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DEVELOPMENT AND TISSUE PLASTICITY
1Department of Nutritional Sciences, University of Wisconsin-Madison, Madison 53706; and 2Department of Pathology and Laboratory Medicine, University of Wisconsin Hospitals and Clinics, Madison, Wisconsin 53792
Submitted 10 January 2003 ; accepted in final form 19 May 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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enterocyte proliferation and apoptosis; insulin-like growth factor-I; intestinal adaptation; bowel resection; total parenteral nutrition
The role that alterations in enterocyte kinetics play in regulating intestinal adaptive growth after resection is incompletely understood (13). For instance, a few reports showed increases in both enterocyte proliferation and apoptosis in association with intestinal adaptive growth after bowel resection (8, 9). Thus it has been suggested that proliferation and apoptosis are coordinately regulated (8). However, other observations of disparate rates of proliferation and apoptosis dispute the notion that proliferation and apoptosis are regulated by the same stimuli (2, 33, 35). Thus further knowledge of both enterocyte proliferation and apoptosis is a vital step in elucidating the factors responsible for the adaptive response to resection and the ability of IGF-I to induce resection-induced adaptation.
In this study, we determine structural adaptation and concomitant changes in enterocyte proliferation, apoptosis, and migration of the jejunum in growing, parenterally fed rats after mid small bowel resection or small bowel transection, and treatment with IGF-I or vehicle. Our objective was to determine if exogenous IGF-I augments the adaptive response to mid small bowel resection in association with changes in enterocyte kinetics.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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The experimental design included four parenterally fed treatment groups run concurrently in a 2 x 2 factorial treatment design as follows: gut resection (R; n = 13), resection + IGF-I (R + I; n = 13), gut transection (T; n = 13), and transection + IGF-I (T + I; n = 12). The experiment began with 14 animals in each group immediately after surgery; one animal died during surgery. During the administration of exclusive total parenteral nutrition (TPN), one to two animals were removed from each group due to loss of catheter patency. Thus 7 days after surgery, 85-93% of the animals initially assigned to each group completed the study (n = 12-13).
Surgical protocol and tissue collection. Animals were adapted to the facility for 3-4 days while being fed a nutritionally complete, semipurified powdered diet ad libitum (3). Three days before surgery, animals were fed a semielemental, residue-free, liquid diet ad libitum (Vital, donated by Ross Labs, Columbus, OH) (2). On the day of surgery (day 0), rats were anesthetized, given ampicillin (200 mg/kg sc) to prevent infection (2, 4), and prepped for surgery (2). Resected animals underwent a 70% mid jejunoileal resection as previously described in detail (2). Briefly, resected animals had bowel from 15 cm distal to the ligament of Treitz until 15 cm proximal to the cecum removed and continuity restored with an end-to-end jejunoileal anastomosis. Transected animals received a transection cut in the ileum (2) and suturing to reestablish continuity. The TPN catheter was placed in the superior vena cava via the external jugular vein (16) after closing the midline abdominal incision.
Immediately after surgery (day 0), infusion of a nutritionally
complete TPN solution (2,
3) was initiated, and water was
provided ad libitum. For 24-48 h after surgery, animals received oxymorphone
HCl for pain management and ampicillin to prevent infection (200 mg/kg iv
every 12 h) (2,
4). Body weights were recorded
daily. Changes in body weight due to resection or IGF-I treatments were
calculated as the difference between body weights on the day animals were
killed (day 7) and the preoperative body weights on the day of
surgery (day 0). Resected rats lost 
5 g of intestinal tissue due
to surgery. Urine was collected daily into vials containing a final
concentration 0.01% boric acid and then stored at 4°C before determination
of nitrogen concentration as previously outlined
(43). After 7 days of TPN,
rats were anesthetized, killed by exsanguination, and the jejunum was
obtained, processed, and analyzed for histology and mucosal mass, protein, and
DNA as previously described
(2).
IGF-I administration and assessment. IGF-I-treated animals received 3.2 mg recombinant human IGF-I (rhIGF-I) · kg body wt-1 · day-1 concurrent with continuous infusion of TPN for 6 days (rhIGF-I supplied through the courtesy of Genentech, South San Francisco, CA). Confirmation of IGF-I administration was assessed by analyzing total serum IGF-I concentrations by radioimmunoassay (19). Serum levels of IGFBPs were estimated by modified Western ligand blotting (7, 14).
Jejunal kinetics: enterocyte proliferation and migration. Bromo-2'-deoxyuridine (BrdU) incorporation into proliferating (S phase) cells in jejunal tissue sections was used to determine enterocyte proliferation and migration rates (12). Animals received an intravenous bolus of BrdU (Sigma Chemical, St. Louis, MO) at a dose of 0.2 mg/g body wt. Animals were injected at the same time of day (0900) and killed 1 or 25 h later (n = 4-7 animals per time point per group). The 24-h difference in time points and the same injection time (0900) were selected to account for circadian variations in mucosal proliferation and enterocyte movement patterns (26). The paraffin-embedded tissue was cut into 5-µm sections, processed for immunoperoxidase staining of BrdU-labeled cells (5, 15), and counterstained with Mayer's hematoxylin (Sigma Chemical).
One investigator, blinded to the treatment groups, assessed an average of seven well-oriented crypt-villus axes per animal under a light microscope. For each animal, the total number of cells and the number and position of BrdU-labeled cells were recorded. The scoring was initiated with the cell at the base of the crypt that was designated cell position 1 and continued to the crypt-villus junction in the 1-h animals and until the last labeled cell in the villus of the 25-h animals. From these data, three parameters were assessed. First, enterocyte proliferation was assessed by counting the number of labeled cells in a column and the total number of cells per column in the crypts of animals injected 1 h before death. The proliferation index was determined by expressing the number of labeled crypt cells to total crypt cells as a percentage. Second, patterns of labeling were identified in animals injected 1 h before death from labeling index distribution curves based on group means that plotted cell position vs. percent labeling at each position similar to Steeb et al. (31). Third, migration rate was assessed by comparing both median-labeled cell (MLC) or foremost-labeled cell (FLC) positions on each crypt-villus axis at 1 or 25 h. MLC, defined as the 50th percentile value at which labeling occurred, can be thought of as the "centrally" labeled cell and was used as a descriptive means of location in the asymmetric distributions. FLC, defined as the highest labeled cell from the base of the crypt, can be thought of as the "leader" cell. Migration rates were calculated as the difference between means of MLC or FLC positions in animals injected at 1 or 25 h and expressed as change in position of MLC or FLC over 24 h to account for circadian rhythms in migration rate (26). A conservative method was used for the statistical assessment of proliferation and migration. That is, each animal, not each crypt-villus axis, was considered as a separate experimental unit to allow for between-animal variation on the mean.
Jejunal mitosis and apoptosis. Conventional light microscopy of hematoxylin- and eosin-stained specimens was used to quantitate mitosis and apoptosis in the jejunum as previously detailed (2, 3). Briefly, 50 crypt and 50 villus columns were assessed per animal (n = 5-6 animals per group) for characteristic findings of mitotic and apoptotic cells (3).
Data are presented two ways as before (2) to normalize for the postoperative effects of resection and/or IGF-I to increase the total number of cells in the crypt or villus columns. First, data are presented as the mean number of mitotic or apoptotic cells per column. Second, data are presented as a mitotic or an apoptotic index. As in the BrdU-labeled cell analyses, each animal, not each column, was considered a separate experimental unit.
Statistical analysis. The four TPN groups in the factorial
arrangement were compared in a two-way ANOVA, unless otherwise stated, which
determined the significance of main effects and interaction between resection
and IGF-I using generalized linear models in SAS. Main effects for resection,
IGF-I, or their interaction were considered to be significant at P
0.05. Outcomes were predicted in an additive manner if there was a lack
of significant interaction in the two-way ANOVA. One-way ANOVA followed by the
protected least-significant differences technique in SAS was used to determine
significant differences between group means at P 0.05.
Changes in body weight were assessed by repeated-measures ANOVA,
incorporating the treatment factors, resection and IGF-I, time effects, and
interactions of these factors. Wilks' Lambda was used to determine
significance at P 0.05. Migration rates were assessed by
contrast analysis that compared means of the four TPN groups while accounting
for group variation. A three-way ANOVA with main effects for time, resection,
and IGF-I was used to isolate the effects of resection and IGF-I on migration
rate. Resection and IGF-I were considered to have an effect on migration rate
if the interactions of resection x time and IGF-I x time,
respectively, were significant (P 0.05). Data are presented as
means ±SE. Statistics were performed on transformed data for parameters
of apoptosis because residual plots indicated that there was unequal variance
between groups. The sample size is 12-13 rats per group for jejunal structure
and composition data and 4-7 rats per group for enterocyte proliferation,
apoptosis, and migration data, unless otherwise stated.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Body weight gains in resection and transection animals not given IGF-I were not significantly different after 7 days of TPN (R, 10 ± 2; T, 12 ± 2 g body wt gain/7 days). IGF-I treatment for 6 days nearly tripled body weight gain in both resected and transected rats compared with non-IGF-I-treated animals (main effects, 2-way ANOVA, IGF-I, P < 0.0001; R + I, 29 ± 2; T + I, 33 ± 2 g body wt gain/7 days). Repeated-measures analysis of body weight confirmed that IGF-I administration significantly increased body weight (main effects, IGF-I x time, P < 0.0001) and indicated that resection had no overall effect on body weight.
Total nitrogen retention data over 7 days of TPN are summarized in Fig. 1, inset. Nitrogen intake was not significantly different among groups, but nitrogen excretion was significantly greater in animals not given IGF-I (data not shown; main effects, 2-way ANOVA, IGF-I, P < 0.0018). Thus treatment with IGF-I resulted in significantly greater nitrogen retention in both resected and transected rats. There were no significant differences in nitrogen retention between resected and transected animals maintained with TPN without IGF-I. Cumulative nitrogen retention was positively correlated with changes in body weight (r = 0.76, P < 0.0003, n = 4-5 animals per group), suggesting that increases in body weight reflected, in part, increases in lean body mass.
Coinfusion of IGF-I with the TPN solution was confirmed by serum IGF-I concentrations. Total serum IGF-I concentrations were over twofold greater in animals treated with IGF-I than in animals maintained with TPN alone (R, 362 ± 11; T, 337 ± 23; R + I, 882 ± 44; T + I, 857 ± 43 µg/l). Both IGF-I and resection increased serum IGFBP-3 at 38-43 kDa, IGFBP-1, -2, -4, and -5 at 30-34 kDa, and total IGFBPs (Fig. 2; main effects, resection or IGF-I, 2-way ANOVA, P < 0.0142) (7). Neither resection nor IGF-I treatments significantly affected IGFBP-6 at 24 kDa.
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Jejunal composition and histology. Resection and IGF-I had additive effects to significantly increase jejunal mucosal dry mass and concentrations of protein and DNA as evidenced by significant main effects for resection and IGF-I without significant interaction (Fig. 3; main effects, resection or IGF-I, 2-way ANOVA, P < 0.0001). Parallel significant increases in the concentrations of mucosal protein and DNA with resection or IGF-I administration indicate that intestinal resection or IGF-I treatment induced mucosal hyperplasia. Resection or IGF-I treatment significantly increased villus height; however, IGF-I treatment did not increase villus height further in resection animals compared with animals receiving resection alone (Fig. 4; main effects, resection x IGF-I, 2-way ANOVA, P = 0.0005). IGF-I may have heightened villus height in an additive manner as it did mucosal mass and cellularity had the adaptive response been assessed after more cycles of enterocyte turnover took place.
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Enterocyte proliferation in the jejunum. Resection significantly increased both the number of cells in a crypt column and the number of BrdU-labeled cells in the crypt column (Table 1; main effects, 2-way ANOVA, resection, P < 0.0192). Animals receiving resection alone also had significantly more mitotic cells per column than transected animals not given IGF-I (Table 1). The proliferation index, or the percentage of cells in the crypt incorporating BrdU, as well as the mitotic index, was not significantly different between groups. Constant labeling indexes are often seen after resection (40). Based on a greater absolute number of crypt cells that incorporated BrdU and a greater number of mitotic cells per crypt column, this suggests resection increased proliferation by contributing to a greater number of cell births. Likewise, IGF-I increased proliferation by significantly increasing the number of cells in a crypt column, the number of BrdU-labeled cells in the crypt column, and the number of mitotic cells per crypt column (Table 1; main effects, 2-way ANOVA, IGF-I, P < 0.0117).
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To further assess the mitogenic properties of resection and/or IGF-I on the
jejunal epithelium, we constructed BrdU-labeling distribution profiles
(31) for each group based on
data from animals injected with BrdU 1 h before death
(Fig. 5). By dividing the
crypts into thirds based on cell position (cp) (lower, cp 1-10; mid, cp 11-20;
upper, cp 21-30), we determined three trends from these curves. First,
resection animals receiving no growth factor had the greatest average labeling
indexes in the lower-third of the crypt (45%) compared with the other TPN
groups (27-32%). Second, IGF-I treatment increased the average labeling
indexes in midcrypt positions compared with groups receiving no growth factor
(50 vs. 35%). Third, IGF-I administration increased the average labeling
indexes in the upper-third of the crypt compared with groups receiving no
growth factor (15 vs. 2%).
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In summary, resection or IGF-I treatment significantly increased jejunal proliferation by increasing crypt cell populations and establishing a greater number of cell births. Increased proliferation with resection was due to increasing the proportion of proliferative cells in lower positions of the proliferative zone whereas IGF-I treatment increased proliferation at higher positions of the proliferative zone as shown by the increased average labeling indexes in the mid- and upper crypt. Thus IGF-I increased the overall area of the proliferative compartment in the crypt.
Enterocyte apoptosis in the jejunum. In the crypt, resection significantly decreased the mean apoptotic index over 50% in animals not given IGF-I based on 1-way ANOVA due to significant interaction in the main effects (Table 2). Like resection, IGF-I treatment also decreased the mean apoptotic index in the crypt compared with transected animals given TPN alone (Table 2). However, IGF-I treatment did not further decrease the crypt apoptotic index in resected animals. Unlike the effects of resection or IGF-I to decrease apoptosis in the crypt, neither resection nor IGF-I treatment significantly affected the mean apoptotic index in the villus.
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Enterocyte migration rate in the jejunum. Migration rate data are shown in Table 3. There were no significant differences in MLC, i.e., the central cell, or FLC, i.e., the leader cell, positions between resected and transected animals injected 1 h before death. However, the FLC position was significantly higher (15 cell positions) in resected animals injected 25 h before death compared with transected animals maintained with TPN alone. Thus resection significantly increased the migration rate of the FLC. Resection also tended to increase the migration rate of the MLC (P = 0.0634).
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IGF-I treatment, unlike resection, resulted in a significantly greater MLC and FLC positions in animals injected 1 h before death, consistent with an increase in the proliferative zone of the crypt. In animals injected 25 h before death, the FLC was also greater in IGF-I-treated animals compared with transected animals given TPN alone; however, IGF-I did not increase migration rate further in resected animals.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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The effect of IGF-I to additively increase jejunal mucosal growth and
cellularity in parenterally fed, resected rats is similar to IGF-I's ability
to induce small intestinal adaptation after mid small bowel resection in
orally (17,
38) or gastrostomy
(44,
45)-fed animals. Yet, our
parenterally fed mid small bowel resected animals had a net body weight gain
that was nearly tripled with IGF-I treatment, whereas animals fed orally or
intragastrically in the presence
(45) or in the absence
(17,
44,
45) of IGF-I had a net body
weight loss over 7 days after mid small bowel resection. The more anabolic
condition of our TPN rats was reflected not only in an overall positive
nitrogen balance but also in similar concentrations of total circulating IGF-I
in resection compared with transection animals. This is in contrast to the
weight loss and 16% decrease in plasma IGF-I after resection and
gastrostomy feeding (45).
Resection and IGF-I significantly increased serum IGFBPs in an additive manner. This suggests that a potential decrease in the pool of circulating free IGF-I that is available to IGF-I receptors does not hinder the additive response in resection-induced intestinal growth in IGF-I-treated animals. Moreover, the resection-induced adaptation was not associated with alterations in abundance of jejunal IGF-I mRNA based on preliminary studies with this model (1).
The ability of both resection and IGF-I to induce mucosal hyperplasia was associated with increased enterocyte proliferation, based on a greater absolute number of BrdU-labeled cells, a greater number of mitotic cells, and an increased total cell number in the crypt. The resection-induced increase is consistent with increases in epithelial proliferation that have been described after mid small bowel resection and oral feeding (8, 9, 30, 36). This heightened proliferative activity may have been accomplished by a decrease in the cell cycle time in enterocytes in lower cell positions (31). The ability of IGF-I to augment intestinal adaptation is consistent with the ability of acute exogenous IGF-I to stimulate proliferation in a distal small bowel resection and cecectomy model (5) and in intact rats fed orally (25, 31, 32) or parenterally (3) and with the ability of chronic endogenous IGF-I excess to increase mitogenesis threefold in IGF-I transgenic mice (39). IGF-I also expanded the size of the proliferative compartment, as reflected by an increase in the leading edge of labeled cells along the crypt column in animals injected 1 h before death (27). Moreover, 6 days of IGF-I administration resulted in a greater proportion of cycling cells in the upper crypt cell positions, suggesting that migrating enterocytes retained their proliferative properties and had not crossed into the maturation zone of the crypt, similar to that reported in rat small bowel after 3 days of treatment with an IGF-I analog (31).
Although we observed additive increases in proliferation due to IGF-I and
mid small bowel resection, we observe significant interaction in crypt cell
apoptosis. Specifically, resection alone compared with transection decreased
crypt cell apoptosis over 50% whereas IGF-I-treatment after resection did not
significantly alter crypt cell apoptosis compared with resection alone. The
lack of a further decrease in apoptosis after resection in IGF-I-treated
animals contrasts with our previous report of an IGF-I-induced decrease in
apoptosis of 75% in parenterally fed rats with intact bowel
(3). Moreover, others have
observed significant 70 and 60% decreases in spontaneous and
irradiation-induced apoptosis, respectively, in the jejunum after chronic
endogenous IGF-I excess in transgenic mice that overexpress IGF-I
(39) and a reduction in
apoptosis in the ileal mucosa of experimentally jaundiced rats treated with
exogenous IGF-I (28). Thus
resection in combination with TPN appears to diminish the ability of IGF-I to
reduce enterocyte apoptosis.
We speculate that the inability of IGF-I to decrease apoptosis further after resection is due to the fact that incidences of apoptosis in the presence of resection and/or IGF-I in parenterally fed rats are already at low levels we previously observed in orally fed animals (3). This may also be due to the ability of resection or IGF-I to impact on the same cellular signaling pathways leading to enterocyte apoptosis. Specifically, alterations in the proapoptotic Bax proteins and the antiapoptotic Bcl-2 subfamily of proteins are associated with changes in enterocyte apoptosis after small bowel resection (34, 35) or administration of IGF-I (39). Furthermore, apoptosis may be intimately linked with villus height, and the equally tall villi in parenterally fed resected and/or IGF-I-treated animals are all associated with similar low levels of crypt cell apoptosis. Nevertheless, others have suggested that the taller villi and deeper crypts that characterize the adaptive response to resection are maintained by concomitant increases in enterocyte proliferation and apoptosis. In particular, resection significantly increased intestinal growth in conjunction with increases in both proliferation and apoptosis in orally fed rabbits (36) and mice (8, 9). The discrepancies that exist between incidences of apoptosis after mid small bowel resection and TPN (2), oral feeding (2, 8, 9, 36), and/or administration of growth factors must be interpreted cautiously as differences in methods of detecting apoptosis exist (2).
Resection but not IGF-I significantly increased enterocyte migration rate.
The resection-induced increase in migration was similar to that reported in
orally fed rats (40). The
IGF-I-induced significant increase in proliferation but no significant
increase in migration after resection is consistent with the 40% increase
in proliferation but no increase in migration in formula-fed piglets treated
with IGF-I compared with vehicle for 14 days
(10). Yet, IGF-I
administration stimulated increases in migration rate in gastrostomyfed infant
rats (23) and in a distal
small bowel resection and cecectomy model
(5) and tended to increase
migration in our previous report of parenterally fed rats with intact gut
(21). We cannot reconcile our
contrasting observations of IGF-I-induced effects on migration rate with a
species-specific phenomenon, so it is perhaps a function of the distinct
animal models or the statistical methods used to determine migration.
Nevertheless, we observe the calculated migration rate was 60-85%
greater for all treatment groups based on FLC rather than MLC positions. This
suggests the migration velocity increases as cells move up the crypt-villus
axis (26). The factors driving
the greater migration with resection are unknown. Yet, it seems clear that
proliferation within the intestinal crypts and enterocyte migration along the
crypt-villus axis are independently regulated as enhanced proliferation does
not necessarily drive migration
(11,
24).
In conclusion, we have shown that IGF-I augments increases in mucosal mass and concentrations of protein and DNA stimulated by the endogenous response to resection. The mucosal hyperplasia induced by resection alone was associated with increased enterocyte proliferation and migration and decreased apoptosis. IGF-I additively increased the resection-induced growth and hyperplasia in association with increased enterocyte proliferation and expansion of the proliferative compartment in the crypt. IGF-I did not confer any significant additional effect beyond resection alone with respect to enterocyte apoptosis or migration. The enhancement of the endogenous hyperplastic response to resection by IGF-I treatment substantiates the role of IGF-I as an intestinal mitogen that promotes tissue regeneration. The lack of a further decrease in apoptosis in resected rats given IGF-I may suggest that IGF-I therapy would pose a modest risk for cancer when used after intestinal resection. Introduction of oral feeding after acute treatment with IGF-I after resection may help to sustain the intestinotrophic effects of IGF-I (6).
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DISCLOSURES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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ACKNOWLEDGMENTS |
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Jejunal composition, apoptosis, and some proliferation data from the T and R groups were previously published (2) but are included in the current report to establish a baseline for the additive effects of IGF-I and resection within the experimental design utilized.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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