* Department of Toxicology, School of Pharmacy, The University of Louisiana at Monroe, Monroe, Louisiana 71209;
Department of Neurology, University of Mississippi Medical Center, Jackson, Mississippi 39216; and
Pathology AssociatesA Charles River Company, National Center for Toxicological Research, Jefferson, Arkansas 72079
Received October 17, 2002; accepted December 2, 2002
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ABSTRACT |
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Key Words: apoptosis; HGF; IL-6; iNOS; TGF-; tissue repair; thioacetamide; caloric restriction, cytokines, growth factors, toxic challenge.
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INTRODUCTION |
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In a low-dose study (50 mg TA/kg), DR rats exhibited 6-fold higher initial bioactivation-based liver injury. In spite of such high liver damage, DR rats survived due to enhanced tissue repair response. The increased liver injury of TA in DR rats was attributed to the induction of CYP2E1, the primary enzyme involved in bioactivation of TA (Wang et al., 2000; Ramaiah et al., 2001
). To investigate whether the higher tissue repair in DR rats was stimulated by the greater injury, an equitoxic dose study was conducted. In this study DR rats were treated with a low dose of TA (50 mg/kg) and AL rats were treated with a 12-fold higher dose of TA (600 mg/kg); the two treatments produced equal initial liver injury. Even though the initial liver injury was the same, AL rats experienced a progressive increase in liver injury leading to 90% lethality, while DR rats experienced complete survival due to prompt tissue repair in the DR rats, which in case of the AL rats was delayed and inhibited. These studies indicated that the mechanism of higher survival in DR rats exposed to TA is stimulated tissue repair, and this tissue repair is not dependent on the extent of initial liver injury.
The present study is based on the hypothesis that earlier (timely) and enhanced promitogenic signaling via proinflammatory cytokines and growth factors is the mechanism behind higher tissue repair in DR rats. Literature evidence points towards TNF- and IL-6 as major candidates involved in priming the hepatocytes to enter G1 phase from G0. Growth factors such as TGF-
and HGF further stimulate these cells to undergo mitosis. Nitric oxide is also known to prime the hepatocytes as well as stimulate them to undergo mitosis (Apte et al., 2002
; Dalu et al., 1995
; Diehl, 2000; Fausto et al., 1995
; Michalopoulos and DeFrances, 1997
; Streetz et al., 2000
; Yamada and Fausto, 1998
). Expression of these mitogenic factors was studied over the time course in AL and DR rats after either a low dose (50 mg TA/kg) or an equitoxic dose (50 mg/kg in DR vs. 600 mg/kg in AL). Thioacetamide is known to induce apoptosis at lower doses (Mangipudy et al., 1998
; Witzmann et al., 1996
). To test for the possibility of increased apoptosis in DR rats after TA administration, and to evaluate the role played by increased apoptosis in final outcome of TA-induced liver injury, the number of apoptotic cells was evaluated using TUNEL assay. DR rats did have higher apoptosis after TA administration, which further increased the efficiency of tissue repair in these rats. Here we present evidence that these promitogenic factors are expressed at earlier time points and in higher quantities in DR rats upon TA exposure. The enhanced liver regeneration in DR rats is due to the prompt promitogenic signaling stimulated by these factors in DR rats after TA-induced liver injury. Tissue repair is inhibited in AL rats because of delayed and/or inhibited mitogenic signaling. We report here that even though the initial liver injury is equal, DR rats are able to survive through timely compensatory cell division stimulated by earlier and higher expression of cytokines, nitric oxide, and growth factors.
Our data indicate that the extent of initial bioactivation-based injury does not govern the extent of tissue repair. The signal transduction processes modulated by physiology of diet restriction, which can operate effectively even under substantial stress of tissue injury, can stimulate higher tissue repair in DR rats independent of the dose of TA.
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MATERIALS AND METHODS |
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Animals and treatment.
Male Sprague-Dawley rats (250290 g) were subjected to moderate DR as described previously (Ramaiah et al., 1998b). Briefly, DR rats were allowed to eat 65% of the AL food consumption (Harlan Teklad Rat chow No. 7001, Madison, WI: protein 25%, fat 4.25%, fiber 4.67%, vitamins and minerals supplemented, calories 3.94 Kcal/g) and free access to water for 21 days. AL rats had free access to food and water at all times. Diet restriction was carried out for 21 days, and on day 22 both AL and DR rats were exposed to various TA treatments. All animals received humane care according to the criteria outlined in the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals.
In the low-dose studies, rats in both groups received a single nonlethal dose of TA (50 mg/kg, ip, in 6 ml saline/kg). For equitoxic dose studies, DR rats and AL rats (n = 10 per group) received 50 and 600 mg/kg TA (ip, in 6 ml saline/kg), respectively. After exposure to the equitoxic doses rats were observed for 14 days, twice daily, and signs of toxicity and deaths were recorded. For the time course studies, separate groups of AL and DR rats were treated with the either a low dose (50 mg TA/kg) or equitoxic doses (50 or 600 mg TA/kg for DR and AL, respectively) and killed under diethyl ether anesthesia at various time points. Blood was collected from individual rats in separate heparinized tubes from the dorsal aorta, and plasma was obtained by centrifugation (1000 x g for 20 min). The median lobe of the liver was fixed in 10% neutral buffered formalin and further processed for histopathological analysis. The remainder was stored at 75°C till further analysis. Neither the plasma samples nor the liver samples were pooled, and individual samples were used for further analysis.
Estimation of liver injury and cell division.
Plasma was separated by centrifugation and used for the estimation of alanine aminotransferase activity (ALT; EC 2.6.1.2.) as a marker of liver injury, using Sigma kit No. 59 UV (ALT) (Sigma Chemical Co., St Louis, MO). Liver cell division was estimated by incorporation of 3H-thymidine (3H-T) in hepatonuclear DNA as previously described (Chang and Looney, 1965). Rats were treated with 50 µCi 3H-T/rat (ip) 2 h prior to sacrifice at each time point. Total DNA content was measured by diphenylamine reaction.
Assessment of apoptotic cells.
Apoptotic cells were visualized and counted by TUNEL assay using ApoTag kit (Oncor, Gaithersburg, MD) according to the manufacturers protocol. Thin (5 µm) sections of liver from AL and DR rats, sampled at various time points (0 to 72 h) after TA administration were used. Three slides (animals)/group/time point were examined microscopically, and apoptotic cells were identified by dark brown staining. Necrotic areas were avoided while counting the apoptotic cells.
TNF- and IL-6 ELISA.
TNF- levels were estimated in the plasma of AL and DR rats treated with TA using a rat-specific TNF-
sandwich ELISA (Amersham Life Sciences, Piscataway, NJ) according to manufacturers protocol. Briefly, heparinized plasma samples (n = 4 per time point) were incubated with anti-TNF-
antibody for 1 h followed by biotinylated detection antibody. Visualization was carried out by peroxidase reaction and color intensity was measured at 450 nm in BioRad Model 550 microplate reader (BioRad, Hercules, CA). IL-6 was measured in plasma samples collected at different time points using a rat-specific IL-6 ELISA kit (R&D Systems) according to manufacturers protocol and similar to TNF-
ELISA.
Immunohistochemistry.
TGF-, HGF, and IL-6 protein were evaluated immunohistochemically using paraffinized sections of liver collected over the time course. Antigen retrieval was carried out by flooding the liver sections with 0.05% saponin for 30 min, followed by treatment with TGF-
specific antibody (Ab-1, Oncogene, Cambridge, MA) at 1:500 concentration for 18 h at 4°C. For HGF, antigen retrieval was performed by citrate buffer treatment while for IL-6 no antigen retrieval was necessary. The concentrations of primary antibody were 1:200 and 1:50 for HGF and IL-6, respectively. After treatment with secondary antibody (concentration 1:10,000) and streptavidin conjugate, visualization was achieved by peroxidase reaction in all cases. Three slides were stained per time point. To get a quantitative estimate of the growth factor production from the staining intensity, a scoring scheme was devised using a scale of 04 staining intensity, which has been used by other investigators to get a quantitative estimate of immunohistochemical analysis (Roberts et al., 1991
; Williams et al., 1996
). Slides were observed under a light microscope and staining intensity was graded on coded sections (blinded), at a scale of 0 to 4 (0, none; 1, low; 2, medium; 3, high; and 4, very high staining intensity).
iNOS assay.
iNOS activity was determined according to the method of Bredt et al.(1992). The iNOS assay medium (400 ml) contained 100 mM HEPES, pH 7.2; 2 mM NADPH; [3H]-arginine (0.2 µCi/ml), and 400 mg of liver cytosolic protein. The reaction mixture was incubated for 30 min at 37°C and stopped by addition of stop-buffer containing 20 mM HEPES and 10 mM EGTA at pH 5.5. The entire reaction mixture was passed through Dowex AG 50 Wx-8 resin (Na+ form) to elute the fraction containing [3H]-citrulline, which was estimated in a Beckman 6000 liquid scintillation spectrometer.
Statistical analysis.
Group comparisons were performed using an independent t-test. A one-way analysis of variance was used to determine statistical significance that might exist between more than two distributions or sample groups. Statistical analyses were performed using SPSS 10.0 software (SPSS Inc., Chicago, IL). Statistical significance was set at p 0.05.
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RESULTS |
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Apoptosis in AL and DR rats after TA treatment.
Apoptotic cells detected by TUNEL assay were counted with a light microscope. A modest but significant increase in the number of apoptotic cells was evident in AL rats from 12 to 60 h after the low dose of TA (Fig. 10A). A significant increase in apoptosis in DR rats was found from 12 to 36 h and again at 60 h after the low dose. TA induced greater apoptosis in DR rats than in AL rats from 12 to 36 h and again at 60 h after low-dose exposure. After equitoxic doses, AL rats had significant increases in apoptosis at 36 h, which remained higher until 48 h after treatment (Fig. 10B
). DR rats exhibited increased apoptosis from 12 to 36 h and again at 60 h after equitoxic doses. Although AL rats had higher apoptosis than DR rats at 36 and 48 h, DR rats exhibited increased apoptotic cells as early as 12 h, which lasted until 60 h, indicating greater total apoptosis over the time course. Although significant increases in apoptosis were found in DR rats after TA treatment, the primary type of cell death was coagulative necrosis in the centrilobular region, affecting half or more of the hepatocytes in the lobule.
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DISCUSSION |
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To assess if the extent of tissue repair after toxic challenge is governed by the extent of initial injury, an equitoxic dose experiment was conducted. In this study, DR rats treated with a 12-fold lower dose (50 mg TA/kg, ip) experienced equal liver injury to that observed in AL rats treated with 600 mg TA/kg, a lethal dose (Ramaiah et al., 1998a). The increased susceptibility to liver injury in DR rats was caused by prompt induction of CYP2E1, the principal enzyme involved in TA bioactivation (Ramaiah et al., 2001
; Wang et al., 2000
). TA is bioactivated primarily by CYP2E1 to TA-sulfoxide and TA-sulf-dioxide, which are the penultimate and ultimate reactive metabolites, respectively. Data indicated that flavin-containing monooxygenase (FMO) is not involved in bioactivation of TA. Indeed, inhibition of FMO by indole-3-carbinol in AL and DR rats lead to increase in TA-induced liver injury suggesting that FMO may detoxify TA. There was no difference in the FMO activity between AL and DR rats, ruling out the possibility of higher detoxification of TA in DR rats (Ramaiah et al., 2001
). After the equitoxic dose, despite equal initial liver injury, 100% of the DR rats survived while only 10% of the AL rats survived. Timely and robust stimulation of liver tissue repair led to prompt recovery in DR rats (Ramaiah et al., 1998a
).
Although initial injury is essential to trigger tissue repair, these data indicate that the regenerative response in DR rats does not depend upon the extent of initial injury. Although the initial liver injury was equal in AL and DR rats (Fig. 2A), the final outcome was dichotomous because of differences in liver cell division and tissue repair (Fig. 2B
). Unlike the AL rats, the DR rats escape death after the equitoxic liver injury because of prompt and robust stimulation of cell proliferation and tissue repair, which enables them to restore the structure and function of the liver. In the 10% surviving AL rats after equitoxic doses of TA, tissue repair is very high, explaining the survival. This is also reflected in the higher tissue repair values of the AL group between 60 and 120 h in Figure 2
(lower panel). Secondly, in DR rats, the number of apoptotic cells increases rapidly and remains high until 60 h after TA administration. This early and sustained increase in apoptosis rapidly removes damaged cells that would otherwise die later via necrosis, permitting more rapid replacement. Apoptosis has been recognized as a controlled programmed cell death leading to minimal damage to the surrounding tissue (Barros et al., 2001
; Sartorius et al., 2001
). The increase in apoptosis in DR rats seems to be independent of TNF-
since no substantial increase in TNF-
was observed in DR rats after TA treatment. Inhibition of compensatory cell division and apoptosis in AL rats receiving the equitoxic dose of TA leads to progression of liver injury and death. These observations suggest that the AL feeding regimen does not promote the same rate of apoptosis of weaker hepatocytes and timely compensatory tissue repair.
We hypothesized that the mechanism of timely and robust tissue repair in DR rats upon toxic challenge is a higher expression of promitogenic cytokines and growth factors accompanied by upregulated signaling. Higher hepatocyte division in caloric restriction has been demonstrated by Keenan et al.(1995) in both male and female Sprague-Dawley rats fed a special diet (Purina Certified Rodent Chow 2009), which restricted the calories to 65% of AL rats. Caloric restricted (60% of AL) Fisher-344 rats also have better liver regeneration after partial hepatectomy (Chou et al., 1995
). Cuenca and associates have recently reported that caloric restriction improves liver regeneration after partial hepatectomy, due to early mobilization of hepatocytes into S-phase (Cuenca et al., 2001
). The priming action of proinflammatory cytokines such as TNF-
, IL-6, and nitric oxide is essential to fully activate the promitogenic stimulus of growth factors such as TGF-
and HGF (Galum et al., 2000
; Lindros et al., 1991; Rai et al., 1998
; Scotte et al., 1997
; Webber et al., 1998
). The role of growth factors such as TGF-
and HGF in stimulation of liver regeneration has been ascertained in great detail after partial hepatectomy and to some extent after chemical-induced injury (Dalu et al., 1995
; Diehl, 2000; Fausto et al., 1995
; Lindros et al., 1991; Soni et al., 1999
).
The increase in cell division during the first 48 h in DR rats plays a crucial role in the final outcome of TA-induced injury. This timely and robust stimulation of tissue repair is essential for survival as illustrated in the AL rats, where the initiation of repair is delayed until after 48 h. The early upregulation of cell division by prompt and elevated expression of IL-6 and DR-induced iNOS appears to be the key for early onset of tissue repair. Both of these molecules are known to prime the hepatocytes to move from G0 to G1 phase (Diez-Fernandez et al., 1997; Gallucci et al., 2000
; Galum et al., 2000
; Hui et al., 2002
; Rai et al., 1998
). The primed hepatocytes are further stimulated by growth factors to progress in the cell cycle, undergo DNA synthesis, and eventually undergo mitosis. Extensive evidence suggests that stimulation by growth factors is essential for completion of the cell cycle (Boylan and Gruppusso, 1994; Burr et al., 1993
; Factor et al., 1997
; Kao et al., 1996
; Seki et al., 1997
; Webber et al., 1993
). The role of TGF-
and HGF has been particularly well studied during regeneration after toxic insult (Dalu et al., 1995
; Horada et al., 1999
; Lindroos et al., 1991
; Michalopoulos and DeFrances, 1997
; Scotte et al., 1997
; Tomiya et al., 1998
).
Our data reveal earlier and elevated expression of TGF- and earlier increase in HGF in the liver of DR rats upon equitoxic challenge. The timely increase in these growth factors coincides with the earlier increase in S-phase DNA synthesis in DR rats. These growth factors also increase in AL rats but the increase is delayed and diminishes very rapidly. This transient activity and lack of stimulation by growth factors leads to diminished cell division in the AL rats upon toxic challenge. TGF-
signals hepatocyte DNA synthesis and division via the MAPK pathway (Horada et al., 1999
). The increase in TGF-
expression in DR rats coincides with S-phase DNA synthesis. The earlier and higher increase in TGF-
stimulates timely cell division in DR rats. The lack of timely increase in cell division in AL rats is partly explained by the delayed increase in TGF-
.
Hepatocyte growth factor is a potent mitogen for hepatocytes and is produced mainly in extrahepatic tissues. Liver cells produce HGF under certain conditions such as embryonic and fetal development, endotoxin challenge, and cirrhosis (Gao et al., 1999; Masson et al., 2001
; Pediaditakis et al., 2001
). In our study, both parenchymal and nonparenchymal cells stained positive for HGF. After equitoxic doses, the earlier increase in HGF in DR rats (at 12 h after TA treatment) correlates with the early stimulation of S-phase in the DR rats. AL rats did have increased expression of HGF at 24 to 48 h but a corresponding increase in cell division was not observed. This indicates a flaw in downstream signaling of HGF. Such downstream inhibition of signaling has been previously reported in regeneration in models of nonalcoholic fatty liver disease (Yang et al., 2001
).
The data presented here lead to three important conclusions. (1) Tissue repair in AL rats was inhibited, in spite of equal initial liver injury as that seen. This is clearly the function of high dose and confirms the observation by our group and others that high dose leads to inhibition of repair. (2) Even more critical is the observation that in DR rats the tissue repair was not inhibited, even after massive initial liver injury, indicating that DR rats have a mechanism that can operate under extreme stress of injury to promptly stimulate the tissue repair. The signaling mechanisms in DR rats are viable, even during the massive liver injury, regardless of whether it is from a low dose due to induction of CYP2E1 or due to a high dose, thereby highlighting the benefits of diet restriction, which enable the animal to operate even under substantial stress of injury. (3) These data indicate that the stimulation of tissue repair is independent of the extent of initial liver injury. Stimulation of tissue repair is a function of physiological state of diet restriction and allows stimulation of tissue repair to occur even after exposure to a high dose, which normally inhibits it. The reason behind the prompt stimulation of tissue repair in DR, even after massive liver injury, is a timely expression of promitogenic molecules such as IL-6 and TGF- in DR rats following TA administration. The AL rats, on the other hand, are unable to mount a tissue repair response (even though the initial liver injury is same as DR) due to inhibition of timely expression of these molecules.
Although one might surmise that the higher liver injury in DR rats receiving a normally lethal dose of TA drives the prompt and robust tissue repair, our data suggest that it is not the extent of liver injury that stimulates the vigorous tissue repair. It is the physiology of DR that leads to prompt tissue repair upon toxic challenge. Liver injury in AL rats matching that observed in DR rats failed to stimulate similar tissue repair (Fig. 11). This is rooted in the delay in expression of critical promitogenic molecules in AL rats. The reason the DR rats are able to mount robust tissue repair is prompt upregulation of signaling via the cytokines and growth factors. In AL rats this signaling is inhibited. Our studies reveal that physiological changes produced by DR lead to upregulation of the compensatory mitogenic signaling mechanisms and to survival after a normally lethal toxic challenge of TA.
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ACKNOWLEDGMENTS |
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NOTES |
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1 To whom correspondence should be addressed at The University of Louisiana at Monroe, Department of Toxicology, 700 University Avenue, Sugar Hall #306B, Monroe, LA 71209-0495. Fax: (318) 342-1686. E-mail: mehendale{at}ulm.edu.
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