagen accumulation induced by GH, providing a mechanism for the reduced potency of GH compared to IGF-I on intestinal collagen synthesis. The FDA recently approved the use of GH for patients with Crohns disease and short bowel syndrome. Our data support the potential for GH treatment to minimize intestinal fibrosis while promoting wound healing.
Publications
- Fruchtman, S., Simmons, J.G., Michaylira, C.Z., Miller, M.E., Greenhalgh, C.J., Ney, D.M. and Lund, P.K. 2005. Suppressor of cytokine signaling-2 modulates the fibrogenic actions of GH and IGF-I in intestinal mesenchymal cells. Am. J. Physiol. 289:G342-G350.
- Kritsch, K.R., Murali, S., Adamo, M.L., Clayton, M.K. and Ney, D.M. 2005. Hypoenergetic high-carbohydrate or high-fat parenteral nutrition induces a similar metabolic response with differential effects on hepatic IGF-I mRNA in dexamethasone-treated rats. J. Nutr. 135:479-485.
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Progress 01/01/04 to 12/31/04
Outputs
In parenterally fed rats, administration of growth hormone (GH) or insulin-like growth factor-I (IGF-I) improves body weight gain, but only IGF-I stimulates jejunal mucosal hyperplasia. Our objective was to determine whether the intestinal mucosa is resistant to the mitogenic effects of exogenous GH but sensitive to exogenous IGF-I during parenteral nutrition because of decreased GH receptor (GHR) binding or postreceptor responsiveness to GH. Exogenous GH did not reduce GH-specific binding in jejunum suggesting that the inability of GH to stimulate mucosal hyperplasia is not due to low levels of the GHR. IGF-I, but not GH, induced acute expression of c-fos and c-jun mRNAs in jejunum 60 min after a single IV bolus of IGF-I or GH. This suggests that IGF-I, but not GH, activates early postreceptor growth-related signaling pathways in jejunum. In summary, the jejunal mucosa is resistant to exogenous GH between GHR activation and induction of immediate early genes, and
this may contribute to the inability of mucosal cells to respond to the trophic effects of GH.
Impacts
The FDA has recently approved the use of growth hormone for patients with short bowel syndrome. This action is controversial because only 2 of 5 clinical studies show positive results with growth hormone treatment. Our data offer an explanation for why growth hormone does not consistently stimulate intestinal growth because of a postreceptor defect.
Publications
- Dahly, E.M., MIller, M.E., Lund, P.K., and Ney, D.M. 2004. Postreceptor resistance to exogenous growth hormone exists in the jejunal mucosa of parenterally fed rats. J. Nutr. 134:530-537.
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Progress 01/01/03 to 12/31/03
Outputs
We determined the ability of acute treatment with insulin-like growth factor I (IGF-I) to facilitate weaning from total parenteral nutrition (TPN) to enteral feeding in a rat model of human short bowel syndrome. Following a 60% jejuno-ileal resection + cecectomy, rats treated with IGF-I or vehicle were maintained exclusively with TPN for 4 days and transitioned to oral feeding. TPN and IGF-I were stopped 7 days after resection and rats were maintained exclusively with oral feeding for 10 more days. Acute IGF-I treatment induced sustained jejunal hyperplasia based on significantly greater concentrations of jejunal mucosal protein and DNA that was associated with maintenance of a greater body weight 17 days after resection. These results indicate successful weaning or transition from parenteral to enteral nutrition in a rat model of human short bowel syndrome.
Impacts
This is the first report to demonstrate the ability of an intestinal growth factor to sustain intestinal growth after administration is stopped and to successfully facilitate the transition from parenteral to enteral feeding after massive intestinal resection in an animal model. This approach demonstrates the functional significance of the intestinal growth.
Publications
- Gillingham, M.B., Dahly, E.M., Murali, S.G., and Ney, D.M. 2003. IGF-I treatment facilitates transition from parenteral to enteral nutrition in rats with short bowel syndrome. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284:R363-R371.
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Progress 01/01/02 to 12/31/02
Outputs
Since the project was initiated during the last 3 months of 2002 there are no completed experiments to report at this time. Two experiments are ongoing: 1) a study to determine the role of parenteral lipid and intestinal eicosanoids in stimulation of intestinal adaptation to mid-small bowel resection and 2) a study to determine whether the inability of growth hormone (GH) to stimulate intestinal growth during parenteral nutrition is affected by the method of GH administration.
Impacts
We hope to show how growth factors attenuate the mucosal intestinal atrophy associated with parenteral nutrition and permit transition to enteral feeding.
Publications
- No publications reported this period
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