Neutrophils (PMNs) may be exposed to high concentrations of biliary products during cholestasis a... 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...
Toxicological sciences : an official journal of the Society of Toxicology, 2018
Inflammation is an important biological process involved in many target organ toxicities. However... 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...
Toxicological sciences : an official journal of the Society of Toxicology, 2004
Botanical dietary supplements (herbal products) have flooded the market in the United States over... 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...
Monocrotaline (MCT) is a pyrrolizidine alkaloid plant toxin that produces hepatotoxicity in human... 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...
Under certain circumstances, segmented neutrophils (PMNs) injure extrahepatic tissue by releasing... 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...
The Journal of pharmacology and experimental therapeutics, 1991
alpha-Naphthylisothiocyanate (ANIT) causes cholestasis and injury to bile duct epithelium and hep... 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...
Laboratory investigation; a journal of technical methods and pathology, 1992
Neutrophil (PMN) infiltration is an early occurrence in the liver after exposure to hepatotoxic d... 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 ...
Journal of Toxicology and Environmental Health, Part B, 1998
Monocrotaline (MCT) is a toxic pyrrolizidine alkaloid of plant origin. Administration of small do... 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.
Neutrophils (PMNs) may be exposed to high concentrations of biliary products during cholestasis a... 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...
Toxicological sciences : an official journal of the Society of Toxicology, 2018
Inflammation is an important biological process involved in many target organ toxicities. However... 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...
Toxicological sciences : an official journal of the Society of Toxicology, 2004
Botanical dietary supplements (herbal products) have flooded the market in the United States over... 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...
Monocrotaline (MCT) is a pyrrolizidine alkaloid plant toxin that produces hepatotoxicity in human... 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...
Under certain circumstances, segmented neutrophils (PMNs) injure extrahepatic tissue by releasing... 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...
The Journal of pharmacology and experimental therapeutics, 1991
alpha-Naphthylisothiocyanate (ANIT) causes cholestasis and injury to bile duct epithelium and hep... 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...
Laboratory investigation; a journal of technical methods and pathology, 1992
Neutrophil (PMN) infiltration is an early occurrence in the liver after exposure to hepatotoxic d... 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 ...
Journal of Toxicology and Environmental Health, Part B, 1998
Monocrotaline (MCT) is a toxic pyrrolizidine alkaloid of plant origin. Administration of small do... 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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Papers by Robert Roth