Neutrophils (PMNs) may be exposed to high concentrations of biliary products during cholestasis and other hepatic disorders. We have previously reported that bile and certain bile salts enhance superoxide (O2-) release from neutrophils... more
Neutrophils (PMNs) may be exposed to high concentrations of biliary products during cholestasis and other hepatic disorders. We have previously reported that bile and certain bile salts enhance superoxide (O2-) release from neutrophils activated with phorbol myristate acetate (PMA) (Dahm et al.: Toxicol. Appl. Pharmacol. 95,82,1988), suggesting that PMN oxidative metabolism might be altered in toxicoses or disease states characterized by elevations in serum bile salts and other biliary products. In the present study, we characterized the priming effect of lithocholate for O2- release and also examined the effects of lithocholate on enzyme release from PMNs. PMNs preincubated with lithocholate at concentrations which did not directly stimulate O2- release (3–100 μM) and activated with PMA released greater amounts of O2- than controls exposed to PMA alone, illustrating a priming effect O2- release from lithocholate-primed PMNs rose sharply between 5 and 10 min after PMA addition and t...
Research Interests: Immunology, Biology, Calcium, Medicine, Incubation, and 9 moreAnimals, Male, Neutrophils, Rats, Time Factors, Rat, Superoxide, Oxides, and Extracellular
Inflammation is an important biological process involved in many target organ toxicities. However, there has been little consensus on how to represent inflammatory processes using the adverse outcome pathway (AOP) framework. In... more
Inflammation is an important biological process involved in many target organ toxicities. However, there has been little consensus on how to represent inflammatory processes using the adverse outcome pathway (AOP) framework. In particular, there were concerns that inflammation was not being represented in a way that it would be recognized as a highly connected, central node within the global AOP network. The consideration of salient features common to the inflammatory process across tissues was used as a basis to propose 3 hub key events (KEs) for use in AOP network development. Each event, "tissue resident cell activation", "increased pro-inflammatory mediators", and "leukocyte recruitment/activation," is viewed as a hallmark of inflammation, independent of tissue, and can be independently measured. Using these proposed hub KEs, it was possible to link together a series of AOPs that previously had no shared KEs. Significant challenges remain with regar...
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Botanical dietary supplements (herbal products) have flooded the market in the United States over the past decade, and studies show a significant percentage of Americans use them. With increasing frequency and duration of exposure, some... more
Botanical dietary supplements (herbal products) have flooded the market in the United States over the past decade, and studies show a significant percentage of Americans use them. With increasing frequency and duration of exposure, some serious adverse effects, though relatively uncommon, have been reported. Among the most troublesome is the association of some botanicals with serious hepatotoxicity. In some cases, hepatotoxicity has been linked to the consumption of botanicals with recognized hepatotoxic components (e.g., pyrrolizidine alkaloids). However, in other cases, the causative agent(s) is less clear and, overall, the mechanisms of hepatotoxicity are poorly understood. To help create a scientific basis for understanding botanical-induced hepatotoxicity and better tools for hepatotoxicity assessment and prediction, the National Center for Natural Product Research (NCNPR) hosted a workshop (September 8 and 9, 2003) in cooperation with the Center for Food Safety and Applied Nu...
Research Interests: Pharmacovigilance, Medicine, Phytotherapy, Humans, Liver, and 9 moreUnited States, Animals, Dietary Supplements, Dietary Supplement, Food and Drug Administration, Drug Induced Liver Injury, Pyrrolizidine Alkaloids, United States Food and Drug Administration, and Pharmacology and pharmaceutical sciences
Monocrotaline (MCT) is a pyrrolizidine alkaloid plant toxin that produces hepatotoxicity in humans and animals. Human exposure to MCT occurs through consumption of contaminated grains and herbal medicines. Administration of MCT to rats... more
Monocrotaline (MCT) is a pyrrolizidine alkaloid plant toxin that produces hepatotoxicity in humans and animals. Human exposure to MCT occurs through consumption of contaminated grains and herbal medicines. Administration of MCT to rats stimulates activation of the coagulation system and fibrin deposition in the liver. Fibrin deposition occurs simultaneously with endothelial cell damage and prior to hepatic parenchymal cell injury. Accordingly, the hypothesis that activation of the coagulation system is required for MCT-induced liver injury was tested. Treatment of rats with either heparin or warfarin significantly reduced MCT-induced activation of the coagulation system and the increase in alanine aminotransferase activity in the plasma, a biomarker of hepatic parenchymal cell injury. Histopathological examination of liver sections revealed that heparin decreased parenchymal cell necrosis but did not affect central venular endothelial cell damage, congestion and dilation of the sinu...
Research Interests: Medicine, Herbal Medicine, Fibrin, Heparin, Liver, and 15 moreAnimals, Male, Key words, Anticoagulants, Morphometric Analysis, Hyaluronic Acid, Endothelial cell, Analysis of Variance, Alanine Aminotransferase, Coagulation, ENDOTHELIUM, Drug Induced Liver Injury, Liver injury, Human Exposure, and monocrotaline
Under certain circumstances, segmented neutrophils (PMNs) injure extrahepatic tissue by releasing toxic oxygen species and degradative enzymes. The authors used an isolated, perfused rat liver preparation to determine whether PMNs might... more
Under certain circumstances, segmented neutrophils (PMNs) injure extrahepatic tissue by releasing toxic oxygen species and degradative enzymes. The authors used an isolated, perfused rat liver preparation to determine whether PMNs might injure the liver. Livers from fasted rats were perfused with Krebs-Ringer bicarbonate buffer (pH 7.4) containing 3% bovine serum albumin (BSA) in a recirculating system. Rat peritoneal PMNs (4 x 10(8] or vehicle (Hank's balanced salt solution [HBSS], pH 7.35) were added, and liver injury was assessed 90 minutes later by release of alanine aminotransferase (ALT) into the perfusion medium and histopathologic analysis of liver sections. Perfusion of livers receiving only HBSS for 90 minutes resulted in a small increase in ALT activity in the perfusion medium but did not significantly alter histologic features of liver sections. Addition of unstimulated PMNs did not increase further the ALT activity and, with the exception of vascular neutrophilia, d...
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alpha-Naphthylisothiocyanate (ANIT) causes cholestasis and injury to bile duct epithelium and hepatic parenchymal cells in rats. The mechanism of toxicity is unknown. Neutrophils (PMNs) infiltrate periportal regions of the liver after... more
alpha-Naphthylisothiocyanate (ANIT) causes cholestasis and injury to bile duct epithelium and hepatic parenchymal cells in rats. The mechanism of toxicity is unknown. Neutrophils (PMNs) infiltrate periportal regions of the liver after ANIT intoxication. Because PMNs play a causal role in other extrahepatic models of tissue injury, we determined whether PMNs might be involved in ANIT-induced liver injury in rats by reducing circulating PMN numbers with a polyclonal antibody (antineutrophil serum). ANIT treatment caused cholestasis and elevations in serum of total bilirubin concentration, total bile acid concentration, aspartate amino-transferase activity, gamma-glutamyltransferase activity and histologic lesions consistent with acute, neutrophilic cholangiohepatitis. Cotreatment of rats with antineutrophil serum reduced circulating PMN numbers, prevented ANIT-induced cholestasis and attenuated other markers of liver injury elevated by ANIT. In addition, antineutrophil serum treatment...
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Neutrophil (PMN) infiltration is an early occurrence in the liver after exposure to hepatotoxic doses of endotoxin lipopolysaccharide (LPS). The purpose of this study was to test the hypothesis that PMNs contribute to the pathogenesis of... more
Neutrophil (PMN) infiltration is an early occurrence in the liver after exposure to hepatotoxic doses of endotoxin lipopolysaccharide (LPS). The purpose of this study was to test the hypothesis that PMNs contribute to the pathogenesis of LPS hepatotoxicity. The immunoglobulin fraction from serum of rabbits immunized with rat PMNs (anti-PMN Ig) was administered intravenously to rats 18 and 6 hours before exposure to an hepatotoxic dose of LPS (Escherichia coli 0128:B12). This protocol caused a greater than 95% reduction in circulating PMNs, which was maintained for the duration of the study. The immunoglobulin fraction from nonimmunized rabbits was used as a control (control Ig). Rats pretreated with control Ig exhibited a marked increase in the number of PMNs in the liver 1.5 hours after LPS exposure. This increase in hepatic PMNs was significantly reduced by pretreatment with anti-PMN Ig. Marked elevations in both alanine and aspartate aminotransferase activities (1086 +/- 311 and ...
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Research Interests: Pharmacology, Chemistry, Toxicology, Oxidative Stress, Medicine, and 15 moreGene expression, Lipopolysaccharide, Humans, Liver, Reactive Oxygen Species, Animals, Male, Cell Death, Animal Model, Hydrogen Peroxide, Lipopolysaccharides, Rats, Adverse Drug Reaction, Liver injury, and Pharmacology and pharmaceutical sciences
Research Interests: Biology, Enzyme Inhibitors, Apoptosis, Medicine, Caspases, and 15 moreLiver, Mice, Animals, Male, Cell Death, Morphometric Analysis, Caspase, Endothelial cell, Alanine Aminotransferase, Hepatocytes, Kupffer cells, Alanine Transaminase, Liver injury, Pharmacology and pharmaceutical sciences, and monocrotaline
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Monocrotaline (MCT) is a toxic pyrrolizidine alkaloid of plant origin. Administration of small doses of MCT or its active metabolite, monocrotaline pyrrole (MCTP), to rats causes delayed and progressive lung injury characterized by... more
Monocrotaline (MCT) is a toxic pyrrolizidine alkaloid of plant origin. Administration of small doses of MCT or its active metabolite, monocrotaline pyrrole (MCTP), to rats causes delayed and progressive lung injury characterized by pulmonary vascular remodeling, pulmonary hypertension, and compensatory right heart hypertrophy. The lesions induced by MCT(P) administration in rats are similar to those observed in certain chronic pulmonary vascular diseases of people. This review begins with a synopsis of the hemostatic system, emphasizing the role of endothelium since endothelial cell dysfunction likely underlies the pathogenesis of MCT(P)-induced pneumotoxicity. MCT toxicology is discussed, focusing on morphologic, pulmonary mechanical, hemodynamic, and biochemical and molecular alterations that occur after toxicant exposure. Fibrin and platelet thrombosis of the pulmonary microvasculature occurs after administration of MCT(P) to rats, and several investigators have hypothesized that thrombi contribute to the lung injury and pulmonary hypertension. The evidence for involvement of the various components of the hemostatic system in MCT(P)-induced vascular injury and remodeling is reviewed. Current evidence is consistent with involvement of platelets and an altered fibrinolytic system, yet much remains to be learned about specific events and signals in the vascular pathogenesis.
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Research Interests: Pharmacology, Gastroenterology, Biology, Immunohistochemistry, Medicine, and 15 moreMetformin, Mice, Animals, Ethanol, AMPK, Clinical Sciences, Fatty Liver, Liver Disease, Growth Factor, Neurosciences, Plasminogen Activator Inhibitor, Plasminogen Activator, Liver injury, reverse transcriptase polymerase chain reaction, and Paediatrics and reproductive medicine
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Research Interests: Chemistry, Medicine, Animals, Acetylcholinesterase, Research article, and 12 moreVascular endothelium, Enzyme, Cattle, Rats, Swine, Angiotensin Converting Enzyme, ENDOTHELIUM, Angiotensin II, Angiotensin Converting Enzyme Inhibitors, Pulmonary Artery, Pharmacology and pharmaceutical sciences, and monocrotaline
The monocrotaline pyrrole (MCTP)-treated rat is a useful model for the study of certain chronic pulmonary vascular diseases. A single, i.v. administration of a low dose of MCTP causes pneumotoxicity, pulmonary vascular remodeling,... more
The monocrotaline pyrrole (MCTP)-treated rat is a useful model for the study of certain chronic pulmonary vascular diseases. A single, i.v. administration of a low dose of MCTP causes pneumotoxicity, pulmonary vascular remodeling, sustained increases in pulmonary arterial pressure, and right ventricular hypertrophy in rats. The pulmonary vascular lesions are characterized by endothelial cell alterations, platelet and fibrin microvascular thrombosis, pulmonary edema, and thickening of the intimal and medial layers of the vessel wall. These lesions suggest that some dysfunction of the hemostatic system occurs in the lungs of rats treated with MCTP. We evaluated the concentrations of two adhesion proteins, cellular fibronectin (cFn) and von Willebrand factor (vWF), in the plasma of rats treated with MCTP. We hypothesized that changes in these factors occur along with markers of pneumotoxicity and ventricular hypertrophy and that such changes might contribute to the genesis of the vascular lesions. Enzyme-linked immunosorbent assays were used to measure cFn and vWF concentrations in the plasma of rats after MCTP treatment. Rats treated with a single i.v. injection of 3.5 mg MCTP/kg body weight had delayed and progressive lung injury characterized at 5 days post-treatment by increases in the lung-to-body weight ratio and in lactate dehydrogenase activity and protein concentration in cell-free bronchoalveolar lavage fluid (BALF). Values for these markers were further increased at 8 days and reached a plateau thereafter. The number of nucleated cells within the BALF was increased at 8 and 14 days. Right ventricular hypertrophy, an indirect marker of pulmonary hypertension, was evident at 14 days. The cFn concentration was increased in plasma in rats at 8 and 14 days after treatment with MCTP. There was no difference between the vWF concentration in plasma of rats treated with MCTP and those treated with vehicle at any time. We conclude that an increase in plasma cFn concentration occurs prior to the onset of right ventricular hypertrophy and that this change is consistent with a role for cFn in the genesis of vascular remodeling and pulmonary hypertension in the MCTP-treated rat. The lung vascular injury and pulmonary hypertension in this model were not reflected in altered vWF concentration in the plasma.
Research Interests: Medicine, Pulmonary Hypertension, Low Dose, Animals, Male, and 15 moreLung, Rats, Fibronectin, Endothelial cell, Body Weight, BIOCHEMICAL PHARMACOLOGY, Lactate dehydrogenase, Lung Injury, Enzyme Linked Immunosorbent Assay, Pulmonary Edema, Bronchoalveolar lavage, Left Ventricular, Pharmacology and pharmaceutical sciences, monocrotaline, and right ventricular hypertrophy
Page 1. Vol. 278, No. 1 Printed in USA ABBREVIATIONS: LPS, lipopolysaccharide; APIT, activated partial thromboplastin time; ALT, alanine aminotransferase; SAL, saline; PPP, platelet-poor plasma. 378 0O22.3565/96/2781 ...
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Research Interests: Pharmacology, Chemistry, Biology, Medicine, Lipopolysaccharide, and 15 moreEnvironmental Sciences, Liver, Escherichia coli, Female, Animals, Male, Neutrophils, In Vivo, Lipopolysaccharides, Rats, Drug Induced Liver Injury, Liver function tests, Liver injury, Drug synergism, and Medical and Health Sciences
Bacterial endotoxin [lipopolysaccharide (LPS)] causes liver injury in vivo that is dependent on platelets, neutrophils [polymorphonuclear leukocytes (PMNs)], and several inflammatory mediators, including thrombin. We tested the hypothesis... more
Bacterial endotoxin [lipopolysaccharide (LPS)] causes liver injury in vivo that is dependent on platelets, neutrophils [polymorphonuclear leukocytes (PMNs)], and several inflammatory mediators, including thrombin. We tested the hypothesis that thrombin contributes to LPS-induced hepatocellular injury through direct interactions with platelets and/or PMNs in vitro. Perfusion of isolated livers from LPS-treated rats with buffer containing thrombin resulted in a significant increase in alanine aminotransferase (ALT) activity in the perfusion medium, indicating hepatocellular damage. This effect was completely abolished by prior depletion of PMNs from the LPS-treated donor rats but not by depletion of platelets, suggesting interaction between thrombin and PMNs in the pathogenesis. Thrombin did not, however, enhance degranulation of rat PMNs in vitro, and it was not directly toxic to isolated rat hepatocytes in the presence of PMNs even after LPS exposure, suggesting that hepatocellular ...
Research Interests: Kinetics, Biology, Medicine, Liver diseases, Lipopolysaccharide, and 15 moreLiver, Escherichia coli, Animals, Male, American, Medical Physiology, In Vivo, Lipopolysaccharides, Digestive System, Drug Induced Liver Injury, Alanine Transaminase, Liver injury, Blood platelets, degranulation, and Inflammation Mediators
Endotoxemia is marked by a global activation of inflammatory responses, which can lead to shock, multiple organ failure, and the suppression of immune and wound healing processes. Neutrophils (PMNs) play a central role in some of these... more
Endotoxemia is marked by a global activation of inflammatory responses, which can lead to shock, multiple organ failure, and the suppression of immune and wound healing processes. Neutrophils (PMNs) play a central role in some of these responses by accumulating in tissues and releasing reactive oxygen species and proteases that injure host structures. This review focuses on altered PMN migratory responses that occur during endotoxemia and their consequences in the development of pulmonary infection. The inflammatory mediators that might be responsible for these altered responses are discussed. The oxidant potential of PMNs is increased after exposure to endotoxin both in vitro and during clinical and experimental endotoxemia. However, other functions such as chemotaxis and phagocytosis are often depressed in these same cells. Endotoxin exposure renders PMNs hyperadhesive to endothelium. The sum of these effects produces activated inflammatory cells that are incapable of leaving the ...
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Diclofenac (DCLF) is a widely used NSAID that is associated with idiosyncratic, drug-induced liver injury (IDILI) in humans. The mechanisms of DCLF-induced liver injury are unknown; however, patients with certain inflammatory diseases... more
Diclofenac (DCLF) is a widely used NSAID that is associated with idiosyncratic, drug-induced liver injury (IDILI) in humans. The mechanisms of DCLF-induced liver injury are unknown; however, patients with certain inflammatory diseases have an increased risk of developing IDILI, which raises the possibility that immune mediators play a role in the pathogenesis. DCLF synergizes with the cytokines tumor necrosis factor-alpha (TNF) and interferon-gamma (IFN) to cause hepatocellular apoptosis in vitro by a mechanism that involves activation of the endoplasmic reticulum (ER) stress response pathway and of the mitogen activated protein kinases, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). DCLF also causes an increase in intracellular calcium (Ca(++)) in hepatocytes, but the role of this in the cytotoxic synergy between DCLF and cytokines is unknown. We tested the hypothesis that Ca(++) contributes to DCLF/cytokine-induced cytotoxic synergy. Treatment of He...
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Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most frequent causes of idiosyncratic, drug-induced liver injury (IDILI). Mechanisms of IDILI are unknown, but immune responses are suspected to underlie them. In animal models... more
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most frequent causes of idiosyncratic, drug-induced liver injury (IDILI). Mechanisms of IDILI are unknown, but immune responses are suspected to underlie them. In animal models of IDILI, the cytokines tumor necrosis factor-alpha (TNFα) and interferon-gamma (IFNγ) are essential to the pathogenesis. Some drugs associated with IDILI interact with cytokines to kill hepatocytes in vitro, and mitogen-activated protein kinases (MAPKs) might play a role. We tested the hypothesis that caspases and MAPKs are involved in NSAID/cytokine-induced cytotoxicity. NSAIDs that are acetic acid (AA) derivatives and associated with IDILI synergized with TNFα in causing cytotoxicity in HepG2 cells, and IFNγ enhanced this interaction. NSAIDs that are propionic acid (PA) derivatives and cause IDILI that is of less clinical concern also synergized with TNFα, but IFNγ was without effect. Caspase inhibition prevented cytotoxicity from AA and PA deriva...
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Use of the fluoroquinolone antibiotic trovafloxacin (TVX) was restricted due to idiosyncratic, drug-induced liver injury (IDILI). Previous studies demonstrated that tumor necrosis factor-alpha (TNF) and TVX interact to cause death of... more
Use of the fluoroquinolone antibiotic trovafloxacin (TVX) was restricted due to idiosyncratic, drug-induced liver injury (IDILI). Previous studies demonstrated that tumor necrosis factor-alpha (TNF) and TVX interact to cause death of hepatocytes in vitro that was associated with prolonged activation of c-Jun N-terminal kinase (JNK), activation of caspases 9 and 3, and DNA damage. The purpose of this study was to explore further the mechanism by which TVX interacts with TNF to cause cytotoxicity. Treatment with TVX caused cell cycle arrest, enhanced expression of p21 and impaired proliferation, but cell death only occurred after cotreatment with TVX and TNF. Cell death involved activation of extracellular signal-related kinase (ERK), which in turn activated caspase 3 and ataxia telangiectasia and Rad3-related (ATR), both of which contributed to cytotoxicity. Cotreatment of HepG2 cells with TVX and TNF caused double-strand breaks in DNA, and ERK contributed to this effect. Inhibition ...
Research Interests: Toxicology, Biology, DNA replication, Medicine, Signal Transduction, and 15 moreHumans, Liver, Programmed cell death, Caspase, Kinase, Anti-Bacterial Agents, Time Factors, Hepatocytes, Tumor necrosis factor-alpha, Cell cycle checkpoints, Cell Proliferation, Drug Induced Liver Injury, Protein Kinase Inhibitors, Fluoroquinolones, and Pharmacology and pharmaceutical sciences
Cytokine production is critical in ischemia/reperfusion (IR) injury. Acetylcholine binds to macrophages and inhibits cytokine synthesis, through the cholinergic anti-inflammatory pathway. This study examined the role of the cholinergic... more
Cytokine production is critical in ischemia/reperfusion (IR) injury. Acetylcholine binds to macrophages and inhibits cytokine synthesis, through the cholinergic anti-inflammatory pathway. This study examined the role of the cholinergic pathway in cytokine production and hepatic IR- injury. Adult male mice underwent 90-min of partial liver ischemia followed by reperfusion. The AChR agonists (1,1-dimethyl-4-phenyl-L-pioperazinium-iodide [DMPP], and nicotine) or saline-vehicle were administered i.p. before ischemia. Plasma cytokine tumor necrosis factor (TNF)-alpha, macrophage inflammatory protein-2, and Interleukin-6 were measured. Liver injury was assessed by plasma alanine transaminase (ALT) and liver histopathology. A reperfusion time-dependent hepatocellular injury occurred as was indicated by increased plasma-ALT and histopathology. The injury was associated with marked elevation of plasma cytokines/chemokines. Pre-ischemic treatment of mice with DMPP or nicotine significantly de...
Research Interests: Bioinformatics, Microbiology, Immunology, Life Sciences, Medicine, and 12 moreIschemia Reperfusion Injury, Internal Medicine, Biomedical Research, Acetylcholine, Cytokine, Time Dependent, Tumor necrosis factor-alpha, Cholinergic Systems, Reperfusion injury, Ischemia–reperfusion, Liver injury, and Tumor necrosis factor
Research Interests: Chemistry, Biology, Magnetic Resonance Spectroscopy, Lipopolysaccharide, Discriminant Analysis, and 15 moreLiver, Animals, Male, Lipopolysaccharides, Alanine Aminotransferase, Mass Spectroscopy, Idiosyncrasy, Drug Toxicity, Drug Induced Liver Injury, Aspartate Aminotransferase, Aspartate Aminotransferases, Liver function tests, Alanine Transaminase, Liver injury, and Environmental factor
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Research Interests: Pharmacology, Biology, Cytotoxicity, Apoptosis, Medicine, and 15 moreSignal Transduction, Caspases, Humans, Mice, Animals, Male, Phosphorylation, Programmed cell death, Time Factors, Hepatocytes, Cell Survival, Drug Induced Liver Injury, Protein Kinase Inhibitors, Fluoroquinolones, and Pharmacology and pharmaceutical sciences
Research Interests: Chemistry, Medicine, Cell line, Basement Membrane, Liver, and 15 moreAnimals, Male, Hydrogen Peroxide, Rats, Time Dependent, Endothelial cell, Time Factors, Collagen Type IV, Collagenase, Myeloperoxidase, Matrix Metalloproteinase, frozen section , Liver injury, Pharmacology and pharmaceutical sciences, and monocrotaline
Research Interests: Biology, Immunohistochemistry, Medicine, Lipopolysaccharide, Liver, and 15 moreAnimals, Male, Bacteria, Neutrophils, Lipopolysaccharides, Rats, Endothelial cell, Tumor necrosis factor-alpha, ENDOTHELIUM, Chemokines, Pyrrolizidine Alkaloids, Liver injury, Drug synergism, Pharmacology and pharmaceutical sciences, and monocrotaline
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Research Interests: Pharmacology, Biology, Medicine, Lipopolysaccharide, Liver, and 15 moreEscherichia coli, Animals, Male, Cytokine, Lipopolysaccharides, Rats, Gadolinium, Tumor necrosis factor-alpha, Combination drug therapy, Kupffer cells, Pentoxifylline, Liver injury, Drug synergism, Pharmacology and pharmaceutical sciences, and monocrotaline
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Research Interests: Pharmacology, Inflammation, Medicine, Lipopolysaccharide, Liver, and 15 moreMice, Animals, Male, Lipopolysaccharides, Adverse Drug Reaction, Ofloxacin, Drug Induced Liver Injury, Fluoroquinolones, immunoglobulin G, Levofloxacin, Pentoxifylline, Alanine Transaminase, Liver injury, Drug synergism, and Pharmacology and pharmaceutical sciences
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Research Interests: Medicine, Lipopolysaccharide, Humans, Escherichia coli, Animals, and 15 moreMale, Staphylococcus aureus, Sterilization, Lung, Neutrophils, Lipopolysaccharides, ENDOTOXEMIA, Rats, Trachea, Tumor necrosis factor-alpha, Rat Model, Recombinant Proteins, Biological Assay, Bronchoalveolar lavage, and Cardiovascular medicine and haematology
The liver is sensitive to pathological conditions associated with tissue hypoxia (Hx) and the presence of activated neutrophils that secrete the serine protease elastase (EL). We demonstrated previously that cotreatment of rat hepatocytes... more
The liver is sensitive to pathological conditions associated with tissue hypoxia (Hx) and the presence of activated neutrophils that secrete the serine protease elastase (EL). We demonstrated previously that cotreatment of rat hepatocytes with nontoxic levels of Hx and EL caused synergistic cell death. Hx is sensed by hypoxia-inducible factor (HIF)-1α, a transcription factor that heterodimerizes with HIF-1β/aryl hydrocarbon receptor nuclear translocator and directs expression of many genes, including the pro-cell death gene Bcl-2/adenovirus E1B-interacting protein 3 (BNIP3). Since cell death from EL or Hx also requires MAPK activation, we tested the hypothesis that the cytotoxic interaction of Hx and EL depends on MAPK and HIF-1α signaling. Treatment of Hepa1c1c7 cells with EL in the presence of Hx (2% O2) resulted in synergistic cell death. EL reduced phosphorylated ERK in O2-replete and Hx-exposed cells, and ERK inhibition enhanced the cytotoxicity of EL alone. Hx-EL cotreatment c...
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Idiosyncratic, drug-induced liver injury (IDILI) typically occurs in a small fraction of patients and has resulted in removal of otherwise efficacious drugs from the market. Current preclinical testing methods are ineffective in... more
Idiosyncratic, drug-induced liver injury (IDILI) typically occurs in a small fraction of patients and has resulted in removal of otherwise efficacious drugs from the market. Current preclinical testing methods are ineffective in predicting which drug candidates have IDILI liability. Recent results suggest that immune mediators such as tumor necrosis factor-alpha (TNF) and interferon-gamma (IFN) interact with drugs that cause IDILI to kill hepatocytes. This proof-of-concept study was designed to test the hypothesis that drugs can be classified according to their ability to cause IDILI in humans using logistic regression modeling with covariates derived from concentration-response relationships that describe cytotoxic interaction with cytokines. Human hepatoma (HepG2) cells were treated with drugs associated with IDILI or with drugs lacking IDILI liability and cotreated with TNF and/or IFN. Detailed concentration-response relationships were determined for calculation of parameters suc...
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Idiosyncratic drug-induced liver injury continues to be a human health problem in part because drugs that cause these reactions are not identified in current preclinical testing and because progress in prevention is hampered by incomplete... more
Idiosyncratic drug-induced liver injury continues to be a human health problem in part because drugs that cause these reactions are not identified in current preclinical testing and because progress in prevention is hampered by incomplete knowledge of mechanisms that underlie these adverse responses. Several hypotheses involving adaptive immune responses, inflammatory stress, inability to adapt to stress, and multiple, concurrent factors have been proposed. Yet much remains unknown about how drugs interact with the liver to effect death of hepatocytes. Evidence supporting hypotheses implicating adaptive or innate immune responses in afflicted patients has begun to emerge and is bolstered by results obtained in experimental animal models and in vitro systems. A commonality in adaptive and innate immunity is the production of cytokines, including interferon-γ (IFNγ). IFNγ initiates cell signaling pathways that culminate in cell death or inhibition of proliferative repair. Tumor necros...