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3
*
Department of Medicine,
Department of Pathology and Laboratory Medicine, and
**
Department of Biochemistry, Emory University School of Medicine;
§
Department of Biostatistics, Rollins School of Public Health and the
Nutrition and Health Sciences Program, Emory University, Atlanta, GA 30322
3To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • glutathione • keratinocyte growth factor • intestine • protein-energy malnutrition • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Ziegler et al. 1995
). Fasting or severe protein-energy restriction results
in mucosal atrophy, decreased absorptive capacity and impaired
intestinal barrier function. Malnutrition is also associated with
decreased gut mucosal antioxidant status, including decreased levels of
the tripeptide antioxidant glutathione
(L-glutamyl-L-cysteinyl-glycine;
GSH)4
(Meister 1991
, Ogasawara et al. 1989
).
Enteral feeding in malnourished animals rapidly restores gut
cellularity and improves critical mucosal functions (Hagemann
and Strangand 1977
, Ziegler et al. 1995
).
Peptide growth factors endogenously produced by the intestine, such as
members of the fibroblast growth factor family, are important mediators
of intestinal epithelial growth (Drucker 1997
).
Keratinocyte growth factor (KGF) is an important stimulator of
epithelial cell growth, regeneration and repair
(Estívariz et al. 1998
, Finch et al. 1989
, Housley et al. 1994
). In normal rats
consuming food ad libitum, the administration of recombinant human KGF
increased epithelial cell proliferation in the stomach, duodenum,
colon, liver and pancreas (Housley et al. 1994
). We
recently documented that recombinant KGF enhances rat small bowel and
colonic mucosal growth during enteral nutrient repletion after 3 d
of food deprivation (Estívariz et al. 1998
).
Furthermore, KGF administration in rodents decreases gut mucosal injury
in experimental colitis (Zeeh et al. 1996
) and after
chemotherapy and radiation (Farrell et al. 1998
). The
effects of KGF in these conditions of mucosal inflammation suggest that
a mechanism of KGF gut-trophic action may be to provide critical
protection from toxins or reactive oxygen species.
GSH is the most abundant low molecular weight thiol in mammalian cells
and, with its conversion to the disulfide form glutathione disulfide
(GSSG), plays a key role in the detoxification of cellular free
radicals, toxins and carcinogens (Hagen et al. 1990
,
Meister 1991
). GSH is synthesized endogenously in
mucosal cells using amino acid substrates, can be derived exogenously
from dietary sources and may enter the gut lumen via bile or by direct
secretion from mucosal cells (Dahm and Jones 1994
,
Kaplowitz et al. 1983
, Lash et al. 1986
).
GSH that is present in the gut lumen and within enterocytes appears to
be required for normal intestinal function, in part because it protects
the epithelium from damage by dietary electrophiles and fatty acid
hydroperoxides (Aw et al. 1992
, Dahm and Jones 1994
) and maintains the sulfhydryl/disulfide balance of
proteins (Gilbert 1989
, Ziegler 1985
). In
animal models, food deprivation or an insufficient dietary supply of
amino acids that may serve as GSH substrates (e.g., glutamine and
cysteine) results in decreased GSH levels in both the small intestine
and colon (Cho et al. 1981
, Kelly 1993
).
Decreased GSH in gut epithelial cells because of malnutrition or other
causes may increase susceptibility to oxidative injury and exacerbate
degeneration of the intestinal mucosa (Martensson et al. 1989
).
There is evidence to suggest that GSH is involved in the regulation of
cell growth (Hutter et al. 1997
, Hwang and Sinskey 1991
). In studies that used a variety of cultured
mammalian cells, a more reducing redox potential was associated with
increased cell density, whereas a more oxidized potential was
associated with lower cell density (Hwang and Sinskey 1991
). They further showed that when pH and dissolved oxygen
were controlled, this redox effect was determined by the thiol content.
In a recent study of cultured human fibroblasts, altered cellular GSH
significantly shifted the calculated GSH/GSSG redox potential
(Hutter et al. 1997
). Because a more reducing GSH redox
potential was associated with increased cell density, and a more
oxidized potential was associated with decreased cell density
(Hutter et al. 1997
), cellular growth appeared to be
regulated by GSH redox status. Intracellular and extracellular
antioxidant status appears to influence cell proliferation that is
mediated by growth factors, including platelet-derived growth
factor and epidermal growth factor (Burdon et al. 1994
,
Sundaresan et al. 1995
). The reducing environment that
is regulated by GSH in gut mucosa, thus, may be important for
detoxification reactions that allow normal tissue function and
also for regulating cell proliferation in response to nutrients and
growth factors.
The current study was designed to assess the in vivo effects of both KGF and the level of enteral nutrient repletion on intestinal GSH and GSSG concentrations and the GSH/GSSG ratio in malnourished rats. We also investigated the relationship between changes in mucosal GSH status and indices of intestinal mucosal growth. The results show that KGF improves the GSH redox state and suggest that gut trophic hormones and food intake independently support gut mucosal antioxidant capacity during malnutrition.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Male Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA), weighing 170–200 g, were housed in individual cages in the animal care facility under controlled conditions of temperature and humidity with a 12-h light, 12-h dark cycle. Animals were given free access to water and standard pelleted rat food (Laboratory Rodent Chow 5001, PMI Feeds, St. Louis, MO) during a 3-d acclimation period. The study protocol was approved by the Institutional Animal Use Committee of Emory University, Atlanta, GA.
Treatment regimens.
Rats were given free access to water, but no access to food for 72 h to induce protein-energy malnutrition and intestinal mucosal
atrophy (Ziegler et al. 1995
). Weight-matched
animals were then assigned to one of four refeeding regimens for 3
subsequent days: 1) ad libitum consumption (21.25 g/d) with daily,
intraperitoneal saline; 2) pair-fed to the ad libitum group with
daily, intraperitoneal recombinant human KGF (5
mg·kg-1·d-1, Amgen, Thousand Oaks, CA); 3)
refed 25% of ad libitum food intake (5.3 g/d), with daily,
intraperitoneal saline; or 4) pair-fed to 25% of ad libitum group
with daily, intraperitoneal KGF. Food intake was monitored daily, and
all pair-fed animals consumed their entire dietary ration. For
comparison, additional rats consuming ad libitum food or
food-deprived for 3 d were also studied.
Tissue isolation.
After the 72-h refeeding period, the rats were anesthetized with
intraperitoneal ketamine (100 g/L) and xylazine (20 g/L). The
peritoneal cavity was opened by a midline incision, and the ligament of
Treitz was identified. The small and large bowel segments were stripped
of mesenteric and vascular connections and sequentially removed from
the peritoneum. After tissue extraction, rats were killed by
exsanguination. The lumen of each intestinal segment was flushed with
20–30 mL of ice-cold 9 g NaCl/L to clear the intestinal
contents, and the segment was suspended from a ring stand with a
constant distal weight. The segments used for mucosal GSH analysis were
as follows: jejunum, from 10 to 14 cm distal to the ligament of Treitz;
ileum, from 10 to 14 cm proximal to the ileal-cecal junction;
colon, from 8 to 12 cm distal to the cecum. A 1-cm segment proximal to
these defined regions was excised for histologic analysis of mucosal
growth. The segments used for GSH redox studies were longitudinally
cut, and the mucosa was obtained by gently scraping with a glass slide.
The mucosa was immediately placed in a solution containing 5 g
perchloric acid/L, 0.2 mol boric acid/L and 5 µmol
-glutamyl-glutamate/L for HPLC analysis. With the use of this
collection method, no significant change in mucosal GSH and GSSG
content was detected within a sampling period of 2 min (data not
shown).
Histology.
To assess intestinal mucosal growth, we determined total mucosal height
(TMH) and crypt depth (CD) as indices of mucosal growth in jejunum and
ileum, and CD as the index of mucosal growth in colon. The segments of
jejunum, ileum and colon were cut longitudinally, fixed with formalin,
embedded in paraffin and sectioned. Mucosal CD and villus height in
hematoxylin- and eosin-stained sections from each rat were
measured in 10–25 individual crypts and villi per segment by
pathologists blinded to treatment group. For the jejunum and ileum, TMH
was calculated as the sum of CD and villus height measurements.
Although intestinal villus height can decrease and CD can increase
under some conditions of stress, we found both villus height and CD
decreased in this underfeeding protocol (Estívariz
1998
). Thus, we used TMH as an index of cumulative change in
mucosal cellularity in this model.
GSH and GSSG determination.
Precipitated tissue proteins of the acid-treated mucosal samples
were separated from the acid-soluble supernatant by
microcentrifugation, and the protein pellet was resuspended in 1 mol
NaOH/L. Protein concentrations were measured by using the Bradford
method with rabbit -globulin as the protein standard (Biorad
Laboratories, Hercules, CA). The acid-soluble supernatant was
stored at -70°C for 2–4 wk until thiol analysis, in which GSH and
GSSG were derivatized with dansyl chloride by using a method described
by Jones et al. (1998)
. Stability studies showed that GSH and GSSG were
stable under these storage conditions.
For HPLC analysis, the dansyl-derivatized compounds, including GSH
and GSSG, were separated as previously described (Jones et al. 1998
) on a 3-aminopropyl column (5µm; 4.6 x 25 cm;
Custom LC, Houston, TX) with the use of a Waters 2690 HPLC and
autosampler system (Waters, Milford, MA) with fluorescence detection
using bandpass filters (305–395 nm excitation, 510–650 nm emission;
Gilson Medical Electronics, Middletown, WI). Quantitation of the thiols
was calculated based on integration relative to the internal standard
-glutamyl-glutamate and expressed as nmol/mg protein. The GSH/GSSG
ratio was calculated as an index of the glutathione pool redox state.
Statistical analysis.
The study was arranged as a 2 x 2 factorial design, with diet (ad libitum versus 25% of ad libitum) and treatment (KGF versus saline) as main effects. Two-way ANOVA was initially performed to determine the main effects of diet and KGF treatment and their interaction (P < 0.05). One-way ANOVA was used to detect significant intergroup differences (P < 0.05). In this case, the four specific study groups were compared post hoc by using the Fisher's protected least-significant difference test (Statview for Mac Version 4.5, Abacus Concepts, Berkeley, CA). A Brown-Forsythe test showed no lack of homogeneity of variance, thus no transformations of data were necessary.
Because diet and KGF administration altered both GSH redox and mucosal growth parameters, one-way and two-way analysis of covariance methods were used to evaluate the associations between mucosal GSH levels, the GSH/GSSG ratio and the mucosal growth indices (SAS/STAT Version 6, SAS Institute, Cary, NC). P-values < 0.05 indicated significant differences.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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After 3 d of food deprivation, refeeding at 25% of ad libitum
intake significantly decreased intestinal mucosal GSH in the jejunum,
ileum and colon by 42%, 38% and 57%, respectively, compared to the
values in ad libitum-refed, saline-treated rats (Fig. 1
). Jejunal, ileal and colonic GSH values were significantly higher in
rats given KGF during refeeding at 25% of ad libitum intake,
maintaining GSH at levels not different from ad libitum-refed rats.
KGF did not significantly alter mucosal GSH in ad libitum-refed
rats. These results indicate that KGF prevented the
malnutrition-induced decrease in mucosal GSH content throughout the
intestine.
|
Rats refed at 25% of ad libitum intake demonstrated
tissue-specific differences in mucosal GSSG compared to ad libitum
controls (Fig. 2
): GSSG levels were not different in the jejunum, were significantly
higher in the ileum and were significantly lower in the colon. With
25% refeeding and KGF treatment, GSSG levels in the ileum were
significantly lower, while jejunal and colonic levels were not
different from rats fed 25% of ad libitum intake and treated with
saline. In rats with ad libitum refeeding and KGF treatment, the GSSG
contents in the jejunum, ileum and colon were significantly lower than
in ad libitum-refed rats treated with saline. These data
demonstrate regional changes in gut mucosal GSSG in response to enteral
nutrition and KGF.
|
Refeeding at 25% ad libitum intake resulted in significantly lower
GSH/GSSG ratios in the jejunum and ileum compared to those in the ad
libitum-refed rats (Fig. 3
). With KGF treatment at the lower level of refeeding, GSH/GSSG ratios
in jejunal, ileal, and colonic mucosa were one to 2.7-fold higher,
indicating a more reduced glutathione pool. KGF treatment in ad
libitum-refed rats resulted in GSH/GSSG ratios that were
significantly higher in all intestinal segments, with the colon
exhibiting the greatest increase (3.7-fold). Thus, KGF treatment
resulted in a more reduced glutathione pool at both levels of refeeding
and prevented the oxidation of the glutathione pool during restricted
refeeding at 25% of ad libitum intake.
|
To investigate whether GSH status in vivo is related to intestinal
growth, we measured TMH and CD as gut mucosal growth indices
(Estívariz et al. 1998
). With 25% refeeding,
TMH and CD were significantly lower in the jejunum, and CD was
significantly lower in the ileum. Colonic CD was not different from ad
libitum-refed rats (Table 1
). KGF had no effect on mucosal growth indices in the jejunum at either
level of refeeding. KGF administration in 25% of ad libitum-refed
rats resulted in higher TMH and CD in the ileum. KGF treatment at both
25% and ad libitum refeeding levels resulted in significantly higher
colonic CD.
|
Comparison of GSH and the GSH/GSSG ratio in small bowel and colon.
The comparison of jejunal, ileal and colonic GSH levels in ad
libitum-refed, saline-treated rats showed that mucosal GSH levels
did not differ in the jejunum or ileum, but colonic levels were
1.0–1.7-fold greater than the values for the small intestine
(Fig. 4A
). Ad libitum refeeding resulted in a proximal to distal gradient in
intestinal GSH redox state (GSH/GSSG, Fig. 4
B). The GSH
redox state was most reduced in the colon. The more reduced GSH redox
state in the colon, relative to the tissues of the small
intestine, was unaffected by the level of enteral refeeding or
by KGF administration (see Figs. 1
and 3
).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Bai and Jones 1996
, Martensson et al. 1989
, Ziegler et al. 1995
). Recent strategies to improve intestinal structure
and function during malnutrition have included supplementing specific
nutrients (e.g., glutamine), increasing the supply of antioxidants to
protect against oxidative injury and adding trophic factors to
stimulate cell growth (Aw et al. 1992
, Bray and Taylor 1994
, Ziegler et al. 1997
).
The present animal study employing a food deprivation and hypocaloric
refeeding model was developed to test the efficacy of intervention
strategies for intestinal recovery. KGF improves recovery of intestinal
growth during hypocaloric feeding as measured by crypt depth and villus
height (Estívariz et al. 1998
). In the current
study, we found that KGF also improves gut mucosal GSH concentrations
and redox state. To our knowledge, this is the first demonstration of
growth factor-mediated improvement in tissue antioxidant status in
vivo. Of particular interest, our analyses suggest that improvement of
mucosal GSH status is related to intestinal epithelial growth that is
induced by both KGF and nutrients. These data indicate that in the
ileum, KGF treatment increased CD during 25% of ad libitum refeeding,
in part via changes in ileal GSH levels. In colon, increased CD was
significantly associated with increased mucosal GSH content when
statistically controlling for diet and KGF treatment. Thus, increased
mucosal GSH concentrations may mediate mucosal growth stimulated by
nutrients and KGF.
Although our data are correlative, substantial evidence suggests that
changes in the thiol redox state are directly related to changes in
cell density in a variety of cultured mammalian cell lines
(Hutter et al. 1997
, Hwang and Sinskey 1991
). Briefly, the GSH redox state in normal proliferating
fibroblasts was significantly more reducing than in confluent,
contact-inhibited cells (Hutter et al. 1997
). The
change in redox state in proliferating cultured cells corresponds to a
twofold higher GSH/GSSG ratio, a redox shift of similar magnitude to
those observed in our in vivo model. Thus, the redox state of the
GSH/GSSG pool may be central to a mechanism linking nutrient effects,
growth factor responses and cell growth indices.
The GSH redox state in tissues can be expressed as the reduction
potential of the GSH/GSSG redox couple (Eh). The
reduction potential of the GSH pool (Eh) can be
estimated using the Nernst equation
 |
where R is the gas constant, T is the absolute temperature, F is
Faraday's constant and the standard potential
(Eo) is for the GSH/GSSG redox couple for
the relevant pH. The pH of the small intestinal and colonic mucosa was
previously reported as 7.3–7.4 (Wang et al. 1993
). If
we assume that this is unaffected by the treatment used, we can use the
GSH and GSSG values and Eo = -0.264 V
(Clarke 1960
, Rost and Rapaport 1964
) to
estimate Eh. We found that
Eh values were more positive, which is consistent
with the GSH/GSSG ratio data, indicating a more oxidized GSH pool (or
less reducing potential) with 25% ad libitum refeeding compared to ad
libitum refeeding [jejunum: -193 mV (25%-saline injection [SAL])
vs. -203 mV (A-SAL); ileum: -189 mV vs. -209 mV; colon: -204 mV vs.
-220 mV; P < 0.01]. KGF completely restored the gut
mucosal GSH reducing capacity (Eh) in rats refed
hypocaloric diets compared to those ad libitum refed [e.g., jejunum:
-211 mV (25%-KGF) vs. -203 mV (A-SAL)]. Furthermore, KGF improved
the reductant capacity of GSH during ad libitum refeeding in the
jejunum and colon [jejunum: -209 mV(A-KGF) vs. -203 mV (A-SAL);
colon: -243 mV vs. -220 mV; P < 0.05]. Similar to
the GSH/GSSG ratio, the calculated Eh values show
a proximal to distal graded shift to a more reducing state (jejunum
-203 mV, ileum -209 mV, colon -220 mV; P < 0.05).
However, one must bear in mind that these estimates assume no change in
pH. In studies of rat muscle, Meynial-Denis et al. (1998)
found
that during starvation intracellular pH increased by ~0.2U. An
increase in 0.2 pH units is equivalent to a 12-mV more negative
Eh value (more reducing). Direct measures of
mucosal pH are needed to confirm the observed changes in GSH redox
potential in the intestine.
Decreased mucosal GSH concentrations and reducing capacity associated
with malnutrition may impair intestinal function because
detoxification, mucus fluidity, nutrient transport/absorption and cell
proliferation appear to be dependent upon tissue thiol status
(Darmon et al. 1993
, Smith et al. 1996
).
Our data confirm observations by other investigators that food
deprivation and protein deficiency decrease intestinal GSH content in
rats (Meister 1991
, Ogasawara et al. 1989
, Jahoor et al. 1995
). Intestinal GSH
depletion in response to malnutrition may result from increased
breakdown or decreased synthesis caused by a limited precursor amino
acid supply (cysteine, glycine and glutamate) (Cornell and Meister 1976
, Cho et al. 1981
, Dahm and Jones 1994
). Additionally, nutritional deprivation may alter
cellular GSH transport or efflux, its oxidation to GSSG, or its use in
conjugation reactions via glutathione peroxidase and
glutathione-S-transferase detoxification reactions (Bauman et
al. 1998
, Dahm and Jones 1994
, Lu et al. 1996
, Meister 1991
). Exogenous KGF may increase
intestinal GSH during malnutrition by any of the above mechanisms.
It is possible that enhanced mucosal growth and cellularity itself
increases gut mucosal GSH concentrations or shifts redox to a more
reduced state. In studies of cultured rat hepatocytes, GSH synthesis
was increased in cells plated at low density, which shifts cells from
G0 to G1 phase of the cell
cycle (Cai et al. 1995
). The mRNA levels, protein
expression and activity of -glutamyl-cysteine synthetase, the
rate-limiting enzyme for GSH synthesis, significantly increased
with low cell density compared to cells plated at high density
(Cai et al. 1995
). Thus, KGF stimulation of epithelial
growth, which in turn induces GSH synthesis, may represent a mechanism
by which KGF improves mucosal GSH concentrations and redox state.
GSH levels in the rat intestine during normal ad libitum feeding were
previously reported to be similar throughout the small and large
intestine (Ogasawara 1989
, Seigers
1988
). In contrast, our study showed that the colonic
mucosa had a significantly higher GSH content and a more reducing GSH
pool (GSH/GSSG and Eh) than did the jejunal and
ileal mucosa. These region-specific differences were unaltered by
the level of refeeding or KGF administration, indicating that a
pronounced reducing environment exists in the distal bowel. In a study
of endotoxin exposure in rats, GSH levels increased in the colon, but
decreased in the duodenum and jejunum (Chen et al. 1988
). Thus, the colon appears to have the capacity to maintain
or increase mucosal GSH availability in response to stresses, such as
malnutrition or exposure to endotoxin.
In summary, in rat models of altered levels of refeeding after prolonged food deprivation, the lower level of nutrient repletion markedly decreased GSH content and decreased the GSH/GSSG ratio in rat jejunal, ileal and colonic mucosa. The malnutrition-induced changes in GSH were completely prevented by recombinant KGF administration during refeeding. These results suggest that KGF may be a useful agent to improve GSH-dependent antioxidant functions in malnutrition and other conditions associated with gut mucosal oxidative stress.
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ACKNOWLEDGMENTS |
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|
FOOTNOTES |
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2 Supported by the National Institutes of Health
(NIH) T32DK07734 (C.R.J.), National Institutes of Health Clinical
Associate Physician Award 3M01 RR00039–35S1, the Emory University
Research Committee and Amgen Inc. (T.R.Z.), National Institutes of
Health 5R01 ESO7892–09 (D.P.J.), National Institutes of Health General
Clinical Research Center grant 3 MO1 RR00039 (T.R.Z. and G.A.C.) and
the Spanish Instituto de Salud Carlos III del Ministerio de Sanidad y
Consumo, B.A.E. 96/5515 and 97/5082 (C.F.E.).
4 Abbreviations used: CD, crypt depth;
Eh, reduction potential; GSH, glutathione; GSSG,
glutathione disulfide; KGF, keratinocyte growth factor; SAL, saline
injection; TMH, total mucosal height.
Manuscript received September 24, 1998. Initial review completed January 25, 1999. Revision accepted March 30, 1999.
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