![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
,**
* Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706; and
Department of Nutrition and
** Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
2To whom correspondence should be addressed. E-mail: ney{at}nutrisci.wisc.edu.
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
KEY WORDS: • parenteral nutrition • insulin-like growth factor-I • growth hormone • c-fos • c-jun
Growth hormone (GH)3 and insulin-like growth factor-I (IGF-I) are interrelated anabolic hormones that are under investigation as pharmacologic therapies to stimulate intestinal adaptation. The interrelated nature of the two hormones stems from the dual-effector hypothesis (1) and the ability of GH to stimulate hepatic IGF-I synthesis and subsequent release into circulation. Circulating IGF-I, produced primarily by the liver, is thought to mediate many of the growth-promoting actions of GH. Despite this concept, unique effects of each growth factor were noted in the intestine, consistent with the presence of both GH and IGF-I receptors in this tissue (2–5). In many cell types, induction of c-fos and c-jun RNA is an early response to GH or IGF-I receptor activation (6–11). Induction of these immediate early genes is associated with increased cell proliferation in the intestine (12).
Occasionally, hormones are unable to exert their specific effects in certain tissues due to a resistance to the particular hormone(s). For example, during critical illness, resistance to GH was demonstrated in the liver (13). This results in decreased hepatic production and secretion of IGF-I into the circulation despite increased GH levels. In addition, resistance to endogenous GH was observed in children with malnutrition (14) and resistance to exogenous GH was seen in adults with severe infection (15). Administration of IGF-I, such as that done in Laron-type dwarfism due to the absence of GH receptor (GHR) activity (16), is one approach to circumvent the hepatic GH resistance.
The intestine may also show a form of GH resistance. In parenterally fed rats, administration of GH or IGF-I improves body weight gain, but only IGF-I, given alone or in combination with GH, attenuates the jejunal mucosal atrophy induced by total parenteral nutrition (TPN) (3,5,17,18). The apparent GH resistance that we observe in the intestine does not appear to reflect hepatic resistance to GH because GH increases hepatic expression of IGF-I mRNA and increases circulating IGF-I in TPN fed rats given GH (3,19). IGF-I receptor (IGF-IR) binding is also not limiting for jejunal growth based on a greater IGF-IR binding capacity in the jejunum of GH compared to IGF-I–treated TPN fed rats (5). Thus, we hypothesize that the intestinal mucosa is resistant to the mitogenic effects of exogenous GH during TPN because of decreased GHR binding or postreceptor responsiveness to GH.
Support for our hypothesis of intestinal mucosal resistance to GH during TPN may extend to orally fed animals and clinical studies. Specifically, orally fed transgenic mice that overexpress IGF-I or GH (20,21) show increases in circulating IGF-I, body weight, and mass of the small intestinal mucosa (2). However, in GH transgenics, the increase in intestinal mass reflects an increase in enterocyte life span, not an increase in enterocyte proliferation and decrease in apoptosis as observed in IGF-I transgenic mice (22). Additionally, administration of GH did not consistently stimulate intestinal mucosal hyperplasia in orally fed rats with intact bowel (23) or following bowel resection (24–26). Moreover, GH does not consistently improve intestinal mass in humans with short bowel syndrome (27,28).
We conducted three experiments to test the hypothesis of intestinal mucosal resistance to exogenous GH during TPN in rats. First, we determined whether the method of delivery of exogenous GH affects the intestinal response to GH. Second, we determined whether intestinal GHR binding is altered by administration of GH and/or IGF-I. Third, we assessed acute expression of c-fos and c-jun genes in jejunum after a single i.v. bolus injection of GH or IGF-I. Our findings suggest that TPN is accompanied by jejunal mucosal resistance to exogenous GH at the postreceptor level.
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
Experiment 1. The purpose of this study was to determine whether the method of delivery of exogenous GH, pulsatile s.c. or continuous i.v., affects the intestinal response to GH. This experimental design included four groups, all provided with TPN: a control group receiving saline vehicle (Sal; n = 7); a group receiving pulsatile s.c. GH twice daily [GH(p); n = 6]; and groups receiving i.v. GH or i.v. IGF-I continuously coinfused with TPN solution [GH(c); n = 6 and IGF-I; n = 5].
Following anesthesia (17), catheters were placed in the superior vena cava via the external jugular vein for the continuous delivery of nutritionally adequate TPN (31). Immediately after surgery (d 0), infusion of TPN solution (29) was initiated and rats had unrestricted access to water. The infusion rate of the TPN solution was gradually increased from 30 mL on d 0 to 50 mL on d 1 and 60 mL on d 2–7. This was the sole source of nutrition until the end of the experiment. Energy intake over the 8 d was 870 kJ · kg-1 · d-1. Daily and cumulative energy intakes did not differ between TPN groups.
Growth factor administration commenced in TPN rats on postoperative d 2 and continued until rats were killed on d 8. Rats received 800 µg (3.2 mg/kg) of recombinant human GH (rhGH) or recombinant human IGF-I (rhIGF-I) daily (both supplied courtesy of Genentech). GH was administered s.c. (400 µg twice daily at 0900 and 2100 h) to mimic the pulsatile secretion of GH or as a continuous i.v. infusion concomitant with the TPN solution, similar to the continuous i.v. infusion of IGF-I (17). Sham s.c. saline injections were given to rats not receiving pulsatile s.c. GH. Confirmation of IGF-I administration or GH-stimulated hepatic IGF-I production was performed by analyzing total serum IGF-I concentrations by radioimmunoassay (32). After 8 d of exclusive TPN with 6 d of concomitant growth factor treatment, parenterally fed rats were anesthetized (17) and killed by cardiac exsanguination 12 h after the last GH or sham injection. Seven rats were initially assigned to each treatment group; a total of 4 rats were unable to complete the study due to loss of catheter patency. Thus, the survival rate after 8 d of exclusive TPN was 86%.
Jejunum composition and histology. The jejunum (designated as the segment from Treitz’s ligament to 25 cm proximal to the cecum) was removed, flushed, and cut into defined lengths (29). The first 10-cm segment of jejunum was used for the determination of wet and dry weights. The second 10-cm section of jejunum was used for the analysis of mucosal protein and DNA concentrations (17). The next 2-cm section of jejunum was fixed in HistoChoice (Amresco) and used for routine histomorphometric measurements (33).
Experiment 2. The purpose of this study was to determine whether intestinal GHR binding is altered by administration of GH and/or IGF-I during TPN. We adjusted the time slightly relative to Expt. 1 to use the minimum duration of TPN or growth factor treatment known to induce mucosal growth effects with the rationale that this would minimize secondary changes in receptor binding due to ligand-dependent downregulation. The experiment included an orally fed group (Oral; n = 6) and four TPN groups: TPN saline vehicle control (Sal; n = 6); GH, 400 µg (1.6 mg/kg) s.c. twice daily (GH; n = 6); IGF-I, 800 µg (3.2 mg · kg-1 · d-1) infused continuously with TPN solution (IGF-I; n = 5); and a combination of both IGF-I and GH, 800 µg (3.2 mg · kg-1 · d-1) IGF-I infused continuously and 400 µg (1.6 mg/kg) GH s.c. twice daily (IGF-I+GH; n = 5). The anabolic and intestinal response, but not the GHR binding response, to GH and/or IGF-I from these rats was previously reported (5) and is similar to that of the current study and our other reports (3,17). After 4 d of exclusive TPN with 3 d of concomitant growth factor treatment, rats were anesthetized and killed and the distal third of the jejunum was flushed with ice-cold homogenization buffer, frozen in liquid nitrogen, and stored for later isolation of microsomal membranes for GHR binding studies.
The frozen jejunal segments were placed in 5 mL of ice-cold homogenization buffer (25 mmol/L Tris-HCl, pH 7.8; 300 mmol/L sucrose, 10 mmol/L benzamidine, 3 nmol/L aminoacetonitrile hydrochloride; 1 mmol/L phenylmethylsulfonyl fluoride, and 27 trypsin inhibitor units/mL aprotinin) per g of tissue and immediately homogenized using a Tekmar Tissumizer for 30 s on ice. The homogenate was centrifuged at 10,000 x g for 10 min at 4°C. The supernatant was discarded and the crude membrane pellet resuspended in homogenization buffer at 2 mL/g initial jejunal weight. The protein concentration was determined using the bicinchoninic acid protein assay (Pierce). The membranes were stored at –70°C.
The receptor binding assays for GH were performed in triplicate using polyethylene microfuge tubes (34). The assay buffer consisted of 50 mmol/L Tris-HCl, pH 7.4, 20 mmol/L MgCl2, and 5 g/L BSA. Each tube contained 700 µg membrane protein and 4.3 µg/L of [125I]rhGH (Genentech). The tracer was radiolabeled using the Iodogen method to 87 Ci/g and purified using a Sephadex G-100 column. The final volume of the assay was 500 µL/tube. After being incubated at 22°C for 16 h the bound and free hormone were separated by centrifugation at 14,000 x g for 5 min at room temperature (RT). The supernatant was aspirated and used to assess tracer degradation. The pellet was washed with 1 mL of ice-cold assay buffer and centrifuged at 14,000 x g for 5 min at RT. The tips of the tubes were removed and the 125I in the final pellet was quantitated using a Wallac gamma counter.
Nonspecific binding was measured in the presence of 10 µg/tube unlabeled ovine GH (NIDDK, AFP-9220A). Total GH binding was determined in the absence of cold competitor. Specific binding was calculated by subtracting nonspecific binding from total binding. Radioligand degradation was estimated utilizing trichloroacetic acid precipitation of the supernatant, which showed that 88% of the [125I]rhGH initially added remained intact after the incubation period. The specificity of the assay was confirmed by the failure of excess porcine leutinizing hormone (NIDDK, AFP-12389A), porcine follicle-stimulating hormone (NIDDK, AFP-10640B), rhIGF-I (Genentech), and porcine insulin (Sigma) to displace the radiolabeled rhGH (35).
Experiment 3. The purpose of this study was to determine the postreceptor responsiveness to exogenous GH or IGF-I by assessing the expression of c-fos and c-jun mRNAs as functional indicators of early postreceptor activation of GH and IGF-I signaling pathways in the intestine. Rats used to analyze early induction of c-fos and c-jun mRNA were fed with nutritionally adequate TPN for 3 d and then given 500 µg rhGH (2.0 mg/kg; n = 4), 500 µg rhIGF-I (2.0 mg/kg; n = 3), or saline vehicle (Sal; n = 4) directly into the central line as a single bolus injection 60 min prior to being killed. The 60-min time point was chosen based on published information about the time frame of maximal induction of c-fos or c-jun mRNA (6).
Rats were anesthetized (17) and the jejunum was removed, flushed, and sectioned. The first 15-cm segment was snap frozen in liquid nitrogen, stored at –80°C, and later used to determine expression of c-fos and c-jun mRNAs as detailed below. The next 5-cm section was embedded in OCT compound (Miles), frozen in cold isopentane on dry ice, and cut into 10-µm cryostat sections collected on positively charged glass slides for in situ hybridization histochemistry (ISHH).
Northern blot hybridization of c-fos and c-jun mRNAs. Total RNA was isolated from jejunum by the guanidine thiocyanate-cesium chloride method (36,37). Abundance of c-fos and c-jun was determined by Northern blot hybridization assays using [32P]-labeled antisense cRNA or cDNA probes. Plasmids encoding rat c-fos or c-jun (38–40) were provided by Dr. Tom Curran (Roche Institute of Molecular Biology).
For Northern blots, 40-µg aliquots of total RNA were denatured with glyoxal and dimethyl sulfoxide, electrophoresed through a 1% agarose gel, and transferred to Genescreen membranes (NEN Life Sciences Products). Blots were hybridized with [32P]-labeled cRNA or cDNA probes as previously described (36). After being washed, blots were exposed to phosphorimager screens. Abundance of mRNA was measured using Image Quant software (Molecular Dynamics). Blots were subsequently hybridized with [32P]-labeled probe for the constitutively expressed ribosomal protein pyridoxal (PL)-7 (41) kindly provided by Dr. Ken Korach (National Institute of Environmental Health Sciences). Abundance of test mRNAs in each sample was normalized to that of PL-7 mRNA as a control for RNA loading.
In situ hybridization analysis to localize c-fos and c-jun mRNAs. ISHH was performed using antisense RNA probes for c-fos and c-jun mRNAs labeled with [35S]-UTP as described previously (36,42). Briefly, tissue sections were postfixed in 4% paraformaldehyde, treated with proteinase K (0.5–1.0 mg/L) for 10 min, acetylated by incubation in 0.1 mol/L trimethylammonium and 0.25% acetic anhydride, and then dehydrated through graded alcohols. Slides were incubated with labeled RNA probe in hybridization buffer (75% deionized formamide; 3X SSC:20X SSC = 3 mol/L NaCl, 0.3 mol/L sodium citrate, pH 7.0; 50X Denhardt’s, 10 g/L yeast tRNA, 1 mol/L sodium phosphate, dextran sulfate, 10 mmol/L dithiothreitol) at 55°C for 18 h and then treated with RNase and washed in 0.5–2.0X SSC (0.5X = 0.075 mol/L NaCl, 0.0075 mol/L sodium citrate, pH 7.0) at 55°C. Slides were dehydrated and exposed to Ilford nuclear autoradiographic emulsion (Polyscience) at 4°C for 10–21 d. Slides were developed and counterstained with Mayer’s hematoxylin for histological examination and then examined and photographed under both dark- and light-field illumination. Specificity of the hybridization signal obtained with antisense probes was verified by comparison with sections probed with sense control RNA probes.
Statistical analysis. TPN groups within each experiment were compared using one-way ANOVA using the general linear models program in SAS (SAS Institute) and considered different at P < 0.05 as determined by the protected least significant differences test.
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
|
Jejunal composition and morphology (Expt. 1).
GH or IGF-I treatment significantly increased intact wet mass of jejunum (which contained both the mucosal and the muscularis layers) by 
20 and 62%, respectively (Fig. 2A). However, only IGF-I significantly increased mucosal dry mass by 110% (Fig. 2B). Taken together, these data suggest that GH may have greater effects in the muscularis than in the mucosa. Consistent with the observed effects in the mucosal dry mass, only IGF-I significantly increased protein and DNA concentrations in the jejunal mucosa (Fig. 2C and 2D, respectively). The increases in protein and DNA induced by IGF-I are consistent with mucosal hyperplasia.
|
|
|
|
|
|
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
Our prior studies administered GH as twice-daily s.c. injections and IGF-I continuously coinfused with the TPN solution via the i.v. catheter (3,5,17). In the present study, we conducted the first experiment to rule out that inefficacy of GH may be due to the different method of delivery compared with IGF-I. We observed that only IGF-I, but neither pulsatile s.c. nor continuous i.v. GH, stimulated jejunal mucosal hyperplasia, further demonstrating that the intestinal mucosa is resistant to exogenous GH during parenteral feeding. As a result, we conducted the second experiment to determine whether intestinal GHR binding is altered by administration of GH and/or IGF-I during TPN. We found that neither TPN alone (compared with oral feeding) nor exogenous GH during TPN reduces GH-specific binding. These findings suggest that the inability of GH to stimulate mucosal hyperplasia is not due to low levels of the receptor. We furthered our investigation of the intestinal resistance to exogenous GH by conducting the third experiment to determine the postreceptor responsiveness to GH or IGF-I. We found that jejunal mucosal c-fos is not induced by GH, but is induced by IGF-I during TPN, which mirrors the differential mucosal growth effects seen with the two hormonal treatments. These experiments support the hypothesis that postreceptor growth insensitivity to exogenous GH exists during TPN.
Consistently throughout our studies in TPN models, it appears that the inability of GH to stimulate intestinal mucosal hyperplasia is a tissue-specific resistance (3,5,17). Here we compared the method of delivery of GH to determine whether providing a continuous supply of GH to the intestine versus mimicking physiological pulses of GH secretion from the pituitary altered the intestinal response to GH. We observed that although both pulsatile s.c. GH and continuous i.v. GH significantly increased endogenous serum IGF-I concentrations and promoted similar whole-body growth during TPN, neither method of delivery of exogenous GH stimulated jejunal mucosal hyperplasia. The ability of GH to stimulate increased plasma IGF-I largely reflects increased hepatic IGF-I synthesis and indicates GH sensitivity in the liver. Thus, the hepatic GH resistance characteristic of catabolic states (13–15) was not observed during TPN. The similar body weight gain in GH and IGF-I treated TPN fed rats also indicates that organs such as skeletal muscle are responsive to GH and GH-induced IGF-I. The similar effects of GH and IGF-I on body weight are important in the light of somewhat lower levels of serum IGF-I in GH versus IGF-I treated rats because they argue against differences in serum IGF-I as mediators of differences in growth-promoting effects in the intestine. Indeed, in other TPN experiments, we have found lack of efficacy of GH on intestinal growth even when serum IGF-I levels were virtually identical to that achieved by IGF-I treatment (3). This strengthens the case that there is specific resistance to GH in the intestinal mucosa, possibly at the level of the receptor and/or in cell signaling.
It seems unlikely that the lack of efficacy of GH compared with IGF-I in stimulating mucosal growth is due to limiting amounts of GH or IGF-I receptor or effects of GH on receptor number. Our prior studies have documented higher levels of IGF-I receptor in jejunum of GH compared with IGF-I treated parenterally fed rats (5). The current studies document higher jejunal GH binding capacity in GH compared with IGF-I treated rats during TPN. Intriguingly, IGF-I alone or in combination with GH downregulated total GH binding. This is consistent with our prior findings that IGF-I, but not GH treatment in parenterally-fed rats, downregulates GHR mRNA by >50% in jejunal mucosa (19). The functional importance of this observation requires additional study but the findings argue against GH resistance operating at the level of receptor number and support the concept of postreceptor GH resistance.
We tested the possibility of postreceptor defects in GH signaling in the TPN model by determining whether exogenous GH or IGF-I induced the immediate early genes c-fos or c-jun. GH was unable to induce jejunal c-fos or c-jun mRNA while IGF-I administration significantly induced c-fos mRNA. Although only a trend (P = 0.053) was observed for induction of c-jun mRNA by IGF-I, the constitutive expression of c-jun would still permit formation of a functional AP-1 transcription complex with c-fos (10,11). Furthermore, c-fos and c-jun mRNAs were localized primarily to cells of the mucosal layer, where trophic effects occur in response to IGF-I, but not GH, during TPN (3,17). The absence of mucosal c-fos or c-jun induction by GH in TPN rats would be predicted to impact on mucosal growth responses because the transcription factor AP-1 regulates expression of secondary growth-associated genes (46). This is further supported by the fact that mucosal atrophy observed during fasting is associated with relatively lower levels of c-fos and c-jun mRNAs than during refeeding, when increased mucosal growth occurs (12), indicating that altered c-fos and c-jun expression correlated with altered mucosal growth.
In summary, we conclude that the lack of early c-fos induction in response to GH in TPN rats indicates that the jejunal mucosal is insensitive to 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. The postreceptor activation of GH signaling pathways is complex, but the defect may involve either the suppressor of cytokine signaling proteins or the transcription initiation factors (13,47).
Although continuous i.v. or pulsatile s.c. GH did not stimulate intestinal mucosal proliferation in TPN rats, GH may be useful in the treatment of human intestinal disease. Our data show that GH increases protein synthesis in the muscularis layer of the jejunum (4). Additionally, we and others have shown that GH has positive functional effects on intestinal ion transport activity (3,22,48,49). Also, recent evidence suggests that administration of GH induces clinical improvement in patients with Crohn’s disease when they consumed a high-protein diet (50) and improves intestinal absorption in adults with short bowel syndrome who are dependent on parenteral nutrition (28). Further research on the mechanism of action of GH and IGF-I is needed to fully define the clinical appropriateness of these growth factors in particular settings. Moreover, the unique effects of each growth factor possibly indicate that the combined administration of GH and IGF-I may be the optimum therapy in the treatment of an array of human intestinal diseases.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
3 Abbreviations used: GH, growth hormone; GHR, growth hormone receptor; GLP-2, glucagon-like peptide-2; IGF-I, insulin-like growth factor-I; IGF-IR, insulin-like growth factor-I receptor; ISHH, in situ hybridization histochemisty; rhGH, recombinant human growth hormone; rhIGF-I, recombinant human insulin-like growth factor-I; RT, room temperature; TPN, total parenteral nutrition.
Manuscript received 19 August 2003. Initial review completed 5 October 2003. Revision accepted 25 November 2003.
|
LITERATURE CITED |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
1. Zezulak, K. M. & Green, H. (1986) The generation of insulin-like growth factor-1–sensitive cells by growth hormone action. Science 233:551-553.
2. Ney, D. M. (1999) Effects of insulin-like growth factor-I and growth hormone in models of parenteral nutrition. J. Parenter. Enteral Nutr. 23:S184-S189.
3. Peterson, C. A., Carey, H. V., Hinton, P. L., Lo, H. C. & Ney, D. M. (1997) GH elevates serum IGF-I levels but does not alter mucosal atrophy in parenterally fed rats. Am. J. Physiol. Gastrointest. Liver Physiol. 272:G1100-G1108.
4. Lo, H. C. & Ney, D. M. (1996) GH and IGF-I differentially increase protein synthesis in skeletal muscle and jejunum of parenterally fed rats. Am. J. Physiol. Endocrinol. Metab. 271:E872-E878.
5. Ney, D. M., Huss, D. J., Gillingham, M. B., Kritsch, K. R., Dahly, E. M., Talamantez, J. L. & Adamo, M. L. (1999) Investigation of insulin-like growth factor (IGF)-I and insulin receptor binding and expression in jejunum of parenterally fed rats treated with IGF-I or growth hormone. Endocrinology 140:4850-4860.
6. Gronowski, A. M. & Rotwein, P. (1995) Rapid changes in gene expression after in vivo growth hormone treatment. Endocrinology 136:4741-4748.[Abstract]
7. Hodge, C., Liao, J., Stofega, M., Guan, K., Carter-Su, C. & Schwartz, J. (1998) Growth hormone stimulates phosphorylation and activation of elk-1 and expression of c-fos, egr-1, and junB through activation of extracellular signal-regulated kinases 1 and 2. J. Biol. Chem. 273:31327-31336.
8. Sumantran, V. N., Tsai, M. L. & Schwartz, J. (1992) Growth hormone induces c-fos and c-jun expression in cells with varying requirements for differentiation. Endocrinology 130:2016-2024.[Abstract]
9. Liao, J., Hodge, C., Meyer, D., Ho, P. S., Rosenspire, K. & Schwartz, J. (1997) Growth hormone regulates ternary complex factors and serum response factor associated with the c-fos serum response element. J. Biol. Chem. 272:25951-25958.
10. Monnier, D., Boutillier, A. L., Giraud, P., Chiu, R., Aunis, D., Feltz, P., Zwiller, J. & Loeffler, J. P. (1994) Insulin-like growth factor-I stimulates c-fos and c-jun transcription in PC12 cells. Mol. Cell. Endocrinol. 104:139-145.[Medline]
11. Simmons, J. G., Hoyt, E. C., Westwick, J. K., Brenner, D. A., Pucilowska, J. B. & Lund, P. K. (1995) Insulin-like growth factor-I and epidermal growth factor interact to regulate growth and gene expression in IEC-6 intestinal epithelial cells. Mol. Endocrinol. 9:1157-1165.[Abstract]
12. Hodin, R. A., Graham, J. R., Meng, S. & Upton, M. P. (1994) Temporal pattern of rat small intestinal gene expression with refeeding. Am. J. Physiol. 266:G83-G89.[Medline]
13. Mao, Y., Ling, P. R., Fitzgibbons, T. P., McCowen, K. C., Frick, G. P., Bistrian, B. R. & Smith, R. J. (1999) Endotoxin-induced inhibition of growth hormone receptor signaling in rat liver in vivo. Endocrinology 140:5505-5515.
14. Hintz, R. L., Suskind, R., Amatayakul, K., Thanangkul, O. & Olson, R. (1978) Plasma somatomedin and growth hormone values in children with protein-calorie malnutrition. J. Pediatr. 92:153-156.[Medline]
15. Dahn, M. S., Lange, M. P. & Jacobs, L. A. (1988) Insulin-like growth factor 1 production is inhibited in human sepsis. Arch. Surg. 123:1409-1414.[Abstract]
16. Ranke, M. B., Savage, M. O., Chatelain, P. G., Preece, M. A., Rosenfeld, R. G. & Wilton, P. (1999) Long-term treatment of growth hormone insensitivity syndrome with IGF-I. Results of the European Multicentre Study. The Working Group on Growth Hormone Insensitivity Syndromes. Horm. Res. 51:128-134.[Medline]
17. Peterson, C. A., Gillingham, M. B., Mohapatra, N. K., Dahly, E. M., Adamo, M. L., Carey, H. V., Lund, P. K. & Ney, D. M. (2000) Enterotrophic effect of insulin-like growth factor-I but not growth hormone and localized expression of insulin-like growth factor-I, insulin-like growth factor binding protein-3 and -5 mRNAs in jejunum of parenterally fed rats. J. Parenter. Enteral Nutr. 24:288-295.[Abstract]
18. Inaba, T., Saito, H., Fukushima, R., Hashiguchi, Y., Lin, M. T., Inoue, T., Fukatsu, K., Muto, T., Takenaka, A., Takahashi, S. & Noguchi, T. (1996) Effects of growth hormone and insulin-like growth factor 1 (IGF-1) treatments on the nitrogen metabolism and hepatic IGF-1-messenger RNA expression in postoperative parenterally fed rats [see comments]. J. Parenter. Enteral Nutr. 20:325-331.[Abstract]
19. Yang, H., Ney, D. M., Peterson, C. A., Lo, H. C., Carey, H. V. & Adamo, M. L. (1997) Stimulation of intestinal growth is associated with increased insulin- like growth factor-binding protein 5 mRNA in the jejunal mucosa of insulin-like growth factor-I-treated parenterally fed rats. Proc. Soc. Exp. Biol. Med. 216:438-445.[Abstract]
20. Ohneda, K., Ulshen, M. H., Fuller, C. R., D’Ercole, A. J. & Lund, P. K. (1997) Enhanced growth of small bowel in transgenic mice expressing human insulin-like growth factor I. Gastroenterology 112:444-454.[Medline]
21. Ulshen, M. H., Dowling, R. H., Fuller, C. R., Zimmermann, E. M. & Lund, P. K. (1993) Enhanced growth of small bowel in transgenic mice overexpressing bovine growth hormone [see comments]. Gastroenterology 104:973-980.[Medline]
22. Lund, P. K. (1998) Molecular basis of intestinal adaptation: the role of the insulin-like growth factor system. Ann. N.Y. Acad. Sci. 859:18-36.
23. Dahly, E. M. (2003) Nutritional and Hormonal Factors in Intestinal Adaptation following Bowel Resection. Doctoral Dissertation. Nutritional Sciences 2003 University of Wisconsin-Madison Madison.
24. Park, J. H. & Vanderhoof, J. A. (1996) Growth hormone did not enhance mucosal hyperplasia after small-bowel resection. Scand. J. Gastroenterol. 31:349-354.[Medline]
25. Shulman, D. I., Hu, C. S., Duckett, G. & Lavallee-Grey, M. (1992) Effects of short-term growth hormone therapy in rats undergoing 75% small intestinal resection. J. Pediatr. Gastroenterol. Nutr. 14:3-11.[Medline]
26. Benhamou, P. H., Canarelli, J. P., Leroy, C., De Boissieu, D. & Dupont, C. (1994) Stimulation by recombinant human growth hormone of growth and development of remaining bowel after subtotal ileojejunectomy in rats. J. Pediatr. Gastroenterol. Nutr. 18:446-452.[Medline]
27. Scolapio, J. S., Camilleri, M., Fleming, C. R., Oenning, L. V., Burton, D. D., Sebo, T. J., Batts, K. P. & Kelly, D. G. (1997) Effect of growth hormone, glutamine, and diet on adaptation in short-bowel syndrome: a randomized, controlled study. Gastroenterology 113:1074-1081.[Medline]
28. Seguy, D., Vahedi, K., Kapel, N., Souberbielle, J. C. & Messing, B. (2003) Low-dose growth hormone in adult home parenteral nutrition-dependent short bowel syndrome patients: a positive study. Gastroenterology 124:293-302.[Medline]
29. Dahly, E. M., Guo, Z. & Ney, D. M. (2002) Alterations in enterocyte proliferation and apoptosis accompany TPN-induced mucosal hypoplasia and IGF-I-induced hyperplasia in rats. J. Nutr. 132:2010-2014.
30. Clark, R.G.L., Carlsson, L.M.S. & Mortensen, D. (1994) Additive effects on body growth of insulin-like growth factor-I and growth hormone on hypophysectomized rats. Endocrinol. Metab. 1:49-54.
31. Lasekan, J. B., Rivera, J., Hirvonen, M. D., Keesey, R. E. & Ney, D. M. (1992) Energy expenditure in rats maintained with intravenous or intragastric infusion of total parenteral nutrition solutions containing medium- or long-chain triglyceride emulsions. J. Nutr. 122:1483-1492.
32. Ney, D. M., Yang, H., Smith, S. M. & Unterman, T. G. (1995) High-calorie total parenteral nutrition reduces hepatic insulin-like growth factor-I mRNA and alters serum levels of insulin-like growth factor-binding protein-1, -3, -5, and -6 in the rat. Metabolism 44:152-160.[Medline]
33. Gillingham, M. B., Dahly, E. M., Carey, H. V., Clark, M. D., Kritsch, K. R. & Ney, D. M. (2000) Differential jejunal and colonic adaptation due to resection and IGF-I in parenterally fed rats. Am. J. Physiol. Gastrointest. Liver Physiol. 278:G700-G709.
34. Lobie, P. E., Breipohl, W. & Waters, M. J. (1990) Growth hormone receptor expression in the rat gastrointestinal tract. Endocrinology 126:299-306.[Abstract]
35. Kritsch, K. R., Murali, S., Adamo, M. L. & Ney, D. M. (2002) Dexamethasone decreases serum and liver IGF-I and maintains liver IGF-I mRNA in parenterally fed rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 282:R528-R536.
36. Savendahl, L., Underwood, L. E., Haldeman, K. M., Ulshen, M. H. & Lund, P. K. (1997) Fasting prevents experimental murine colitis produced by dextran sulfate sodium and decreases interleukin-1 beta and insulin-like growth factor I messenger ribonucleic acid. Endocrinology 138:734-740.
37. Wilkins, H. R., Ohneda, K., Keku, T. O., D’Ercole, A. J., Fuller, C. R., Williams, K. L. & Lund, P. K. (2002) Reduction of spontaneous and irradiation-induced apoptosis in small intestine of IGF-I transgenic mice. Am. J. Physiol. Gastrointest. Liver Physiol. 283:G457-G464.
38. Curran, T., Gordon, M. B., Rubino, K. L. & Sambucetti, L. C. (1987) Isolation and characterization of the c-fos(rat) cDNA and analysis of post-translational modification in vitro. Oncogene 2:79-84.[Medline]
39. Rauscher, F. J., 3rd, Cohen, D. R., Curran, T., Bos, T. J., Vogt, P. K., Bohmann, D., Tjian, R. & Franza, B. R., Jr (1988) Fos-associated protein p39 is the product of the jun proto-oncogene. Science 240:1010-1016.
40. Adams, T. E., Hansen, J. A., Starr, R., Nicola, N. A., Hilton, D. J. & Billestrup, N. (1998) Growth hormone preferentially induces the rapid, transient expression of SOCS-3, a novel inhibitor of cytokine receptor signaling. J. Biol. Chem. 273:1285-1287.
41. Meyuhas, O. & Klein, A. (1990) The mouse ribosomal protein L7 gene. Its primary structure and functional analysis of the promoter region. J. Biol. Chem. 265:11465-11473.
42. Stenvers, K. L., Lund, P. K. & Gallagher, M. (1996) Increased expression of type 1 insulin-like growth factor receptor messenger RNA in rat hippocampal formation is associated with aging and behavioral impairment. Neuroscience 72:505-518.[Medline]
43. Lo, H. C., Hinton, P. S., Peterson, C. A. & Ney, D. M. (1995) Simultaneous treatment with IGF-I and GH additively increases anabolism in parenterally fed rats. Am. J. Physiol. 269:E368-E376.
44. Howarth, G. S. (2003) Insulin-like growth factor-I and the gastrointestinal system: therapeutic indications and safety implications. J. Nutr. 133:2109-2112.
45. Burrin, D. G., Petersen, Y., Stoll, B. & Sangild, P. (2001) Glucagon-like peptide 2: a nutrient-responsive gut growth factor. J. Nutr. 131:709-712.
46. Angel, P. & Karin, M. (1991) The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim. Biophys. Acta 1072:129-157.[Medline]
47. Greenhalgh, C. J., Miller, M. E., Hilton, D. J. & Lund, P. K. (2002) Suppressors of cytokine signaling: relevance to gastrointestinal function and disease. Gastroenterology 123:2064-2081.[Medline]
48. Guarino, A., Canani, R. B., Iafusco, M., Casola, A., Russo, R. & Rubino, A. (1995) In vivo and in vitro effects of human growth hormone on rat intestinal ion transport. Pediatr. Res. 37:576-580.[Medline]
49. Berni Canani, R., Iafusco, M., Russo, R., Bisceglia, M., Polito, G. & Guarino, A. (1996) Comparative effects of growth hormone on water and ion transport in rat jejunum, ileum, and colon. Dig. Dis. Sci. 41:1076-1081.[Medline]
50. Slonim, A. E., Bulone, L., Damore, M. B., Goldberg, T., Wingertzahn, M. A. & McKinley, M. J. (2000) A preliminary study of growth hormone therapy for Crohn’s disease. N. Engl. J. Med. 342:1633-1637.
This article has been cited by other articles:
|
|
 |
|
  C. Z. Michaylira, J. G. Simmons, N. M. Ramocki, B. P. Scull, K. K. McNaughton, C. R. Fuller, and P. K. Lund Suppressor of cytokine signaling-2 limits intestinal growth and enterotrophic actions of IGF-I in vivo Am J Physiol Gastrointest Liver Physiol, September 1, 2006; 291(3): G472 - G481. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Z. Michaylira, N. M. Ramocki, J. G. Simmons, C. K. Tanner, K. K. McNaughton, J. T. Woosley, C. J. Greenhalgh, and P. K. Lund Haplotype Insufficiency for Suppressor of Cytokine Signaling-2 Enhances Intestinal Growth and Promotes Polyp Formation in Growth Hormone-Transgenic Mice Endocrinology, April 1, 2006; 147(4): 1632 - 1641. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Fruchtman, J. G. Simmons, C. Z. Michaylira, M. E. Miller, C. J. Greenhalgh, D. M. Ney, and P. K. Lund Suppressor of cytokine signaling-2 modulates the fibrogenic actions of GH and IGF-I in intestinal mesenchymal cells Am J Physiol Gastrointest Liver Physiol, August 1, 2005; 289(2): G342 - G350. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. Paine, S. S. Ludington, M.-L. Chen, P. W. Stewart, S.-M. Huang, and P. B. Watkins DO MEN AND WOMEN DIFFER IN PROXIMAL SMALL INTESTINAL CYP3A OR P-GLYCOPROTEIN EXPRESSION? Drug Metab. Dispos., March 1, 2005; 33(3): 426 - 433. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
