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TOXICOLOGY
Division of Pharmaceutics, College of Pharmacy, The University of Iowa, Iowa City, Iowa (S.D.P., F.D.K., C.K.S.); and Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan (F.D.K., C.K.S.)
Received January 6, 2006; accepted March 27, 2006.
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Abstract |
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). It has been estimated that the annual economic impact of these reactions ranges between $30 and $130 billion (Johnson and Bootman, 1995). The unpredictable and serious nature of these reactions makes ADR a significant problem in clinical practice, public health, and drug development.
Of the various forms of ADR, drug-induced hepatotoxicity is arguably the most serious in terms of magnitude of health and economic consequences, constituting a large percentage of these reactions. Drugs can induce a wide spectrum of liver injury, the most serious resulting in acute liver failure. Indeed, xenobiotic-induced liver injury is the primary cause of liver failure in the United States (Bissell et al., 2001) and is also the most common cause of drug withdrawal from the pharmaceutical market (Larrey and Pageaux, 2005).
Only a small fraction of subjects exposed to a xenobiotic associated with liver injury will develop hepatotoxicity, as the incidence of hepatotoxicity ranges from 1/10,000 to 1/100,000 for the majority of drugs (Larrey and Pageaux, 2005). Identified predisposing factors for drug-induced liver injury include age, sex, concomitant use of other drugs, and genetic polymorphisms in metabolic pathways involved in activation or disposition of drugs (Maddrey, 2005). However, our growing understanding of the multifactorial nature of disease suggests that transient phenomena, such as environmental, dietary, and phytochemical factors, concurrent with xenobiotic exposure may also play a critical role in determining whether such a reaction is manifested. Thus, although genetics may predispose a subject to the development of hepatotoxicity, environmental factors may be the final determinant as to whether such a reaction is manifested in a particular patient.
One element that may serve as a predisposing factor to the development of xenobiotic toxicity is environmental stress. Recent studies have shown that experimental stress (e.g., restraint, uncontrollable shock, and noise) may be associated with a variety of alterations of the immune system in mice and rats (McEwen et al., 1997). These changes include altered leukocyte margination, macrophage activation, and cytokine secretion. Stress has also been shown to alter antitumor drug efficacy, wound healing, viral immunity, and cell-mediated immunity (Padgett et al., 1998; Sheridan, 1998; Zorzet et al., 1998). Recognizing that growing evidence indicates an important role for an altered immune system and hypothalamic-pituitary-adrenal axis response in xenobiotic-induced toxicity (Roberts et al., 1995; Roth et al., 1997; Dhabhar et al., 2000), we hypothesized that acute stress might also alter hepatotoxicity. In the studies described herein, we show that acute restraint is able to activate Kupffer cells and enhance the liver injury caused by two classic hepatotoxicants, carbon tetrachloride (CCl4) and allyl alcohol.
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Materials and Methods |
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Animals and Restraint. Male or female BALB/c mice were obtained at 6 weeks of age and allowed to acclimate for 7 to 10 days in our animal care facility. Throughout the experiments, animals were maintained on a 12-h light/dark cycle under controlled temperature and humidity. Except during the period of acute restraint, animals were allowed access to food and water ad libitum. On the day of an experiment, animals were placed in Plexiglas restraint cages for varying periods or left to roam free in their home cages. The restraint cage was well ventilated and prevented animals from turning or ambulating, but it did not squeeze the mice. At the beginning of the restraint period, food and water were removed from control and restrained animals. After restraint, mice were transferred to their home cages, and food and water were restored for both restrained and control groups. Both control and restrained mice were euthanized under CO2 narcosis either immediately after restraint or at specific time points after cessation of stress. Blood was collected either by decapitation or from the vena cava. Livers were removed and perfused using isotonic saline.
For xenobiotic administration experiments, animals received CCl4, allyl alcohol, or vehicle (corn oil for CCl4 and saline for allyl alcohol) i.p. at the doses and time points designated under Results. The concentration of xenobiotic in vehicle was adjusted to permit the administration of 
0.2 ml of total volume per mouse. Doses of CCl4 administered are expressed as volume of CCl4/kg body weight, whereas doses of allyl alcohol are expressed as milligram per kilogram of xenobiotic administered. After xenobiotic administration, animals remained free roaming in their home cages until euthanized at the time designated for blood sampling. Sentinel mice (1-2) were maintained from each lot and were evaluated for viral or bacterial pathogens at 1 to 2 months after receipt.
Liver Injury Assessment. Collected blood samples were allowed to clot on ice for 30 min. Sera were isolated by centrifugation at 8000 rpm for 30 min. Isolated serum samples were assayed for alanine aminotransferase (ALT) content using a commercially available colorimetric assay modified for 96-well plate analysis (Sigma Chemicals or Advanced Bio-Screen, Fullerton, CA).
Corticosterone Determination. Corticosterone content in serum was determined using an enzyme immune assay (Assay Design, Ann Arbor, MI). Sample concentrations were quantified by comparison with a standard curve of known concentrations. All the concentrations were determined in duplicate.
Liver Tissue Processing. Perfused livers were blotted, weighed, and homogenized using 1:10 w/v phosphate buffer (30 mM Na2HPO4, 30 mM NaH2PO4, 0.1 M NaCl, and 0.5% Triton X-100, pH 7.4). Aliquots of homogenate were assayed for protein content by the Bradford assay. To the remaining homogenate, 10% trichloroacetic acid was added. Denatured proteins were pelleted by centrifugation at 5000 rpm for 5 min. Supernatants were frozen at -80°C until analysis for GSH content.
Glutathione Determination. Hepatic-reduced GSH content was determined by a modified Ellman's method. Supernatants obtained after denaturation of proteins were diluted 1:5 using phosphate buffer (0.25 mM NaH2PO4 and 0.25 mM Na2HPO4, pH 7.4). The reaction mixture for GSH determination contained 90 mM phosphate buffer, a series of standard GSH concentrations or samples, and 0.15 mM DTNB in a total volume of 200 µl. The reaction was initiated by the addition of DTNB and incubated at room temperature for 15 min. Increase in absorbance was measured at 405 nm using a UV-visible microtiter plate reader (Molecular Dynamics, Sunnyvale, CA). Corresponding sample concentrations were determined from a standard curve. GSH concentration was normalized to homogenate protein content.
Immunohistochemistry. For immunohistochemical analysis, the perfused livers from restrained and free roaming mice were blotted and sectioned (3/4 inch). These sections were snap frozen in liquid nitrogen using cryopreserving optimal cutting temperature compound (Electron Microscopy Sciences, Hatfield, PA) and stored at -80°C. Frozen livers were sectioned using a microtome cryostat into 12-µm sections, and the slides were stored at -80°C until further analysis. Immunohistological examination of liver sections to determine macrophage activation was performed by modifying the method described by Dambach et al. (2002). The activation of Kupffer cells was determined by using rat anti-mouse macrosialin (CD68) antibody (Serotec, Raleigh, NC) and immunofluorescent confocal microscopy. Frozen liver sections were fixed in acetone at 4°C for 10 min and then air dried. Blocking was performed using a 5% normal rabbit serum/1% bovine serum albumin mixture for 20 min at room temperature. This was followed by second blocking step using avidin D for 15 min and biotin for 15 min from avidin/biotin blocking kit (Vector Laboratories, Burlingame, CA). After the blocking step, sections were incubated with rat anti-mouse CD68 primary antibody for macrosialin (1:100) for 1 h at room temperature. After washing with phosphate-buffered saline, the slides were incubated with biotinylated anti-rat immunoglobulin G secondary antibody (1:200; Vector Laboratories) for 30 min at room temperature. The sections were washed five times with phosphate-buffered saline and incubated with fluorescein isothiocyanate-labeled streptavidin (1: 100; Vector Laboratories, emission 
-520 nm) for 30 min, followed by staining with propidium iodide (PI) (1:20; BD PharMingen, San Diego, CA, emission -615 nm) for 5 min in the dark. Rat immunoglobulin G was used as a negative control (Vector Laboratories). The stimulation and infiltration of Kupffer cells in restrained and free roaming mice were compared by measuring fluorescent intensity (FI) and counting the number of fluorescent cells in a selected field. FI of fluorescein isothiocyanate-positive sections was determined using the Image J software, in which two slides from each liver and three fields from each slide were measured for FI (at 10x objective). The average FI for each liver was determined as the average of all six measurements (2 slides x 3 fields), and the mean (S.D.) was determined for each group of animals using the mean value from these samples for each mouse liver. The number of fluorescent cells was determined in each slide by counting the cells that were both positive for PI and CD68 (nucleus in the center surrounded by a fluorescent ring).
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Varying doses of CCl4, ranging from 1 to 100 µl/kg, were administered to free roaming male mice or mice that had been restrained for 2.5 h before CCl4 administration. In free roaming mice, liver injury was only observed after a dose of 100 µl/kg (Fig. 1). In contrast, in mice that were restrained before CCl4 administration, the threshold dose for liver injury was reduced, such that liver injury was evident after a dose of either 10 or 100 µl/kg (Fig. 1). The mean serum ALT in mice receiving 10 µl/kg after restraint was 30 times that seen in mice receiving the same dose but without previous restraint. The magnitude of liver injury in restrained mice receiving a dose of 100 µl/kg did not differ significantly from mice receiving the same dose without previous restraint.
Assessment of the effect of duration of restraint on CCl4-induced liver injury, with xenobiotic administration immediately after the period of restraint, revealed that the enhancement of CCl4-induced liver injury was dependent on the duration of restraint (Fig. 2). Restraint for periods of 0.5 or 1.5 h did not significantly enhance the liver injury observed, whereas animals restrained for 2.5 h exhibited a significant increase in liver injury. Hence, this duration of restraint was used in subsequent experiments.
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Effect of Restraint on Allyl Alcohol-Induced Liver Injury. To determine whether the liver injury-enhancing effect of acute restraint occurs with other xenobiotics, we examined the ability of acute restraint to enhance liver injury after administration of allyl alcohol. After a 90-mg/kg dose of allyl alcohol, both restrained and free roaming male mice exhibited significant liver injury (Fig. 4). However, whereas a dose of 30 mg/kg did not induce liver injury in free roaming mice, restraint before administration of this dose did result in significant liver injury. Interestingly, vehicle-treated mice that were restrained exhibited a statistically significant elevation in ALT. However, the absolute increase in ALT content was less than the 3-fold increase commonly used to designate hepatotoxicity in clinical studies. An increase in vehicle-treated animals that were restrained has not been reproduced in subsequent studies. Hence, we do not believe this observation is of biological significance.
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Prolonged Effect of Restraint on CCl4-Induced Liver Injury. The observation that hepatic GSH content was most significantly reduced at 5 h after (2:30 PM) acute restraint stress suggested that the liver injury enhancement seen after stress might occur even when xenobiotic administration is delayed. Hence, we sought to determine whether withholding xenobiotic administration until 5 h after restraint results in an enhanced liver injury. Because CCl4-induced liver injury exhibits a circadian variation, we first determined the hepatotoxic dose of CCl4 at this time point in the day. Doses of 2.5, 5, and 7.5 µl of CCl4/kg in free roaming male mice were found to induce liver injury (Fig. 7), exhibiting a clear dose-dependent effect on serum ALT content. The magnitude of liver injury induced by a dose of 2.5 µl/kg is less than the 3-fold increase commonly used to define liver injury in clinical studies. Hence, a dose of 2.5 µl of CCl4/kg was administered to determine the effect of delayed xenobiotic administration on restraint-induced enhancement of liver injury caused by CCl4. In free roaming mice, ALT levels 24 h after CCl4 increased above vehicle-treated animals approximately 2.3-fold, whereas the increase in restrained mice administered CCl4 was 3.7-fold (Fig. 8). The serum ALT content in restrained mice treated with CCl4 was significantly higher than that seen in animals receiving the same dose but remaining free roaming.
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Effect of Restraint on Hepatic Kupffer Cell Activation. To determine whether acute restraint stress enhancement of hepatic injury is mediated by inflammatory responses in the liver, we examined variations in hepatic Kupffer cell population/activation in liver sections from free roaming and restrained mice receiving no xenobiotic treatment by probing for CD68+ cells. Typical confocal microscopic images (10x objective) of liver slices from restrained and free roaming mice illustrate the enhanced Kupffer cell activation that was observed with 2.5 h of restraint (Fig. 9). Visual examination of each field suggested that the number of CD68+ cells was increased after acute restraint. Liver sections from free roaming mice showed few CD68+ cells, whereas CD68+ cells were fairly abundant in slices from restrained mice. We used a semiquantitative approach using the Image J software to determine FI over the entire field, which revealed that the FI in liver sections stained for CD68 from restrained mice was increased (Fig. 10, p < 0.05). The number of CD68+ cells was also significantly higher in liver sections from restrained mice (Fig. 10, p < 0.05).
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Discussion |
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) but provokes a variety of physiological and biochemical changes that may alter the response of the body to xenobiotics. For example, Dhabhar et al. (2000) have shown that acute stress, in the form of physical restraint, enhances the delayed-type hypersensitivity response observed with 2,4-dinitro-1-fluorobenzene, an observation that has been confirmed by others (Kawaguchi et al., 1997; Dhabhar, 2003). These and other data indicate that psychogenic stress may predispose subjects to ADR.
We hypothesize that such stress may predispose subjects to xenobiotic-induced hepatotoxicity, one of the most common and serious ADR. There are limited data that suggest altered susceptibility to hepatotoxicants may be a global response to environmental stressors. Wei et al. (1971) found that exposure of animals to cold environments (4°C) enhanced liver injury induced by CCl4. However, this observation was made in animals that were also placed into some sort of restraint for an undefined period. The period of exposure to cold (18 h) was also of a length that adaptation might have occurred. In addition, although there was a significant difference in the level of liver enzymes in animals receiving CCl4 on exposure to a cold environment, there was less than a 2-fold increase in the liver enzymes, which is below the magnitude generally used to designate hepatotoxicity. Thus, these investigators failed to show hepatotoxicity under the conditions examined. More significant evidence was provided by Iwai et al. (1986), who observed that foot-shock stress given for 6 h after CCl4 administration enhanced liver injury seen with this hepatotoxicant.
In the present study, we show that previous acute restraint stress increases the liver injury by CCl4 or allyl alcohol administration in a dose- and time-dependent manner. As illustrated in Figs. 1, 3, and 4, the effect of acute restraint was most apparent when a near-hepatotoxic dose was administered. That is, acute restraint was sufficient to provoke detectable liver injury at a dose of toxicant that did not result in detectable liver injury in free roaming animals. At higher doses of hepatotoxicants, the magnitude of liver injury in restrained mice was not significantly greater than in free roaming animals. Moreover, short periods of restraint were not sufficient to enhance the hepatotoxic effect of CCl4 (Fig. 2). This latter observation suggests that the short period of restraint often necessary for xenobiotic administration should not significantly alter the magnitude of liver injury.
Our studies confirmed the anticipated stress response in animals acutely restrained, resulting in an elevated serum corticosterone level (Fig. 5). The decrease in corticosterone concentration observed in the last 30 min of restraint suggests that some form of adaptation had begun to reduce the stress response in these animals before completion of the period of restraint. We also showed that hepatic levels of the critical antioxidant GSH were reduced in response to stress (Fig. 6). Importantly, the maximal decrease in GSH content was observed 5 h after completion of the restraint period and remained below that seen in nonrestrained animals for up to 48 h after restraint. This suggests that susceptibility to liver injury may be increased well beyond the period of restraint.
The mechanism for the reduction in hepatic GSH content is unclear. Previous studies have shown that increased glucocorticoid levels stimulate lipid peroxidation. Thus, glucocorticoids have been associated with oxidative damage as a result of reactive oxygen species (ROS) generation (Sahin and Gumuslu, 2004). Simmons et al. (1990) showed alterations in GSH content in various organs of mice exposed to cold stress. It has also been shown that increased lipid peroxidation and oxidative stress result in reduction of GSH content in many tissues, including liver (Seckin et al., 1997; Schmidt et al., 2002). However, preliminary studies in our laboratory have not found an effect of restraint-induced stress on erythrocyte or renal GSH content (S. D. Panuganti and C.K. Svensson, unpublished results).
Having observed that GSH content differed most markedly between restrained and free roaming animals 5 h after restraint was completed, it was of interest to determine whether susceptibility to liver injury was still increased when xenobiotic was administered this long after restraint. Such an assessment must account for the reported circadian variation in CCl4-induced liver injury (Skrzypinska-Gawrysiak et al., 2000; Bruckner et al., 2002). Hence, we first performed a dose-ranging study to identify the near hepatotoxic dose of CCl4 administered at this time in the circadian cycle (Fig. 7). Using this modified dose, we found that the increased susceptibility to liver injury in restrained animals occurs even when xenobiotic is administered 5 h after restraint (Fig. 8). This suggests that the altered susceptibility is sustained for a significant period after acute stress. Further studies are needed to determine the full duration of this effect and whether shorter periods of stress may perhaps induce a susceptibility that is not apparent unless there is a lag between the period of restraint and the administration of a hepatotoxicant.
Figure 11 illustrates our working hypothesis for the mechanism by which acute restraint enhances xenobiotic hepatotoxicity. When exposed to a stressor, perception of the stress is a key determinant in the biological response to the environmental stress (McEwen et al., 1997). This perception may be psychological in origin (as in psychogenic stress) or arise from biological mediators released by metabolic, pathologic, or traumatic insult (as seen with an infection or penetrating injury). Response to environmental stress often results in stimulation of the hypothalamic-pituitary-adrenal axis. This stimulation will result in a variety of physiological responses through the release of hypothalamic- and pituitary-derived hormones. A key component in this response is the release of adrenocorticotropin-releasing hormone, which results in adrenal stimulation. On adrenal stimulation, we propose three pathways by which acute stress may sensitize hepatocytes to hepatotoxicants.
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Several studies have shown that acute restraint or other forms of stress enhance intestinal permeability in rats (Saunders et al., 1997; Meddings and Swain, 2000), which results in an increase in the passage of gut-derived endotoxin. Acute exercise has also been shown to increase intestinal permeability in normal human subjects (Pals et al., 1997; Lambert et al., 1999). Importantly, experimental models have shown that adrenalectomy or administration of the glucocorticoid antagonist RU-486 prevents the stress-induced increase in intestinal permeability (Meddings and Swain, 2000). In a related observation, it was reported that repeated environmental stress results in a cross-tolerance to the lethal effects of endotoxin in rats (Kawabata et al., 1998), which provides evidence that stress may result in the systemic exposure to endotoxin or common mediators. These observations are significant in light of the well documented role of intestinal-derived endotoxin in chemical-induced hepatotoxicity (Nolan and Camara, 1989; Roth et al., 1997). Thus, increased intestinal permeability toward endotoxin may readily result in a predisposition toward liver injury from a variety of xenobiotics.
Another response that may occur on adrenal stimulation is the release of cytokines into the systemic circulation. Conti et al. (1997) have shown that acute cold stress induced interleukin 18 (also known as interferon-
-inducing factor) gene expression in rat adrenal cortex. The enhanced cutaneous hypersensitivity observed in mice after acute restraint stress is dependent on interferon- (Dhabhar et al., 2000), providing further evidence that psychogenic stress may result in the release of immunomodulatory cytokines. Previous studies have also shown that different forms of stress are able to produce inflammatory responses in different organs such as the brain (Reyes and Coe, 1997; Black, 2002) and the spleen (Cao et al., 2003). A third event after acute stress is adrenergic stimulation. Numerous studies have shown that 
- and 
-adrenergic agents may potentiate the liver injury observed after administration of CCl4, acetaminophen, and methamphetamine (James et al., 1993; Roberts et al., 1995). Any or all of these events may result in an increased sensitivity to hepatotoxic agents.
A common link between these three events is the activation of Kupffer cells, the fixed macrophages in the liver. Numerous studies have shown the importance of soluble mediators from Kupffer cells in sensitizing the liver toward hepatotoxic xenobiotics (Laskin and Pendino, 1995; Morio et al., 2001; Yee et al., 2001). Our novel observation that acute restraint results in Kupffer cell activation provides important support for this element of the hypothesis (Figs. 9 and 10).
Another possibility that may occur after adrenal stimulation is the elevation of lipid peroxidation and successive ROS generation in many tissues. Several studies, including our current research, show that there is a reduction in GSH content in some tissues, particularly in the liver, as a consequence of psychogenic stress (Simmons et al., 1990; Schmidt et al., 2002). Importantly, in addition to producing cytokines, activated Kupffer cells are a major source of ROS in the liver (Vrba and Modriansky, 2002). It has been proposed that activation of Kupffer cells results in the generation of superoxide and tumor necrosis factor-, both of which can lead to tissue damage in the liver (Wheeler, 2003). Our observations raise the possibility that the enhanced xenobiotic-induced hepatotoxicity following acute psychogenic stress is because of activation of macrophages in the liver, which sensitize the surrounding hepatocytes either by generating ROS (thereby consuming and depleting hepatic GSH) or by releasing inflammatory cytokines.
Our studies have shown that environmental stress may represent an important determinant in the development of liver injury after administration of potentially hepatotoxic xenobiotics and that activation of Kupffer cells in the liver may mediate this enhanced susceptibility. Because psychogenic stress is one of, if not the most, common forms of environmental stress, it will be important to further assess the role of such stress as a predisposing factor for ADR. Understanding the mechanism by which stress increases susceptibility to liver injury will be important for identifying biomarkers that may indicate times at which patients are at increased risk for such reactions.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: ADR, adverse drug reaction(s); CCl4, carbon tetrachloride; DTNB, 5,5-dithiobis (2-nitro benzoic acid); GSH, reduced glutathione; ALT, alanine aminotransferase; PI, propidium iodide; FI, fluorescent intensity; ROS, reactive oxygen species; ANOVA, analysis of variance.
Address correspondence to: Dr. Craig K. Svensson, Division of Pharmaceutics, S213, College of Pharmacy, The University of Iowa, 115 South Grand Avenue, Iowa City, IA 52242. E-mail: craig-svensson{at}uiowa.edu
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References |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Bissell DM, Gores GJ, Laskin DL, and Hoofnagle JH (2001) Drug-induced liver injury: mechanisms and test systems. Hepatology 33: 1009-1013.[Medline]
Black PH (2002) Stress and the inflammatory response: a review of neurogenic inflammation. Brain Behav Immun 16: 622-653.[CrossRef][Medline]
Bruckner JV, Ramanathan R, Lee KM, and Muralidhara S (2002) Mechanisms of circadian rhythmicity of carbon tetrachloride hepatotoxicity. J Pharmacol Exp Ther 300: 273-281.
Cao L, Hudson CA, and Lawrence DA (2003) Immune changes during acute cold/restraint stress induced inhibition of host resistance to Listeria. Toxicol Sci 74: 325-334.
Conti B, Jahng JW, Tinti C, Son JH, and Joh TH (1997) Induction of interferon- inducing factor in the adrenal cortex. J Biol Chem 272: 2035-2037.
Dambach DM, Watson LM, Gray KR, Durham SK, and Laskin DL (2002) Role of CCR2 in macrophage migration into the liver during acetaminophen-induced hepatotoxicity in the mouse. Hepatology 35: 1093-1103.[CrossRef][Medline]
Dhabhar FS (2003) Stress, leukocyte trafficking and the augmentation of skin immune function. Ann NY Acad Sci 992: 205-217.
Dhabhar FS, Satoskar AR, Bluethmann H, David JR, and McEwen BS (2000) Stress-induced enhancement of skin immune function: a role for -interferon. Proc Natl Acad Sci USA 97: 2846-2851.
Iwai M, Saheki S, Ohta Y, and Shimazu T (1986) Footshock stress accelerates carbon tetrachloride-induced liver injury in rats: implication of the sympathetic nervous system. Biomed Res 7: 145-154.
James RC, Harbison RD, and Roberts SM (1993) Phenylpropanolamine potentiation of acetaminophen-induced hepatotoxicity: evidence for the glutathione-dependent mechanism. Toxicol Appl Pharmacol 118: 159-168.[Medline]
Johnson JA and Bootman JL (1995) Drug-related morbidity and mortality. A cost-of-illness model. Arch Intern Med 155: 1949-1956.[Abstract]
Kawabata A, Hata T, and Kuroda R (1998) Cross tolerance to environmental stress and endotoxin. Life Sci 62: 327-333.[Medline]
Kawaguchi Y, Okada T, Konishi H, Fujino M, Asai J, and Ito M (1997) Reduction of the DTH response is related to morphological changes of Langerhans cells in mice exposed to acute immobilization stress. Clin Exp Immunol 109: 397-401.[CrossRef][Medline]
Lambert GP, Murray R, Eddy D, Scott W, Laird R, and Gisolfi CV (1999) Intestinal permeability following the 1998 Ironman triathlon. Med Sci Sports Exer 31: S318.
Larrey D and Pageaux GP (2005) Drug-induced liver failure. Eur J Gastroenterol Hepatol 17: 141-143.[Medline]
Laskin DL and Pendino KJ (1995) Macrophages and inflammatory mediators in tissue injury. Ann Rev Pharmacol Toxicol 35: 655-677.[CrossRef][Medline]
Lazarou J, Pomeranz BH, and Corey PN (1998) Incidence of adverse drug reactions in hospitalized patients. A meta-analysis of prospective studies. J Am Med Assoc 279: 1200-1205.
Maddrey WC (2005) Drug-induced hepatotoxicity. J Clin Gastroenterol 39: S83-S89.[Medline]
McEwen BS, Biron CA, Brunson KW, Bulloch K, Chambers WH, Dhabhar FS, Goldfarb RH, Kitson RP, Miller AH, Spencer RL, et al. (1997) The role of adrenalocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions. Brain Res Brain Res Rev 23: 79-133.[CrossRef][Medline]
Meddings J and Swain M (2000) Environmental stress-induced gastrointestinal permeability is mediated by endogenous glucocorticoids in the rat. Gastroenterology 119: 1019-1028.[CrossRef][Medline]
Morio LA, Chiu H, Sprowles KA, Zhou P, Heck DE, Gordon MK, and Laskin DL (2001) Distinct roles of tumor necrosis factor-alpha and nitric oxide in acute liver injury induced by carbon tetrachloride in mice. Toxicol Appl Pharmacol 172: 44-51.[CrossRef][Medline]
Nolan JP and Camara DS (1989) Intestinal endotoxins as co-factors in liver injury. Immunol Investig 18: 325-337.[Medline]
Padgett DA, Marucha PT, and Sheridan JF (1998) Restraint stress slows cutaneous wound healing in mice. Brain Behav Immun 12: 64-73.[CrossRef][Medline]
Pals KL, Chang RT, Ryan AJ, and Gisolfi CV (1997) Effect of running intensity on intestinal permeability. J Appl Physiol 82: 571-576.
Reyes TM and Coe CL (1997) Prenatal manipulators reduce the proinflammatory response to a cytokine challenge in juvenile monkeys. Brain Res 769: 29-35.[CrossRef][Medline]
Roberts SM, Harbison RD, and James RC (1995) Mechanistic studies on the potentiation of carbon tetrachloride hepatotoxicity by methamphetamine. Toxicology 97: 49-57.[Medline]
Roth RA, Harkema JR, Pestka JP, and Ganey PE (1997) Is exposure to bacterial endotoxin a determinant of susceptibility to intoxication from xenobiotic agents? Toxicol Appl Pharmacol 147: 300-311.[CrossRef][Medline]
Sahin E and Gumuslu S (2004) Alterations in brain antioxidant status, protein oxidation and lipid peroxidation in response to different stress models. Behav Brain Res 155: 241-248.[Medline]
Saunders PR, Hanssen NP, and Perdue MH (1997) Cholinergic nerves mediate stress-induced intestinal transport abnormalities in Wistar-Kyoto rats. Am J Physiol 273: G486-G490.[Medline]
Schmidt AJ, Krieg JC, and Vedder H (2002) Differential effects of glucocorticoids and gonadal steroids on glutathoine levels in neuronal and glial cell systems. J Neuorosci Res 67: 544-550.
Seckin S, Alptekin N, Dogru-Abbasoglu S, Kocak-Toker N, Toker G, and Uysal M (1997) The effect of chronic stress on hepatic and gastric lipid peroxidation in long-term depletion of glutathione in rats. Pharmacol Res 36: 55-57.[CrossRef][Medline]
Sheridan JF (1998) Stress-induced modulation of antiviral immunity. Brain Behav Immun 12: 1-6.[CrossRef][Medline]
Simmons HF, James RC, Harbison RD, and Roberts SM (1990) Depression of glutathione by cold restraint in mice. Toxicology 161: 59-71.
Skrzypinska-Gawrysiak M, Piotrowski JK, and Sporny S (2000) Circadian variations in hepatotoxicity of carbon tetrachloride in mice. Intl J Occup Med Environ Health 13: 165-173.
Vrba J and Modriansky M (2002) Oxidative burst of Kupffer cells: target for liver injury treatment. Biomed Papers 146: 15-20.
Wei E, Wong LC, and Hine CH (1971) Potentiation of carbon tetrachloride hepatotoxicity by ethanol and cold. Toxicol Appl Pharmacol 18: 329-334.[Medline]
Wheeler MD (2003) Endotoxin and Kupffer cell activation in alcoholic liver disease. Alcohol Res Health 27: 300-306.[Medline]
Yee SB, Ganey PE, and Roth RA (2001) The role of Kupffer cells and TNF-alpha in monocrotaline and bacterial lipopolysaccharide-induced liver injury. Toxicol Sci 71: 124-132.
Zorzet S, Perissin L, Rapozzi V, and Giraldi T (1998) Restraint stress reduced the antitumor efficacy of cyclophosphamide in tumor-bearing mice. Brain Behav Immun 12: 23-33.[CrossRef][Medline]
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