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*
Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706; and the
Department of Pathology and Laboratory Medicine, University of Wisconsin Hospitals and Clinics, Madison, WI 53792
2To whom correspondence should be addressed. E-mail: ney{at}nutrisci.wisc.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • intestinal atrophy • parenteral nutrition • enterocyte proliferation and apoptosis • insulin-like growth factor-I
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). However, changes in nutritional state including fasting, overfeeding and the route of nutrient administration, such as enteral or parenteral feeding, may alter this rate of turnover and affect intestinal mucosal mass (2
). Specifically, the absence of luminal nutrients due to total parenteral nutrition (TPN)3
induces intestinal mucosal hypoplasia in both rats (3
,4
) and humans (5
). Nevertheless, administration of intestinotrophic peptides, such as insulin-like growth factor-I (IGF-I), attenuates the TPN-induced mucosal hypoplasia (3
,4
).
The mechanisms by which nutrition and growth factors regulate enterocyte turnover and intestinal mass are incompletely understood (6
). A disturbance in enterocyte production and/or loss by apoptosis can affect intestinal mucosal cellularity. Knowledge of both enterocyte proliferation and apoptosis is vital in elucidating how nutrition and growth factors regulate intestinal cell turnover. Our objective was to determine the contribution of enterocyte proliferation and apoptosis to the mucosal hypoplasia induced by TPN and the mucosal hyperplasia induced by IGF-I in growing rats after exclusive TPN and concomitant treatment with IGF-I or vehicle.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The University of Wisconsin-Madison Institutional Animal Care and Use Committee approved the animal facilities and protocols. Male, Sprague-Dawley rats (Harlan, Madison, WI) initially weighing 200–225 g were individually housed and adapted to the facility as before (7
). Rats were randomly assigned to two parenterally fed treatment groups as follows: TPN without IGF-I (TPN, n = 9); and TPN with IGF-I continuously coinfused with TPN solution (TPN + IGF-I, n = 8). In addition, an orally fed, nonsurgical, age-matched group (Oral, n = 8) was included to provide a normal comparison to assess the hypoplastic effects of TPN on the bowel. The Oral group was allowed free access to a nutritionally complete, semipurified, powdered diet4
with a macronutrient composition comparable to the TPN solution.
On the day of surgery (d 0), rats were anesthetized (7
) while the TPN catheter was placed as previously described (9
). After surgery, rats received postoperative care and infusion of TPN solution5
was gradually increased to provide full nutrition (7
). IGF-I-treated rats were infused with 3.2 mg recombinant human IGF-I (rhIGF-I; Genentech, South San Francisco, CA) per kg body weight (BW)/d concurrent with continuous infusion of TPN for 6 d (d 1–6). IGF-I administration was confirmed by analyzing total serum IGF-I concentrations by radioimmunoassay (10
). After 7 d (d 7) of exclusive TPN or oral feeding, rats were anesthetized by intravenous administration of 20 mg ketamine/kg BW and then killed by cardiac exsanguination between 1000 and 1100 h.
Jejunal composition and histology.
On d 7, the jejunum was removed and flushed with ice-cold saline (9 g NaCl/L). The first centimeter distal to the ligament of Treitz was fixed in Carnoy’s solution (60% ethanol, 30% chloroform, 10% glacial acetic acid) for histologic analyses (11
). A 2-cm section, derived from the third and fourth centimeters, was scraped to obtain jejunal mucosa and used to determine dry weights. The following 3-cm section also was scraped and analyzed for mucosal protein and DNA contents (7
). Fixed tissue was paraffin-embedded and 5-µm sections were stained with hematoxylin and eosin (H&E). Jejunum villus height (VH), crypt depth (CD) and muscularis thickness were measured as previously described (7
).
Jejunal apoptosis and mitosis.
Conventional light microscopy of H&E stained specimens was used to detect enterocyte mitosis and apoptosis (11
) as shown in Figure 1
. This method of identifying apoptotic cells, presently considered the reference standard by Potten (12
), is extremely precise if representative morphologic changes are observed (13
) and was chosen to avoid the nonspecific staining with terminal deoxyuridine nick-end labeling (TUNEL) (14
). Jejunal sections as used in the histomorphometric assessment were examined for apoptotic enterocytes in a blinded manner by an experienced human pathologist (Z.G.) based on the characteristic findings of apoptotic cells including condensed chromatin, nuclear fragmentation, intensely eosinophilic cytoplasm and formation of apoptotic bodies (15
). Mitotic cells were identified based on spindle formation, chromatin condensation and actin cytoskeleton rearrangement (16
).
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Data are presented two ways to account for the effects of the TPN and IGF-I treatments in altering the total number of cells in the crypt and villus columns. First, data are presented as the mean number of apoptotic cells per crypt or villus column; this was calculated by dividing the total number of apoptotic cells in 50 well-oriented crypt or villus cell columns by 50 for each rat. The mean number of mitotic cells per crypt column was calculated similarly. Second, data are presented as an apoptotic index (AI). The AI in the crypt or villus compartments was quantified by counting the total number of apoptotic cells in the 50 well-oriented crypt or villus columns and expressing this as the percentage of the total number of cells in the 50 crypt or villus columns for each rat. The mitotic index in the crypt was calculated similarly.
To identify locations of apoptosis along the crypt-villus axis, we constructed AI distribution curves. The curves were constructed based on group means that plotted cell position vs. AI at each position. AI, in this case, was defined as the total number of apoptotic cells at each cell position expressed as the percentage of the total number of cells counted at that cell position. The cell position with the peak incidence of apoptosis was determined from these curves by choosing the cell position with the greatest AI. A very conservative method was used for the statistical assessment of apoptosis and mitosis. That is, the mean of the 50 crypt or villus columns per rat, not each crypt or villus column, was considered a separate experimental unit to allow for between rat variation on the mean.
Statistical analysis.
Data were compared using one-way ANOVA, which included group effects (SAS Institute, Cary, NC). Group means were considered significantly different at P < 0.05, as determined by the protected least-significant difference technique in SAS. Statistics were performed on log-transformed data for apoptotic parameters because residual plots of these data sets indicated there was unequal variance among groups. The sample size was 8–9 rats per group for jejunal composition and histology data and 5–6 rats per group for apoptosis and mitosis data. Data are presented as mean ± SE.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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IGF-I treatment for 6 d more than doubled BW gain compared with rats given TPN alone (TPN + IGF-I, 30 ± 2; TPN, 13 ± 2 g BW gain/7 d; P < 0.0001). BW gains in orally fed rats (28 ± 4 g BW gain/7 d) were not significantly different from IGF-I-treated TPN rats. Consistent with IGF-I administration, total serum IGF-I concentrations were more than doubled in rats treated with IGF-I compared with rats given TPN alone (TPN, 45 ± 3; TPN + IGF-I, 119 ± 3 nmol/L; P < 0.0001). Serum IGF-I concentrations in rats given TPN alone and orally fed rats were not significantly different (Oral, 53 ± 3 nmol/L).
Jejunal composition and histology.
Similar to our previous observations (3
,4
), the absence of luminal nutrients due to TPN induced jejunal mucosal hypoplasia, as indicated by significantly lower concentrations of protein and DNA (Table 1
) in rats given TPN alone than in orally fed rats. Morphological changes were consistent with the TPN hypoplasia, because rats given TPN alone had villi that were 36% shorter than orally fed rats (Table 1)
. Muscularis thickness did not differ between rats given TPN alone (88 ± 4 µm) and orally fed rats (80 ± 3 µm), suggesting that TPN atrophy was limited to the intestinal mucosa.
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28% lower in rats receiving TPN compared with those consuming food orally. Although we did not measure cell size directly, our data are consistent with a decrease in both cell number and cell size with TPN compared with oral feeding.
IGF-I administration induced mucosal hyperplasia compared with rats given TPN alone as shown by significantly greater mucosal dry mass and concentrations of protein and DNA (Table 1)
. Histology was consistent with the hyperplastic changes because IGF-I-treated TPN rats had significantly taller villi and deeper crypts than rats given TPN alone (Table 1)
. Increases in enterocyte number in the crypt and villus paralleled the IGF-I-induced morphological changes (Table 2
).
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Consistent with the TPN mucosal hypoplasia, the number of mitotic cells per crypt column and the mitotic index in the jejunal crypt (Table 2)
were significantly reduced by 37% and 31%, respectively, in rats given TPN alone compared with orally fed rats. IGF-I treatment significantly increased the number of cells per crypt column (by 31%) and the number of mitotic cells per crypt column (by 37%) but did not affect the mitotic index compared with rats given TPN alone as we previously noted (7
). Based on a greater absolute number of mitotic cells per crypt column, this suggests IGF-I increased proliferation by contributing to a greater number of cell births.
Enterocyte apoptosis in the crypt.
Rats given TPN alone had a significant 3.5-fold increase in the crypt AI compared with orally fed rats (Table 2)
. The significant increase in number of apoptotic cells per crypt column in rats given TPN alone compared with orally fed rats indicates that orally fed rats had an average of 1 apoptotic cell per 16 crypt columns and TPN alone increased the incidence of apoptosis to 1 apoptotic cell every four crypt columns. Even in the presence of significantly increased apoptosis with TPN alone, IGF-I treatment significantly decreased both the mean number of apoptotic cells per crypt column and the AI to the levels in rats fed orally (Table 2)
.
To determine where within the crypt the reductions in apoptosis due to IGF-I occurred, we constructed AI distribution curves (Fig. 2
). Peak incidences of apoptosis typically occur in the stem cell zone of the crypt, cell position (cp) 4 from the crypt base (17
), consistent with our observation in orally fed rats (Fig. 2
; cp 5). Although rats given TPN alone also had peak incidences of apoptosis in the stem cell zone (Fig. 2
; cp 3), the apoptosis was spread throughout the entire crypt (cp 1–30) compared with orally fed rats in which the apoptosis was limited to the bottom half of the crypt (cp 1–15). Apoptosis was also dispersed throughout the entire crypt in IGF-I-treated TPN rats. However, the peak AI was not in the stem cell zone but rather higher in the proliferative zone in rats infused with IGF-I (cp 15). Thus, apoptosis was spread throughout the crypt with parenteral feeding, and the reduction in apoptosis with IGF-I treatment was especially evident in the stem cell zone.
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TPN groups had a significant 7- to 13-fold increase in the villus AI compared with orally fed rats (Table 2)
. The significant increase in number of apoptotic cells per villus column in TPN compared with orally fed rats indicates that orally fed rats had an average of 1 apoptotic cell per 33 villus columns and TPN alone increased the incidence of apoptosis to 1 apoptotic cell every three villus columns. Unlike the effects of IGF-I to decrease apoptosis in the crypt, IGF-I treatment did not affect the number of apoptotic cells per villus column or the villus AI compared with rats given TPN alone. Regardless of feeding method, the apoptosis was confined primarily to the bottom one-half of the villus (Fig. 2
; cp 1–40).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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,4
,18
). This study confirms these observations, shows that TPN atrophy is specific to the small bowel mucosa rather than the muscularis, and extends current understanding of the TPN model by demonstrating that TPN-induced mucosal hypoplasia is associated with reductions in enterocyte proliferation and increases in apoptosis in the crypt and villus. We also show that the mucosal hyperplasia induced by coinfusion of IGF-I with TPN solution reflects increased enterocyte proliferation and decreased apoptosis, particularly in the stem cell zone.
Two main factors help explain the consistent observation of intestinal mucosal hypoplasia in rats maintained exclusively with TPN. First, the significantly lower mitotic index in rats given TPN alone compared to orally fed rats suggests that decreased enterocyte proliferation is one of the mechanisms of TPN–induced mucosal hypoplasia. In our rats given TPN alone, a 30% decrease in the mitotic index corresponded with 35% and 18% decreases in mucosal protein and DNA contents, respectively, compared with orally fed rats. Similar to rats, pigs (19
) and rabbits (20
) had significant 30% reductions in jejunal epithelial proliferation rates after 6 and 10 d of parenteral nutrition, respectively, compared with those receiving luminal nutrition. Moreover, decreased levels of total thymidine incorporation into DNA were observed in small bowel biopsies from human patients receiving one month of TPN for inflammatory bowel disease (21
).
Second, the increased frequency of apoptosis in the crypts and villi with parenteral compared with oral feeding suggests that increased enterocyte death is another mechanism of TPN-induced mucosal hypoplasia. The enhanced apoptosis in the crypts affects the number of cells that can proliferate and migrate onto the villi because a single crypt stem cell may give rise to 60–120 enterocytes (15
,22
). Additionally, the 10-fold significant increase in cell loss by apoptosis in the villi of rats given TPN alone vs. orally fed rats may partially explain the TPN villus atrophy similar to that reported in parenterally fed pigs (19
) and mice (23
). Perhaps the increased incidence of apoptosis with TPN accounts in part for the aberrations in intestinal ion transport function and increased permeability that accompany TPN in rats (3
).
To our knowledge, we are the first to report the location of apoptosis during TPN. Peak incidences of spontaneous apoptosis are generally confined to the stem cell zone of the crypt (22
). However, in parenterally fed rats, apoptosis was dispersed throughout the length of the crypt compared with orally fed rats. This suggests that TPN damages enterocyte DNA or alters apoptotic stimuli such as induction of adhesion factors and gene products regulating apoptosis which differ along the crypt-villus axis (22
). Our observations of greater apoptosis near the bottom one-half of the villus in TPN as well as orally fed rats rather than the top one-half of the villus do not support the hypothesis that enterocyte extrusion from the villi tips is apoptosis-mediated (24
). We speculate that our conservative morphological method for assessing apoptosis may help explain the divergent results as the TUNEL method often shows apoptosis occurring at the villi tips (22
,24
).
The ability of IGF-I to induce intestinal mucosal hyperplasia was associated with increased enterocyte proliferation and decreased crypt cell apoptosis. First, IGF-I increased enterocyte proliferation, similar to previous reports (7
,25
). Second, IGF-I induced mucosal hyperplasia by decreasing crypt cell apoptosis, in particular by suppressing its incidence in the stem cell zone. There are limited reports assessing the anti-apoptotic property of IGF-I in vivo, and few are specific to the intestine. Our data demonstrating the anti-apoptotic property of IGF-I in the jejunal mucosa are consistent with the reduction in apoptosis observed in the ileal mucosa of experimentally jaundiced (26
) and abdominally irradiated (27
) rats treated with exogenous IGF-I.
In summary, the absence of luminal nutrients due to TPN induced significant jejunal mucosal hypoplasia that was associated with decreased enterocyte proliferation and increased apoptosis. Despite the lack of exogenous luminal nutrition, coinfusion of IGF-I with the TPN solution mostly normalized the changes in enterocyte kinetics induced by TPN resulting in mucosal hyperplasia. The ability of IGF-I to prevent or reverse TPN-induced mucosal atrophy by stimulating enterocyte proliferation and decreasing apoptosis substantiates the role of growth factors in tissue regeneration. Future studies aimed at discerning the direct and indirect effects of luminal nutrients will provide insight into the intestinal growth-promoting signals that are missing during TPN and the potential for the development of intestinotrophic peptides, such as IGF-I, which will circumvent the hypoplastic effects of TPN.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations: AI, apoptotic index; BW, body weight; CD, crypt depth; cp, cell position; H&E, hematoxylin and eosin; IGF-I; insulin-like growth factor I; TPN, total parenteral nutrition; TUNEL, terminal deoxyuridine nick-end labeling; VH, villus height.
4 The modified AIN-76A diet (8
) contained (in g/kg): 163 casein, 3 DL-methionine, 635 dextrose, 70 soybean oil, 70 safflower oil, 12 cellulose, 35 AIN-76 mineral mix, 10 AIN-76A vitamin mix, 2 choline bitartrate. All diet ingredients were obtained from Teklad (Madison, WI).
5 TPN solution contained (in g/L): 44 amino acids (Travasol 8.5% with electrolytes; Baxter Healthcare, Deerfield, IL), 180 dextrose (Baxter Healthcare), and 28 lipid (142 mL Intralipid; Kabi Pharmacia, Clayton, NC) (7
). TPN solution included vitamins and trace minerals as previously reported (9
) with the exception of the following minerals (in mg/L) provided by Multitrace-4 (American Regent Laboratories, Shirley, NY): 3 zinc, 1.2 copper, 0.3 manganese, and 0.012 chromium.
Manuscript received 22 February 2002. Initial review completed 12 March 2002. Revision accepted 2 April 2002.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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19. Burrin, D. G., Stoll, B., Jiang, R., Petersen, Y., Elnif, J., Buddington, R. K., Schmidt, M., Holst, J. J., Hartmann, B. & Sangild, P. T. (2000) GLP-2 stimulates intestinal growth in premature TPN-fed pigs by suppressing proteolysis and apoptosis. Am. J. Physiol. Gastrointest. Liver Physiol. 279:G1249-G1256.
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E. M. Dahly, M. J. Grahn, A. K. Draxler, and D. M. Ney Intestinal Adaptation Occurs Independently of Parenteral Long-Chain Triacylglycerol and with No Change in Intestinal Eicosanoids after Mid-Small Bowel Resection in Rats J. Nutr., January 1, 2004; 134(1): 112 - 119. [Abstract] [Full Text] [PDF]
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E. M. Dahly, Z. Guo, and D. M. Ney IGF-I augments resection-induced mucosal hyperplasia by altering enterocyte kinetics Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2003; 285(4): R800 - R808. [Abstract] [Full Text] [PDF]
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E. M. Dahly, M. B. Gillingham, Z. Guo, S. G. Murali, D. W. Nelson, J. J. Holst, and D. M. Ney Role of luminal nutrients and endogenous GLP-2 in intestinal adaptation to mid-small bowel resection Am J Physiol Gastrointest Liver Physiol, April 1, 2003; 284(4): G670 - G682. [Abstract] [Full Text] [PDF]
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M. B. Gillingham, E. M. Dahly, S. G. Murali, and D. M. Ney IGF-I treatment facilitates transition from parenteral to enteral nutrition in rats with short bowel syndrome Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2003; 284(2): R363 - R371. [Abstract] [Full Text] [PDF]
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