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2 Nutrition and Health Science Program, Graduate School of Arts and Sciences, Emory University, Atlanta, GA 30322; 3 Department of Medicine and 4 Center for Clinical and Molecular Nutrition, Emory University School of Medicine, Atlanta, GA 30322; 5 Department of Surgery, Toho University School of Medicine, Tokyo, Japan; and 6 Specialty Care Service Line, St. Louis VA Medical Center, St Louis, MO 63106; and 7 Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
* To whom correspondence should be addressed. E-mail: tzieg01{at}emory.edu.
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ABSTRACT |
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 TOP ABSTRACT IntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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Introduction |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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In rodent models of SBR alone, early small bowel adaptive responses, including gene expression changes (6–9) and increased mucosa wet mass, protein, and DNA content (10) are reported within several hours to a few days after intestinal resection. However, in rats, near-maximal adaptive growth occurs 1–2 wk after resection and is fully established by 
4 wk (11,12). The characteristics and extent of this adaptive growth vary over the course of the residual small intestine, with the most marked changes occurring in the ileum in most studies (13–17).
Glutathione (GSH) constitutes the major intracellular low molecular weight thiol. It functions as a substrate in detoxification against oxidative and chemical injury and has a variety of other cytoprotective effects (18). Accumulated observational data in multiple cell lines suggest that increased GSH content is associated with increased cell proliferation (19,20), whereas blockade of GSH synthesis with the specific inhibitor D, L-buthionine-sulfoximine (BSO) decreases cell proliferation in vitro (20–23). Recent in vitro studies in leukemia cells found that GSH depletion with BSO also sensitizes cells to apoptosis signaling (24), whereas other data in lymphoma cells suggest that decreased GSH alone can act as a potent early activator of apoptotic signaling (25).
In small intestine, as epithelial cells move along crypt-villus axis and become less proliferative and more differentiated, their cellular GSH content declines (26) and GSH efflux into the lumen increases (27). In intact rat models of fasting or generalized undernutrition, decreased GSH content and oxidized redox in small intestinal mucosa occurred concomitantly with evidence of impeded mucosal cell growth and increased apoptosis; these changes are reversed by refeeding or keratinocyte growth factor treatment (which restores GSH content), respectively (28,29). In the only previous in vivo study of blockade of GSH synthesis with BSO and intestinal mucosal morphology, BSO administration in mice resulted in severe degeneration of jejunal and colonic epithelial cells; this intestinal damage seemed to be prevented by concomitant GSH administration (30).
GSH levels in tissue may influence cell proliferation and survival through changes in the GSH: GSH disulfide (GSSG) ratio or the redox potential (Eh) of this pool (31,32), which may modify the thiol group of proteins involved in cellular proliferation and apoptosis, such as NF-
b (33). In human fibroblasts, cell density was positively associated with a more reducing intracellular redox state and was inhibited when cells were treated with BSO (34). Similar associations have been made in a number of intestinal and other cell lines (21,34–38), suggesting that a more oxidizing redox state occurs as cells transition from proliferation through contact inhibition, differentiation, and apoptosis lines (34–39).
Despite the studies outlined above, the notion of an essential need of GSH for cell growth is challenged by other research. For example, glutamyl cysteine ligase mutant mice, which cannot synthesize GSH, fail to develop properly and die at fetal stage; however, isolated homozygous mutant blastocysts can grow indefinitely in GSH-free medium supplemented with N-acetylcysteine (40). Additional in vitro studies found that BSO-induced depletion of cellular GSH was not correlated with changes in cell proliferation (32,39,41) or apoptosis (42). In some cell lines (baby hamster kidney fibroblast and human uterine cervical carcinoma cell), cellular levels of GSH actually decline during the normal growth phase (43). Furthermore, studies using the lung carcinoma cell line (A549) (44) and human aortic smooth muscle cells (45) demonstrated upregulated growth in the presence of BSO. Indeed, a subtoxic level of cellular oxidation stimulates cell proliferation and suppresses apoptosis by activating a number of key signaling factors in some systems (46). Such findings point to the complexity of GSH association with cell growth and the need for additional in vitro studies that are lacking.
Given the conflicting in vitro data with regard to the effect of GSH status on cell growth, this in vivo study was undertaken to examine the influence of marked blockade of GSH synthesis with BSO on ileal mucosal growth and cell turnover in a rat model of ileal adaptive growth induced by massive SBR.
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Materials and Methods |
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Experimental design and operative procedures. In Experiment 1, 27 rats (230 ± 2 g) were assigned by weight to 4 groups: 1) sham-operated rats without BSO treatment in which saline was injected as the control after small bowel transection and reanastomosis [transected-saline treated (TX/sal), n = 7]; 2) sham-operated rats given BSO treatment [transected-BSO treated (TX/BSO), n = 7; see dose below]; 3) SBR rats given saline [resected-saline treated (RX/sal), n = 6]; and 4) SBR rats given BSO [resected-BSO treated (RX/BSO), n = 7]. Rats were food deprived overnight before operation. The following day (d 1), the rats underwent laparotomy from 0900 to 1200 for 80% jejunoileal resection or transection, as previously described (35). In RX rats, 80% of the small bowel was removed, using defined landmarks 10 cm distal to the ligament of Treitz and 10 cm proximal to the ileocecal junction, whereas in TX rats, the intestine was transected at the point 10 cm proximal to the ileocecal junction. Rats were allowed access to water after operation and pelleted food from d 2. Rats in groups of TX/sal, TX/BSO, and RX/sal were pair-fed the mean daily food intake of the RX/BSO group. Body weight and food intake were determined daily after operation until killing 7 d after operation. BSO treatment was given for 3 d, beginning on the morning of d 5. BSO was given intraperitoneally (i.p.) at a dose of 0.25 mmol/kg twice daily and 10 mmol/L BSO was also added to the drinking water, as outlined previously by Martensson et al. (17). Rats were injected i.p. with 120 mg/kg 5-BrdU (40 g/L 5-BrdU and 4 g/L 5-fluorodeoxyuridine) 90 min before being killed by exsanguination.
In Experiment 2, rats (229 ± 2 g) were assigned by weight to 3 groups: TX/sal, RX/sal, and RX/BSO (n = 2–5 per group). These rats underwent the same treatments as in the Experiment 1 except that the same dose of BSO or saline was given just prior to operation and continued as outlined above until killing by exanquination at either 2 or 4 d postoperatively. Rats were pair-fed to the mean daily food intake of the RX/BSO group. These studies were performed to assess whether BSO-induced GSH depletion at earlier time points after bowel resection influences postoperative ileal growth responses at earlier stages in the adaptive process.
Tissue collection. Rats were killed between 0900 and 1200 on d 8. The ileum was stripped of mesenteric and vascular connections and removed from the peritoneum. The bowel lumen was flushed with ice-cold saline to clear intestinal contents and suspended from a ring stand with a constant distal weight. The segments used for the endpoints of this study were collected sequentially at equivalent sites of each rat. The segments used for mucosal thiol analysis were longitudinally cut and the mucosa obtained by gentle scraping with a glass slide. The mucosa was then immediately placed in liquid nitrogen for further processing.
Histology. Defined segments of ileum were fixed with 10% formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin. We examined slides for morphological damage by light microscopy. Villus height (VH) and crypt depth (CD) were measured as indices of mucosal growth in longitudinally oriented full-length crypts and villi. The ileal VH and CD data were derived from the mean of 20 representative villi and crypts per rat counted in a blinded fashion. Total mucosal height was calculated as the sum of VH and CD. Ileal samples from additional resected rats, treated with or without BSO, were processed using standard methods for evaluation of microvilli and other ultrastructural elements by electron microscopy.
Crypt cell proliferation. Crypt cell proliferation was assessed using 5-BrdU incorporation to identify cells in the S-phase of cell cycle as previously described (35). 5-BrdU was detected with a monoclonal antibody and a streptavidin-biotin staining system. The number of labeled cells in 10 well-oriented longitudinal crypts of each sample was determined with a light microscope by an examiner unaware of treatments and reported as numbered 5-BrdU-labeled cells per 1000 crypt cells.
Apoptosis. Apoptotic cells were determined in colonic crypts by an examiner who did not know the study groups, using classic morphologic changes, including nuclear condensation, perinuclear clearing, and cell shrinkage as previously described (47). This method of identifying apoptotic cells, presently considered the reference standard by Potten (48), is precise if representative morphologic changes are observed. To confirm the morphological results, we also performed terminal TUNEL immunohistochemistry using the In Situ Cell Death detection kit fluorescein, as described by the manufacturer (Roche Applied Science). Briefly, the slides were washed in PBS and then incubated with FITC-labeled dUTP in the presence of terminal deoxynucleotidyl transferase for 1 h at 37°C. The nuclei were stained with 4',6-diamidino-2-phenylindole. The apoptotic index was calculated as the number of apoptotic cells per 1000 crypt cells counted.
Thiol determination.
The method used for measuring GSH and GSSG has been previously described in detail by our group (16,37). Quantitation was based on integration relative to an internal standard (
-glutamyl-glutamate) and expressed as nmol/mg protein for mucosal samples. The Eh for the GSH/GSSG couples were calculated from the respective concentrations using the Nernst equation as previously described (16,37).
Lipid peroxidation. The free MDA content in the full-thickness defined ileal samples was determined using the Bioxytech LPO-586 kit method. Samples were thawed and homogenized in phosphate buffer (pH 7.4) and then centrifuged at 4000 x g; 10 min. The homogenates were then analyzed following the manufacturer's protocol. Standard curves were constructed using the MDA standards provided with the kit. Results were standardized relative to the tissue weight of the original homogenate.
Statistical analysis. In Experiment 1, the study was arranged as a 2 x 2 factorial design, with operation (RX vs. TX) and BSO treatment (BSO vs. saline) as the 2 main factors. Two-way ANOVA was initially performed to determine the significance of main effects and their interaction (significant if P < 0.05). In Experiment 2, results from the 3 groups of rats in each of the 2 subexperiments (BSO treatment from just before operation until 2 or 4 d after operation, respectively) were analyzed by 1-way ANOVA. This was followed by the post hoc Fisher's protected least-significant difference test if a significant difference was indicated. Variance was accounted for in the ANOVA. All statistics were conducted using SPSS. Data are presented as means ± SEM.
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Results |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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BSO treatment 5–7 d postoperative resulted in marked ileal GSH depletion and oxidative stress without morphologic toxicity.
RX increased ileal GSH, and BSO decreased ileal mucosal GSH and GSSG levels and oxidized ileal Eh (Table 1). Blockade of GSH synthesis with BSO in Experiment 1 (Table 1) resulted in a 
95% decrease in ileal mucosal GSH concentrations (P < 0.05) and a 80% decrease in ileal mucosal GSSG concentrations (P < 0.05). BSO also substantially oxidized the redox potential of the ileal mucosal GSH/GSSG pool (Eh) in both bowel transected rats and in rats undergoing massive SBR (P < 0.05) (Table 1).
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Despite the marked BSO-induced decrease in ileal GSH and GSSG, oxidation of the ileal GSH/GSSG redox pool, and increased ileal MDA concentration, there was no evidence of morphological damage in the ileum of BSO-treated rats as evaluated by light microscopy (Fig. 1A–D). Electron microscopy studies in rats given BSO also showed no evidence of cellular injury (mitochondrial swelling, vacuole formation, or evidence of microvillus shortening) (Fig. 1E,F).
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Effects of BSO administration 5–7 d postoperative and SBR on Ileal crypt cell apoptosis. Morphologic evaluation of ileal crypt cell apoptosis demonstrated that BSO modestly increased and SBR modestly decreased apoptosis (P < 0.05) (Table 1). Apoptosis assessed in the same ileal sections by the TUNEL assay did not show any differences among the groups (Table 1).
BSO administration 0–4 d postoperative depletes ileal GSH and oxidizes GSH/GSSG redox without altering ileal growth. Experiment 2 was performed to determine the time course of postoperative ileal cell proliferation and whether it could be affected by GSH depletion given immediately postoperatively and during the early postresection phase (0–2 and 0–4 d, respectively). The BSO regimen markedly depleted ileal mucosal GSH and GSSG and oxidized GSH/GSSG Eh at each of these early time points (Table 2). Although no changes in CD or VH were evident at 2 and 4 d postoperative (Table 2), the BrdU incorporation tended to be higher (P = 0.054) in RX/sal rats than in TX/sal rats at 2 d (Table 2), indicating stimulation of DNA synthesis before growth changes are evident as CD or VH. Despite marked mucosal GSH depletion, neither ileal VH, CD, or BrdU incorporation were altered by BSO at either of these 2 early postoperative time points (Table 2).
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Discussion |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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In rats, indices of adaptive ileal mucosal growth after SBR occur within hours or a few days after resection, but the largest proportion of ileal adaptation is established by 7 d after operation (10,11,49). In this study, the increase of ileal growth indices occurred subsequent to ileal crypt cell BrdU incorporation in resected rats. The rate of BrdU incorporation reached a peak at 2 d after operation (>50% labeling of total crypt cells) then gradually declined to 40% on d 4 and <30% by d 7. A similar rate of BrdU labeling using the same incubation time and staining method has been previously reported in a mouse SBS model (47).
Given the rapidity of small bowel enterocyte turnover in this model (49) and the fact that BSO is a fast-acting, potent, and irreversible inhibitor of GSH synthesis (51), a 2- to 4-d period of BSO-induced GSH depletion should be a sufficient period of time to have an impact on the ileal adaptive growth indices we measured if GSH was involved in the regulation of such growth. Martensson et al. (30) administered BSO in intact mice for a longer period of time (2 wk) than in our experiments, which resulted in jejunal villous atrophy and marked morphologic derangements of both jejunal and colonic mucosal epithelial cells. Our study used shorter periods of treatment and lower doses of BSO dose than were used by Martensson et al. (30). However, we demonstrated a similar extent of GSH depletion in gut mucosa (95%). In contrast to the observations in mouse jejunum and colon by Martensson et al. (30), we found no evidence of mucosal injury in our rat ileal samples. This raises the possibility that some of the effects observed by Martensson et al. (30) may have been secondary to nonspecific toxicity at high BSO doses. In addition, species differences and differences in the gut mucosal response to BSO in intact vs. small-bowel operated rats and in jejunum vs. ileum may have contributed to the different outcomes.
When GSH was markedly decreased by BSO, a marginal increase in ileal crypt cell apoptosis occurred, but morphologic and subcellular growth indices and ileal crypt cell proliferation were unaffected in both transected and bowel-resected rats. Although several studies found increased apoptosis in the residual ileal crypts in murine and rabbit models of SBS (1,4), previous reports on apoptosis in rat models of SBS are variable (2,5,10). Previous data in rodent SBS models also suggest that apoptosis and small bowel mucosal adaptive growth responses are disassociated (52). Consistent with this, in our study, the tendency for BSO to increase ileal crypt cell apoptosis did not significantly blunt the net increase in adaptive ileal growth after SBR. Longer time course studies with BSO treatment after massive SBR would be of interest to assess whether increased epithelial apoptosis persists during GSH depletion and whether this is associated with blunted adaptive small bowel mucosal growth.
As noted, numerous previous reports document an association between cellular GSH status and cell turnover in vitro (19–25), supporting the view that GSH concentration is positively associated with proliferation and growth and negatively with apoptosis. Our data suggest that GSH depletion may in fact modestly increase apoptosis in rat ileum in vivo. The underlying mechanisms of these associations are unclear but have been attributed to the effect of GSH/GSSG redox status on redox signaling, i.e. through reversible modification of the sulfhydryl group on active cysteine residues of signaling molecules (31). Recent studies reveal that redox signaling is a highly complicated process in which cellular signaling pathways are subjected to dual (both stimulatory and inhibitory) redox regulation (2,53). The change of GSH status may bring about changes of other redox-sensitive systems such as reactive oxygen species, the cysteine/cystine couple, and thioredoxins, which have diverse regulatory signaling effects in cell turnover (50,53). Our results show that despite marked depletion of the ileal mucosal GSH redox pool and oxidation of the Eh, ileal growth and proliferative indices were not significantly affected in our rat models. Such a lack of association between in vitro cell growth and local GSH concentrations has been reported in literature (45,46). Such observations suggest that a close and conserved cause and effect relation between GSH status and cell growth/proliferation may not occur in vivo. A limitation of our study was that the change in the GSH/GSSG pool is only 1 index of oxidative stress. Thus, we measured MDA as a marker of lipid peroxidation, but this is a relatively crude index. Additional studies on other measures of oxidative stress, such as oxidatively modified proteins or nucleic acids, would be of interest in our models.
In summary, marked GSH depletion and oxidation of GSH/GSSG redox in rats did not significantly alter ileal epithelial cell proliferation or morphologic indices in intact rats or in rats after SBR. Our in vivo data suggest that local GSH redox status does not regulate ileal mucosal growth after SBR in rats.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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8 Abbreviations used: BrdU, bromodeoxyuridine; BSO, D, L-buthionine-sulfoximine; GSH, glutathione; GSSG, glutathione disulfide; MDA, malondialdehyde; RX, resected; RX/sal, resected-saline treated; RX/BSO, resected-BSO treated; SBR, massive small bowel resection; SBS, short bowel syndrome; TUNEL, terminal deoxyUridine nick-end labeling; TX, transected; TX/BSO, transected-BSO treated; TX/sal, transected-saline treated.
Manuscript received 10 July 2006. Initial review completed 18 August 2006. Revision accepted 9 November 2006.
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LITERATURE CITED |
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