Biomedical subjects

A E Schultze

Publications and source records attributed to A E Schultze.

At least 19 recordsLinked to original sources

PubMed2006

A model for educational enrichment and employment recruitment for clinical laboratory science students.

An educational partnership was initiated between a pharmaceutical company and a university-based clinical laboratory science program to achieve mutually beneficial objectives. This external enrichment site provides a unique educational experience for the students that cannot be duplicated any where else in the community. The framework for the educational experience was established with a full day's schedule of visits and presentations guided by a list of twenty learning objectives. Clinical laboratory science students interact with laboratory professionals who are employed by the pharmaceutical company and assigned to a variety of traditional and non-traditional roles. During the visit, pharmaceutical company employees observe student interactions in small group settings and assess the learners' interest in the work environment and specimen testing process. Employee feedback may be applied to future employment decision making. This article describes how employer outreach goals and initiatives and educational enrichment objectives can be met through cooperative team work.

Chemistry, Clinical↗

PubMed2003

Gene expression analysis of the acute phase response using a canine microarray.

The safety of pharmaceuticals is typically assessed in the dog and rat prior to investigation in humans. As a result, a greater understanding of adverse effects in these preclinical testing species would improve safety assessment. Despite this need, there is a lack of tools to examine mechanisms and identify biomarkers in the dog. To address this issue, we developed an Affymetrix-based oligonucleotide microarray capable of monitoring the expression of thousands of canine genes in parallel. The custom canine array contains 22,774 probe sets, consisting of 13,729 canine and 9045 human-derived probe sets. To improve cross-species hybridization with human-derived probes, the detection region was moved from the variable 3' UTR to the more homologous coding region. Testing of this strategy was accomplished by comparing hybridization of naive dog liver RNA to the canine array (coding region design) and human U133A array (standard 3' design). Although raw signal intensity was greater with canine-specific probe sets, human-derived probes detected the expression of additional liver transcripts. To assess the ability of this tool to detect differential gene expression, the acute phase response was examined in beagle dogs given lipopolysaccharide (LPS). Hepatic gene expression 4 and 24 h post-LPS administration was compared to gene expression profiles of vehicle-treated dogs (n=3/group). Array data was consistent with an acute inflammatory response, with transcripts for multiple cytokines and acute phase proteins markedly induced 4 h after LPS challenge. Robust changes in the expression of transcripts involved with glucose homeostasis, biotransformation, and extracellular matrix remodeling were observed 24 h post-dose. In addition, the canine array identified several potential biomarkers of hepatic inflammation. Strong correlations were found between gene expression data and alterations in clinical chemistry parameters such as serum amyloid A (SAA), albumin, and alkaline phosphatase (ALP). In summary, this new genomic tool successfully detected basal canine gene expression and identified novel aspects of the acute phase response in dog that shed new light on mechanisms underlying inflammatory processes.

Acute-Phase Reaction↗

PubMed2000

Alterations in hemograms and serum biochemical analytes of steers after prolonged consumption of endophyte-infected tall fescue.

The objective of the current study was to delineate changes that occur in serum analytes and blood cellular elements in cattle that graze endophyte-infested (Neotyphodium coenophialum) tall fescue. Tall fescue is grown on more than 35 million acres (14.2 million ha) of pasture in the United States, and three-fourths of the pastures are infected with the endophyte at a 60% or greater level. Tall fescue toxicosis caused by endophyte-produced ergot alkaloids continues to be the most important grass-related disease in the United States, in terms of economic loss to animal producers. However, the agronomic attributes of tall fescue make it an attractive forage species because of its ability to withstand cool temperatures, drought, poor soil conditions, and intensive defoliation from herbivore species, including insects. Tall fescue toxicosis is a complex disease and the need exists to understand the mechanisms of the toxic effects in order to institute effective, prophylactic control measures. Our group previously reported changes that occur in serum biochemical analytes of cattle that graze endophyte-infected tall fescue. An additional year's worth of data have been added, strengthening and corroborating these data. Consistent and significant changes associated with tall fescue toxicosis during the 3-yr study included decreased serum concentrations of cholesterol, globulin (increased albumin/globulin ratio), prolactin, total protein, and copper. The activity of alanine aminotransferase was decreased in serum, whereas an increase in serum concentrations of creatinine and total bilirubin occurred. The present report also documents comparative hemograms of cattle that grazed endophyte-infected or endophyte-free tall fescue over a prolonged period. The mean erythrocyte counts were increased in cattle that grazed endophyte-infected tall fescue, whereas mean corpuscular hemoglobin and mean corpuscular volume were decreased, as were mean eosinophil counts. Thus, repeatable changes have been identified that occur in serum biochemical and blood cellular values of cattle grazing endophyte-infected tall fescue that will aid in understanding the pathogenesis of the disease. In addition, these consistently altered parameters can be used to assess the effectiveness of potential prophylactic treatments.

Acremonium↗

PubMed1999

Alterations in bovine serum biochemistry profiles associated with prolonged consumption of endophyte-infected tall fescue.

Tall fescue (Festuca arundinacea) is a forage grass that is widely used in pastures in the eastern US for cattle, sheep and horses. The endophytic fungus Neotyphodium coenophialum is endemic in tall fescue pastures in the US. The turfgrass industry intentionally infects fescue cultivars with strains of the fungus to impart desirable growth and disease tolerance qualities to the plants. In contrast, ergot and pyrrolizidine alkaloid toxins produced by fungus-infected plants have been incriminated causally in bovine tall fescue toxicosis, a poorly defined syndrome of morbidity that occurs in cattle that consume endophyte-infected tall fescue (E+TF). We compared the serum biochemistry profiles from cattle that grazed E+TF with those from control cattle that grazed on endophyte-free tall fescue (E-TF). Cattle were bled on 7 dates from April 1 to August 30, 1996 and on 5 dates from May 1 to July 30, 1997. Cattle that grazed E+TF retained rough winter haircoats and had lesser weight gains, typical of tall fescue toxicosis, compared to those grazing E-TF. They had decreased activities of alkaline phosphatase and alanine aminotransferase. Compared to controls, they had lower values for serum prolactin and globulin concentrations. The concentration of creatinine and the albumin/globulin ratio were increased in the cattle grazing E+TF. Isozyme determination of alkaline phosphatase indicated that the decrease in serum activity of cattle grazing E+TF was due to decreases in both intestinal and bone isozymes. Serum protein electrophoresis indicated that the decrease in serum globulin concentration was due to decreases in both alpha and gamma globulin fractions of this protein. The data collected in these experiments add to our understanding of the alterations that occur in the serum chemistry profiles when cattle consume E+TF for prolonged periods of time.

Alkaline Phosphatase↗

PubMed1999

Lymphosarcoma with leukemic blood profile in a Savannah monitor lizard (Varanus exanthematicus).

A 6-mo-old male Savannah monitor lizard (Varanus exanthematicus) was presented for lethargy and anorexia of 7 days duration. Physical examination revealed a slightly raised subcutaneous mass (1 cm diameter) in the left scapular area. Fine-needle aspiration cytology of the mass revealed a population of immature, pleomorphic lymphoid cells consistent with lymphosarcoma. A hemogram indicated marked leukocytosis (465,000 cells/microl) characterized by extreme lymphocytosis and many circulating lymphoid blast cells. The lizard was euthanized at the owner's request. Necropsy revealed severe hepatomegaly and multiple raised, ulcerated mural masses in the gastrointestinal tract. There were many raised, poorly demarcated tan foci in all the parenchymal organs. Histopathologic examination confirmed infiltration of all parenchymal organs by neoplastic lymphoid cells. Transmission electron microscopic examination failed to identify viruses within the neoplastic cells. A literature review revealed few reports of squamate leukemia and lymphosarcoma and none in Savannah monitor lizards.

Animals↗

PubMed1999

Radiographic, histologic, and cytologic lesions associated with mutations in the fitness1(4226SB) locus of mice.

BACKGROUND AND PURPOSE: Previous investigation of fitness1(4226SB) mice revealed growth retardation and microcytic, hypochromic anemia with functional iron deficiency. Serum biochemical analysis suggested protein-losing enteropathy and liver dysfunction. METHODS: Radiography was done to assess lumbar bone lesions in mice hemizygous for fitness1 (fit1) [c fit1(4226SB/Df(c Mod2 sh1)26DVT] and age-matched sibling controls [c(ch)+/c(ch)+] at 40 or 60 days of age. Macroscopic and microscopic lesions were evaluated at necropsy. Bone marrow was examined cytologically to evaluate hematopoietic lesions. RESULTS: Mice hemizygous for fit1 had radiographically evident lumbar vertebral abnormalities, including various degrees of vertebral body fusion, with loss of intervertebral disk spaces and mild, generalized osteopenia. All mutant mice had scoliosis. Several mutant mice had lordosis and/or kyphosis of variable severity and mild subluxation at the lumbosacral junction. Marked splenomegaly and mild cardiomegaly were evident, and bone marrow color ranged from normal to slightly pale. The spleen had marked extramedullary hematopoiesis; lumbar vertebrae contained microscopic lesions that corresponded to the radiographic lesions. Cytologic examination of bone marrow revealed normocellular to hypocellular status, with mild to moderate erythroid hypoplasia characterized by mild increase in the myeloid-to-erythroid cell ratio, decreased percentage of erythroid precursors, and slight increase in percentage of myeloid precursor cells. CONCLUSIONS: Mutations in fit1 directly or indirectly cause alteration(s) in blood, organs of hematopoiesis (bone marrow, spleen, and liver), heart, and vertebral column, and suggest that this mouse may be a good model for study of scoliosis and relationships between iron metabolism and bone growth.

Anemia, Iron-Deficiency↗

PubMed1998

Sodium dodecyl sulfate polyacrylamide gel electrophoresis of canine urinary proteins for the analysis and differentiation of tubular and glomerular diseases.

A preliminary investigation was performed to evaluate the use of a new, noninvasive technique for the localization of canine renal lesions by electrophoresis of urinary proteins. Urine specimens from six clinically healthy, nonproteinuric dogs and 12 dogs with persistent proteinuria were examined by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE). Urine electrophoretic patterns of proteinuric dogs were classified as glomerular (n = 4), tubular (n = 2), or mixed (glomerular and tubular) (n = 6), based on the number and molecular weight of the silver-stained protein bands. Renal tissues from biopsies or necropsies were obtained from eight of the dogs with proteinuric disease. Interpretation of seven of eight electrophoretograms agreed with the histologic interpretation of renal lesions. We concluded SDS PAGE is a potentially valuable technique for detection and localization of renal lesions in dogs with proteinuric disease.

Journal Article↗

PubMed1998

Hepatic extraction efficiency of technetium-99m-mebrofenin in the dog with toxic-induced acute liver disease.

UNLABELLED: Extraction of the hepatobiliary radiopharmaceutical 99mTc-N-(3-bromo-2,4,6-trimethyacetanilide) iminodiacetic acid (mebrofenin; Choletec, Squibb Diagnostic, Princeton, NJ) by the liver may be used as an index of hepatocellular function. The hepatic parenchymal cells extract mebrofenin from the blood using the same active transport mechanism as bilirubin. METHODS: In this study, we induced hepatocellular disease by administering a hepatotoxic drug and compared the hepatic extraction efficiency (HEE), measured directly from an afferent injection of 99mTc-mebrofenin, to quantitative histopathology and to serum biochemistry analysis. RESULTS: The baseline HEE was 95.9% +/- 2.71% (mean +/- s.d.). Dogs that were affected by the hepatotoxic drug had reduced HEE. HEE correlated well to the severity of histologic lesions (r = -0.83, p = 0.003). HEE also correlated well to the increases in the activities of alanine aminotransferase (ALT; r = -0.85, p = 0.002) and aspartate aminotransferase (AST; r = -0.89, p = <0.001), the concentration of fasting bile acid (r = -0.97, p = <0.001), bilirubin (r = -0.92, p = <0.001) and, to a lesser degree, to the activities of alkaline phosphatase (Alk Phos; r = -0.73, p = 0.016). HEE had higher correlation coefficients to the serum biochemistry analysis than did the quantitative liver histopathology. CONCLUSION: Hepatic extraction of 99mTc-mebrofenin is a good predictor of the severity of hepatocellular damage in toxic-induced liver disease.

Aniline Compounds↗

PubMed1997

Bacterial endotoxin enhances the hepatotoxicity of allyl alcohol.

Lipopolysaccharide (LPS), or bacterial endotoxin, causes liver damage at relatively large doses in rats. Smaller doses, however, may influence the response to other hepatotoxicants. The purpose these studies was to examine the effect of exposure to relatively all doses of LPS on the hepatotoxic response to allyl alcohol, which causes periportal necrosis in laboratory rodents through an known mechanism. Rats were pretreated with LPS (100 micrograms/kg) 2 hr before treatment with a minimally toxic dose of allyl alcohol mg/kg), and liver toxicity was assessed 18 hr later from activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in plasma and from histologic changes in liver sections. Plasma ALT and AST activities were not elevated significantly in rats treated with vehicle, LPS, or allyl alcohol alone, but pronounced increases were observed in rats treated with LPS and allyl alcohol. Significant liver injury occurred as early as 2 hr after allyl alcohol treatment in LPS-pretreated rats and peaked at 6 hr. LPS treatment did not affect the activity of alcohol dehydrogenase and did not affect the rate of production of NADH in isolated livers perfused with allyl alcohol; thus, LPS does not appear to increase the metabolic bioactivation of allyl alcohol into acrolein. On the other hand, pretreatment with 4-methylpyrazole, an inhibitor of alcohol dehydrogenase, abolished the hepatotoxicity of allyl alcohol in LPS-treated rats, indicating that production of acrolein was needed for LPS enhancement of the toxicity of allyl alcohol. Pretreatment of rats with gadolinium chloride (10 mg/kg), a known inactivator of Kupffer cell phagocytic function, decreased LPS augmentation of the response to allyl alcohol. These data indicate that LPS markedly enhances the hepatotoxic response to allyl alcohol. Furthermore, the results suggest that the LPS-induced enhancement of allyl alcohol hepatotoxicity occurs through a Kupffer cell-dependent mechanism.

1-Propanol↗

PubMed1997

Gadolinium chloride pretreatment protects against hepatic injury but predisposes the lungs to alveolitis after lipopolysaccharide administration.

Exposure to lipopolysaccharide (LPS) can result in multi-organ failure and death. After an intravenous injection of LPS into rats, neutrophils (PMN) rapidly accumulate in the liver sinusoids and pulmonary vasculature, and PMN play a critical role in producing both hepatic and pulmonary injury. Kupffer cells (KC), the resident macrophages of the liver, phagocytose LPS and produce inflammatory mediators which may be chemotactic and stimulatory for PMN. The purpose of this study was to determine whether inhibition of KC function affects PMN accumulation and the development of parenchymal injury in the liver and lungs after systemic administration of LPS. Female, Sprague-Dawley rats (180-230 g) were pretreated with either gadolinium chloride-6H2O (GdCl3; 10 mg/kg, intravenously), to inactivate KC, or saline vehicle 24 h before receiving either LPS (4 mg/kg, intravenously) or saline vehicle. Rats were killed 1.5, 6, and 24 h after LPS administration. In a preliminary study, exposure to GdCl3 decreased uptake of carbon in the liver, indicating inhibition of phagocytosis by KC. Ninety minutes after administration of LPS, PMN accumulated in the livers of LPS-treated rats, and this effect was not altered by pretreatment with GdCl3. Similarly, exposure to LPS resulted in PMN accumulation in the pulmonary tissue, which was unaffected by GdCl3 pretreatment. Exposure to GdCl3 before LPS administration resulted in a significant increase in the number of PMN recovered by bronchoalveolar lavage at 24 h, indicating diffuse acute alveolitis. LPS-induced hepatic injury was prevented by pretreatment with GdCl3; however, the increased wet lung/body weight ratio observed after LPS administration was unaffected by GdCl3. These results confirm that inactivation of KC protects against hepatic injury and extend this finding by ruling out inhibition of hepatic PMN accumulation as a mechanism for this effect. The data also suggest that treatment with GdCl3 predisposes the lungs to alveolitis during systemic exposure to LPS.

Animals↗

PubMed1997

Repeated physical and cytologic characterizations of subcutaneous postvaccinal reactions in cats.

OBJECTIVES: To examine local reactions and short-term cytologic responses of cats to administration of rabies virus (RV); FeLV; and combined feline rhinotracheitis, calicivirus, and panleukopenia virus (FRCPV) vaccines. ANIMALS: 9 healthy 6- to 7-month-old specific-pathogen-free cats. PROCEDURE: One-milliliter doses of the aforementioned vaccines were administered SC (at different sites) to healthy, specific-pathogen-free cats. Each cat also received 1 ml of sterile saline solution SC as a control. Injection sites were visually examined and palpated daily for 4 weeks. Palpable lesions were measured by use of calipers. Temperature of the vaccination sites was measured weekly by use of a thermocouple. Aspirates were taken from vaccination sites weekly, and smears were submitted for cytologic analysis. RESULTS: There were no significant differences in lesion surface temperature among injection sites at any time. Injections of saline solution and FeLV vaccine resulted in no palpable lesions. The FRCPV vaccine elicited a minor reaction in 1 of the 9 cats. The RV vaccine caused palpable lesions in all cats. Smears of the aspirates from the sites of saline injection were poorly cellular. Cellularity of aspirates from the sites of FRCPV and FeLV vaccinations was moderate at week 1, and decreased with time. Inflammatory infiltrates were composed principally of lymphocytes, with fewer neutrophils and macrophages. In contrast, cellularity of aspirates from RV vaccination sites increased for 21 days and was characterized by increasing numbers of lymphocytes and macrophages. CONCLUSIONS: RV vaccine used in this study induced palpable lesions in many cats. In contrast, FRCPV and FeLV vaccines elicited less severe lesions. CLINICAL RELEVANCE: Subcutaneous administration of killed virus vaccines in cats may result in palpable lesions that are detected by clients or clinicians. Aspiration cytologic examination may reveal a different characteristic pattern of cells that is dependent on the individual vaccine and time elapsed from vaccination.

Alphaherpesvirinae↗

PubMed1996

Cellular fibronectin and von Willebrand factor concentrations in plasma of rats treated with monocrotaline pyrrole.

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.

Animals↗

PubMed1996

Thrombin is a distal mediator of lipopolysaccharide-induced liver injury in the rat.

Previous results demonstrated that rats given Escherichia coli lipopolysaccharide (LPS; 4 mg/kg, i.v.) experience hepatocellular necrosis that begins within 4 hr and that prior treatment with anticoagulants (e.g., heparin) which target thrombin prevents the liver injury. In this study, hepatocellular injury, as marked by increased plasma alanine aminotransferase (ALT) activity and histologic changes, was prevented when heparin or hirudin was administered to rats shortly before the onset of injury. These results suggest that thrombin is a critical mediator that acts distally in the series of inflammatory events that culminates in hepatocellular damage. To explore further this hypothesis, livers isolated from rats 2 hr after LPS administration were perfused with various media. Perfusion of livers with medium comprising diluted blood from heparin-treated donors resulted in no release of ALT activity. By contrast, perfusion with similar medium anticoagulated with ancrod, which prevents clotting by depleting fibrinogen but does not inhibit thrombin, resulted in hepatocellular injury evidenced as a time-dependent appearance of ALT activity in the medium. Moreover, when livers from rats treated 2 hr previously with LPS were perfused with buffer to which thrombin had been added, injury resulted. No injury resulted when thrombin was omitted from the buffer or when livers from saline-treated rats were used. These results indicate that thrombin is a critical and distal mediator of LPS-induced liver damage and contributes to hepatocellular injury through a mechanism that is independent of clot formation. Furthermore, inflammatory events triggered by LPS exposure are a prerequisite for thrombin-induced injury.

Alanine Transaminase↗

PubMed1996

Gadolinium chloride treatment attenuates hepatic platelet accumulation after lipopolysaccharide administration.

Intravenous administration of LPS to rats results in the accumulation of both neutrophils and platelets in the liver and the development of midzonal hepatocellular necrosis. The development of liver injury entails contributions from both cellular and soluble mediators, including neutrophils, platelets, Kupffer cells, tumor necrosis factor-alpha (TNF-alpha), and components of the coagulation system. Much remains unknown about the interactions among these mediators in the pathogenesis of liver injury in vivo. Accordingly, we conducted studies with gadolinium chloride (GdCl3), an agent that inhibits Kupffer cell phagocytosis, to evaluate the role of Kupffer cells in lipopolysaccharide (LPS)-mediated liver injury, elevation in plasma TNF-alpha activity, thrombocytopenia, hepatic platelet accumulation, and activation of the coagulation system. Female Sprague-Dawley rats were pretreated with GdCl3-6H2O (10 mg/kg, i.v.) or saline vehicle 24 h before the administration of LPS (4 mg/kg, i.v.) or saline vehicle. In a preliminary study, this GdCl3 treatment regimen decreased the clearance of colloidal carbon from blood, indicating inhibition of Kupffer cell phagocytosis. Pretreatment with GdCl3 attenuated LPS-induced liver injury, monitored as increased plasma alanine aminotransferase and isocitrate dehydrogenase activities and histologic analysis. Electron micrographs of livers from rats treated with LPS revealed platelets within the sinusoids as well as Kupffer cells with phagolysosomes containing material resembling platelets. Pretreatment with GdCl3 attenuated LPS-induced thrombocytopenia and hepatic platelet accumulation, as measured by radiolabeled platelets. Treatment with GdCl3 did not, however, alter the elevation in plasma TNF-alpha activity or the activation of the coagulation system, as evidenced by a decreased in plasma fibrinogen concentration. These results suggest that Kupffer cells contribute to LPS-induced hepatic platelet accumulation and raise the possibility that protection against LPS-induced hepatic injury by Kupffer cell inactivation may be due at least partly to decreased deposition of platelets within the liver.

Alanine Transaminase↗

PubMed1996

Lipopolysaccharide-induced hepatic injury is enhanced by polychlorinated biphenyls.

After intravenous administration of bacterial lipopolysaccharide (LPS) to rats, polymorphonuclear neutrophils (PMNs) rapidly accumulate in the liver, and midzonal hepatic necrosis is prominent by 6 hr. PMNs are required for the development of hepatic injury in rats. Certain polychlorinated biphenyls (PCBs) can activate PMNs, resulting in production of superoxide anion (O2-.) and release of cytolytic factors from granules. This raises the possibility that PCB exposure might enhance PMN-mediated tissue injury, such as LPS-induced hepatotoxicity. We treated female Sprague-Dawley rats with a minimally toxic dose of LPS in saline (2 mg/kg, intravenous) and 90 min later exposed them to Aroclor 1248 (50 mg/kg, intraperitoneal), a mixture of PCBs. The animals were killed 6 hr after LPS administration, and hepatic injury was assessed. Neither LPS nor Aroclor 1248 alone produced liver injury. Co-treatment with LPS and Aroclor 1248 resulted in pronounced liver injury as demonstrated from increased activities of alanine aminotransferase and isocitrate dehydrogenase in plasma. Histological evaluation indicated increased severity of hepatic necrosis in rats receiving both LPS and Aroclor 1248. Hepatic accumulation of PMNs, normally observed after LPS, was not altered by co-exposure to PCBs. Aroclor 1248 stimulated rat PMNs in vitro to produce O2-. and to degranulate. In addition, PMN-mediated cytotoxicity to isolated rat hepatocytes in culture was increased upon addition of Aroclor 1248. PCBs activate PMNs in vitro and increase PMN-dependent hepatocellular damage in vitro and after LPS treatment in vivo. PCBs may act in vivo as an additional inflammatory stimulus to activate PMNs to become cytotoxic, resulting in increased tissue injury.

Animals↗

PubMed1996

The thrombin inhibitor, hirudin, attenuates lipopolysaccharide-induced liver injury in the rat.

The administration of gram-negative bacterial lipopolysaccharide (LPS) to rats results in hepatic parenchymal cell injury within 6 hr. The coagulation system is critical to the pathogenesis, but previously reported results suggested that its critical role is independent of insoluble clot formation and that thrombin may be a key mediator of liver injury. To test the hypothesis that thrombin is involved in LPS-induced liver injury, animals were treated with the selective thrombin inhibitor, hirudin. The hirudin treatment regimen effectively inhibited thrombin, as evidenced by prolonged activated partial thromboplastin time and by maintenance of plasma fibrinogen concentrations in LPS-treated rats. Treatment with hirudin prevented LPS-induced liver injury, assessed by plasma alanine aminotransferase activity and histological evidence of hepatocellular necrosis. Previous studies have shown that LPS exposure results in the accumulation of neutrophils and platelets within the liver and that both of these cell types are critical for the development of LPS-induced liver injury. Hirudin attenuated in part the decrease in blood platelet concentration that accompanied LPS administration, but did not alter hepatic platelet or neutrophil accumulation. These results support the hypothesis that thrombin is required for hepatic injury from LPS exposure, but that it does not act by promoting the accumulation of platelets or neutrophils within the liver.

Animals↗

PubMed1995

Depletion of neutrophils and modulation of Kupffer cell function in allyl alcohol-induced hepatotoxicity.

The roles of neutrophils (PMNs) and Kupffer cells in hepatotoxicity caused by allyl alcohol in rats in vivo were examined. To test the involvement of PMNs in the response to allyl alcohol, the number of circulating PMNs was reduced to < 500/microliter by treatment with immunoglobulin (Ig) isolated from serum of rabbits treated with rat PMNs (anti-PMN Ig). Rats received anti-PMN Ig or control Ig 6 h before and 6 h after administration of allyl alcohol (40 mg/kg, i.p.). Hepatotoxicity was assessed 18 h after allyl alcohol administration. In rats pretreated with control Ig, treatment with allyl alcohol resulted in hepatotoxicity as evidenced by an increase in the activity of alanine aminotransferase (ALT) in serum. Neutropenia did not attenuate hepatic injury caused by allyl alcohol. Leukopenia induced by pretreatment with cyclophosphamide also did not influence the hepatotoxic response to allyl alcohol. To inhibit the function of Kupffer cells, animals were treated with gadolinium chloride (GdCl3; 10 mg/kg, i.v.) 24 h before administration of allyl alcohol. This dose of GdCl3 decreased in situ clearance of colloidal carbon by 64%. Despite the inhibition of Kupffer cell function, ALT activity in serum was not different in allyl alcohol-treated rats pretreated with GdCl3 and those pretreated with saline vehicle. Histopathologic evaluation of the livers confirmed a lack of protective effect of GdCl3. These results suggest that neither neutrophils nor Kupffer cells play a major role in liver injury due to allyl alcohol.

1-Propanol↗

PubMed1995

Platelet participation in liver injury from gram-negative bacterial lipopolysaccharide in the rat.

Intravenous administration of lipopolysaccharide (LPS) to rats results in multifocal, primarily midzonal hepatic necrosis. The hepatic injury is associated with inflammation and is dependent on neutrophils and the coagulation system. After LPS injection into rats, plasma fibrinogen concentration and numbers of blood platelets and leukocytes decrease. Results of our studies, using immunocytochemistry for the detection of neutrophils and 111indium-labeling to identify platelets, indicate that both neutrophils and platelets accumulate within the liver early after administration of LPS to rats. The accumulation of platelets in the liver before the onset of injury suggested that platelets contribute to the manifestation of LPS-induced hepatotoxicity. To test this hypothesis, the number of circulating blood platelets was decreased by the administration of an anti-rat platelet serum (APS) before LPS administration. The consequent thrombocytopenia by APS administration was associated with an attenuation of both LPS-induced liver injury and the activation of the coagulation system. However, the APS treatment did not prevent the hepatic neutrophil accumulation. These results suggest that platelets contribute to the pathogenesis of liver injury after LPS administration, perhaps through their integral role in coagulation and/or interaction with neutrophils, but they do not appear to contribute to hepatic neutrophil accumulation.

Alanine Transaminase↗