bluuebunny/crossref_metadata_2025 huggingface dataset:
Interleukin 1 and Interferon-γ: Cytokines that Provide Reciprocal Regulation of Macrophage and T Cell Function
Authors: Schultz Richard M.
Published: September 2009

Interactions between macrophages and T cells are symbiotic, since optimal functions of both cell types require interchange of soluble mediators. Upon activation, macrophages release interleukin-1 (alias lymphocyte activating factor, leukocytic endogenous mediator, and endogenous pyrogen), a family of molecules with multivarious biological effects, ranging from induction of fever and the acute phase response to lymphocyte activation and concomitant release of interleukin-2. Interleukin-2 induces activation and replication of several subsets of precursor lymphocytes, including cytotoxic T cells, lymphokine-activated killer (LAK) cells, and natural killer (NK) cells, and enhances their cytotoxic activity for tumor cells. Both interleukin-2 and leukotrienes enhance production of immune interferon (interferon-γ) by activated T cells. Aside from antiviral activity, interferon-γ produces a number of immunomodulatory effects, including macrophage activation (Ia induction, antimicrobial effector function, and activation of oxidative metabolism) and augmentation of NK function. Expression of Ia on accessory cell membranes is required for the initiation of many antigen-specific, T-dependent immune responses. Interferon-γ also synergizes with a variety of microbial agents to augment macrophage tumoricidal function and enhance interleukin-1 secretion. The production of interferon-γ appears to have a critical role in feeding back the cascade of interleukins in a loop of amplification. Both interleukin-1 and interferon-γ modulate release of arachidonate metabolites in various cells. This cascade of cytokines, in collaboration with arachidonate oxygenation products, regulates immunity and sets the stage for many of the events underlying inflammation. Various anti-inflammatory drugs and immunopotentiators appear to act by modulating cytokine pathways.
Immunotoxicology Today
Authors: Koller Loren D.
Published: September 2009

Immunotoxicology is a science which deals with the effects of physical and chemical agents and other toxic substances on the immune system. The discipline includes study of the detection, occurrence, adverse effects, and mechanisms of chemically-induced immune dysfunction. Many drugs and chemicals are known to compromise the immune response of a host which is extremely vulnerable and sensitive to perturbation by these agents. The consequences of immune dysfunction may be expressed in reduced resistance to infectious and neoplastic diseases, or enhanced hypersensitivity and autoimmunity. The immunomodulating profiles of xenobiotics may be diverse, involving several components of the immune system, or they may selectively compromise an individual compartment of the immune response. Many drugs and chemicals are known to result in immune disregulation in animals, but a paucity of information is available to indicate the effects of xenobiotics on systemic immunity in humans. Epidemiological studies and research designed to assess chemical immunomodulation in man are necessary to confirm animal data. Further, a definitive diagnosis for chemically-induced immune dysfunction must include several etiologies and body organ systems, since a triad of reciprocal interactions exists between the immune, endocrine, and central nervous systems.
2,2,2-Trifluoroethanol-Induced Enteropathy in Rats: Chemically or Bacterially Mediated Effects
Authors: Kim James C. S. , Fraser Joanne M. , Samsonoff William A. , Kaminsky Laurence S. , Shin Sang J.
Published: September 2009

The lethal effects of the fluorinated ether anesthetic, fluroxene, in rats are a consequence of its metabolism, which is catalyzed by cytochrome P-450 to the toxic metabolite 2,2,2-trifluoroethanol (TFE). The anesthetic or TFE (0.21 g/kg) caused decreased white blood cell counts, necrosis of bone marrow and lymphocytes, and decreased small intestine dry weight and was associated with septicemia. To elucidate the mechanism of TFE toxicity in rats we undertook histopathologic, ultrastructural and bacteriologic studies. TFE produced severe edema of intestinal lamina propria and submucosae, dilatation of crypts, loss of surface epithelium, vacuolation and necrosis of intestinal epithelial cells, and infiltration of polymorphonuclear leukocytes into the edematous lamina propria. Intestinal epithelial villi lost their cellular tissue integrity. Coccobacillary organisms were numerous in the ulcerated intestine. Hemolytic E. coli were isolated from intestinal tissue at a two-log increase in concentration relative to controls. Hemograms from TFE-treated rats exhibited marked leukopenia and morphologic differences. The platelets lost their discoid shape, extended pseudopods, and centralizing granules. Hemoglobin precipitation as Heinz bodies and crystalloid structures was observed in TFE-treated rats. Together the data suggest that TFE-induced enteropathy was most probably due to E. coli precipitated from TFE-mediated alterations in the population of small intestinal microbes.

The antibiotics erythromycin, active against gram-positive bacteria, and streptomycin, active against gramnegative bacteria, and the antiendotoxin, polymyxin B, were administered to rats prior to TFE in an effort to differentiate between these mechanisms by altering the intestinal bacteria populations. The results indicate that the TFE-induced small intestinal lesions are initiated by the direct focal necrotic effect of TFE or its metabolites on the small intestinal epithelium. The focal coagulation necrosis produced by TFE predisposes the animals to lethal enteritis and systemic bacteremia.
Pathological Changes Induced by Formaldehyde in Open-Ended Rat Tracheal Implants Preexposed to Benzo(a)pyrene
Authors: Shiba Mitsutoshi , Marchok Ann C. , Klein-Szanto Andres J. P. , Yamaguchi Yutaka
Published: September 2009

The promotion effects of 0.1% formaldehyde (HCHO) in phosphate-buffered saline (PBS) were tested in rat tracheal implants preexposed to a minimal carcinogenic dose of 468 μg benzo(a)pyrene (BAP) released over one month from 865 μg BAP-beeswax pellets. At the time of pellet removal, the tracheas were made into open-ended, flow-through, tracheal implants (FTTI), and exposed twice/week to HCHO for 30 weeks. Morphological alterations in the FTTI were monitored biweekly by collection of exfoliated cells from the luminal washings for cytopathologic diagnosis, and periodically by sacrificing animals for histopathology. FTTI exposed to the BAP followed by6 30 weeks of HCHO had extensive squamous metaplasia, a high proliferation index of 7.87 [3H]thymidine-labeled cells/mm basement membrane, and foci of moderate and marked atypia. Clear diagnosis of some of the lesions was difficult because of the acute toxic effects of the repeated exposures to HCHO. These effects were seen in the tissues as well as in the exfoliated cells, which attest to the latter as an efficient, non-destructive, method for determining the responses of the tracheas to exposure to toxic and carcinogenic agents. FTTI exposed to BAP followed by twice weekly PBS, had a mostly flattened epithelium, and a low proliferation index (0.39). FTTI exposed to beeswax pellets, followed by the HCHO had a relatively high proliferation index (4.20) in a mucociliary epithelium exhibiting some basal cell hyperplasia. Control FTTI had a normal mucociliary epithelium with a proliferation index of 1.52 [3H]thymidine labeled cells/mm basement membrane.
Cardiovascular Alterations in Dogs Treated with Hydralazine
Authors: Mesfin Gabre M. , Shawaryn Gregory G. , Higgins Michael J.
Published: September 2009

Groups of 5 male beagle dogs were treated orally with hydralazine tablets in gelatin capsules at a dose of 12 or 24 mg/kg twice a day (6 hours apart) for 2 consecutive days. Five male dogs treated with empty gelatin capsules served as untreated controls. Clinical findings and heart rate changes during treatment and terminal body weight, hematology, and blood chemistry changes were evaluated. The heart, liver, kidneys, spleen, and thymus of each animal were examined microscopically. Dogs in the 12 mg/kg group ate less than control group. Dogs treated with 24 mg/kg did not eat and vomited. Heart rates in both of the treated groups increased by 60 to 80% within 2 hours of treatment and remained high during the entire treatment period. Significant hematologic change was confined to a slight increase in platelet number of dogs treated with 24 mg/kg. Serum glucose was increased in the hydralazine treated dogs. Conjugated serum bilirubin was increased and serum potassium, chloride and phosphorus were decreased in the 24 mg/kg group. Blood urea nitrogen and serum chloride were slightly increased in dogs treated with 12 mg/kg. Treatment-related pathologic alterations were confined to the heart. Two dogs from each of the hydralazine groups experienced acute localized hemorrhage into the epicardium and subepicardium of the right atrium. The media of the muscular branches of the coronary arteries, especially the left coronary artery, was hemorrhagic in 3 dogs from the 24 mg/kg group. Medial necrosis, when seen, tended to be proportional to the severity of medial hemorrhages. There was no necrosis in the papillary muscles of the heart. These acute cardiovascular alterations in dogs treated with hydralazine for 2 days—believed to be related to exaggerated pharmacologic effects of the drug—were similar to the lesions seen in dogs treated with minoxidil for 2 to 3 days.
2,2,2-Trifluoroethanol Toxicity in Hamsters (Mesocricetus auratus)
Authors: Kim James C. S. , Kaminsky Laurence S.
Published: September 2009

As part of an effort to further elucidate the mechanism whereby fluorinated ether anesthetics express their various toxic effects, Golden Syrian hamsters were utilized to determine acute and subchronic toxicities of the anesthetic metabolite 2,2,2–trifluoroethanol (TFE). The major lesion observed with the TFE (0.25 g/kg ip) was coagulation necrosis characterized by nuclear pyknosis in epithelial cells of intestinal villi, the deeper portion of gastric mucosae, lymphoid organs such as thymus, spleen and mesenteric lymph nodules and brain. Hepatocyte hypertrophy with diffuse vacuolar degeneration was also found. Lungs had a characteristic focal terminal bronchiolar epithelial hyperplasia with discrete mucous metaplasia in the terminal bronchioles. In subchronic studies, hamsters were injected with sublethal doses of TFE (0.20 g/kg once per week for 5 weeks). The major lesions observed were severe hepatocyte hyperplasia and hypertrophy with fatty degeneration, necrosis of hair germinal matrix, urinary bladder transitional epithelial cellular hypertrophy, and hyperplasia with vacuolar degeneration and submucosal edema. Ultrastructural studies of acutely treated animals indicate that fat vacuoles formed within the hepatic endoplasmic reticulum characterized by lamellar bodies forming multiple myelin figures within the fat vacuoles. Hepatic cytochrome P-450 concentrations measured as a possible index of endoplasmic reticulum damage, failed to reveal any significant differences between the treated and non-treated hamsters.
Effect of a Sublethal Dose of 2,3,7,8-Tetrachlorodibenzo-p-dioxin on Interscapular Brown Adipose Tissue of Rats
Authors: Rozman Karl , Pereira David , Iatropoulos Michael J.
Published: September 2009

The effect of a sublethal dose (15 μg/kg) of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was studied in selected tissues of male Sprague-Dawley rats by histological techniques 1, 3, 7 and 14 days after TCDD dosage. Histology of the heart, muscle, white adipose tissue, pancreas and the thyroid was unremarkable and that of the liver was found in agreement with previous reports. However, considerable changes were seen in interscapular brown adipose tissue (IBAT) of TCDD-treated rats. Initial accumulation followed by depletion of lipids, appearance of glycogen, cellular, mitochondrial and nuclear transformations were observed. In conjunction with other experiments it is concluded that a sublethal dose of TCDD alters fat and glucose metabolism in IBAT.
Ultrastructural Changes during Acute Acetaminophen-Induced Hepatotoxicity in the Mouse: A Time and Dose Study
Authors: Placke Michael E. , Ginsberg Gary L. , Wyand D. Stuart , Cohen Steven D.
Published: September 2009

This study was undertaken to evaluate the early ultrastructural changes during the development of acetaminophen hepatotoxicity. Doses at or near the threshold for hepatotoxicity were selected to permit comparison of early reversible effects to those which ultimately progressed to necrosis in the absence of early agonal effects or drug-induced mortality. Both 300-and 600-mg/kg doses resulted in similar declines in hepatic glutathione levels to 14 and 22% of control values, respectively, by 2 hours, with more rapid recovery after the low dose. Plasma sorbitol dehydrogenase activity was elevated after 600 mg/kg but not after 300 mg/kg. During the first 2 hours after acetaminophen there was cytomegaly with rapid progression to necrosis after 600 mg/kg but minimal progression after 300 mg/kg. Ultrastructurally, vesiculation, vacuolation and mitochondrial and plasma membrane degeneration culminated in scattered single cell death by 4 hours and widespread centrilobular necrosis by 8 hours after 600 mg/kg. The time course of lesion development was slower after 300 mg/kg with damage restricted to the first two to three rows of centrilobular cells and limited numbers of isolated necrotic cells by 8 hours. By 18 to 24 hours livers of mice given 300 mg/kg appeared normal. Results are consistent with the endoplasmic reticulum being the site of acetaminophen activation and initial attack. However, early ultrastructural changes in mitochondria and plasma membrane observed after the high dose were not prominent after the low dose. This suggests that early acetaminophen damage to these organelles may play a critical role in acetaminophen hepatotoxicity.
Glandular Changes Associated with the Spontaneous Interstitial Cell Tumor of the Rat Testes
Authors: Kanno Jun , Matsuoka Chiaki , Furuta Kyoko , Onodera Hiroshi , Maekawa Akihiko , Hayashi Yuzo
Published: September 2009

Testes of untreated F344 and Wistar rats in the control groups of carcinogenicity studies were histologically examined, and the histopathological characteristics and histogenesis of glandular changes in these testes were studied. In 266 testes of 2-year-old F344 rats, 263 had interstitial cell tumors (ICTs) (98.9%) and 39 had glandular changes (14.7%). These glandular changes were also found in 1 out of 38 1-year-old F344 rat testes (2.6%), and 3 in 154 2-year-old Wistar rat testes (1.9%). The changes were observed exclusively in the interstitial cell tumors (ICTs). These glandular changes showed variation in size, shape and number. They were composed of tubules or cysts lined by a layer of cuboidal or columnar epithelial cells, which had terminal bars, occasionally PAS-and alcian blue-positive brush borders, and rarely, alcian blue-positive cytoplasmic vacuoles. Serial sections revealed that the changes were not connected with the rete testes, but with the degenerative seminiferous tubules involved in the ICTs lined by a layer of flat endothelial-like cells. The findings suggest that the lesions constitute metaplastic changes of the Sertoli cells.
Carrageenan Induces Anomalies in the Chick Emhryo. A Light Microscopic Study
Authors: Rovasio Roberto A. , Monis Benito
Published: September 2009

Chick embryos injected with lambda-carrageenan prior to incubation and studied with light microscopy at 48 hours of development presented various anomalies. Lack of closure at different levels of the neural tube was one of the lesions most frequently seen. Rachischisis and craniorachischisis were commonly associated with various degrees of hyperplasia of the neural tube wall. Diverse patterns of neural hyperplasia ranged from total occlusion of the neural tube to localized thickening of lateral walls leading to a typical “hourglass” appearance of the ependymal lumen. Multiple septa and cavitations of the neural tube lumen were also recorded. Cephalic and/or trunk duplication of the body as well as disorganization of notochord and somites were frequently associated with rachischisis and areas of necrosis or pyknosis of neural tissue. Neural crest cells, which are normally present in paraneural areas at the stages studied, were not encountered in the carrageenan-injected embryos. These areas were frequently occupied by hyperplastic ectodermic folds. Similarity of present findings on carrageenan-treated embryos with the anomalies induced by selective destruction or impairment of migration of neural crest cells suggests that involvement of this cell population may have a role in the causation of the anomalies observed.
Proliferative Exocrine Pancreatic Lesions in Rats. The Effect of Sample Size on the Incidence of Lesions
Authors: Boorman Gary A. , Banas Deborah A. , Eustis Scot L. , Haseman Joseph K.
Published: September 2009

Pancreatic tissue from untreated and corn oil gavage control rats in four chronic (2-year) toxicity and carcinogenicity studies was examined microscopically for the presence of acinar hyperplasia, acinar adenoma, and acinar carcinoma. Formalin-fixed pancreatic tissue that had been saved from these rats was then examined for grossly visible lesions; and all additional available pancreatic tissue was embedded, routinely processed, and sectioned at 5–7 microns for histopathological examination. There were no additional gross lesions identified in the review of the residual tissues. However, microscopic examination of this additional tissue resulted in a marked increase in the number of proliferative lesions diagnosed. The incidence of acinar cell adenomas increased from 1/188 (0.5%) to 28/193 (15%) in untreated control male rats and from 8/194 (4%) to 73/195 (37%) in corn oil gavage vehicle control male rats. There were similar increases in hyperplasia in vehicle and untreated male rats, and similar but much less dramatic increases in hyperplasia and adenoma in vehicle and untreated control female rats. The previously reported effect of increased proliferative lesions of the exocrine pancreas of male rats given corn oil vehicle was confirmed. In addition, examination of a larger tissue sample identified a similar but smaller effect of the corn oil vehicle in female F344 rats that had not been detected by routine sampling of the pancreas.
Neurotoxicity of Amphotericin B Methyl Ester in
Authors: Ellis William G. , Bencken Elizabeth , LeCouteur Richard A. , Barbano Joyce R. , Wolfe Bruce M. , Jennings Myra B.
Published: September 2009

Clinical and neuropathologic effects of chronically administered intravenous (iv) amphotericin B mester (AME) were observed in 3 male dogs (2 German shorthaired pointers and 1 pit bull). Each dog rec 6.2-7.3g of AME (299–327 mg/kg body weight) over a period of 11–12 weeks. One dog developed neurologic signs of severe diffuse brain dysfunction and at necropsy all 3 dogs had a marked leukoencephalopathy, most severe in centrum ovale and subcortical white matter of frontal lobes. Brain histopathology included diffuse myelin loss, oligodendrocyte depletion, accumulation of macrophages filled with sudanophilic lipid, fibrillary astrogliosis, and swelling or fragmentation of many axons. Two control dogs administered iv glucose showed no neuropathologic abnormalities. These findings closely resemble the clinical and neuropathologic abnormalities that developed in patients during the first human trial of AME for treatment of fungal infections, but differ from those of animal studies that did not closely simulate the long-term drug administration required for antifungal therapy in humans. It was concluded that before human clinical trial is authorized, experimental protocols for animal studies of drug toxicity should reflect the anticipated human use of the drug, both in dose and duration.
Methotrexate: Assessment of In Vivo Clastogenicity and Carcinogenicity
Authors: Hall Claudette , Tnham Philip , Manandhar Madhu , Cheng Maria , Noble John F. , Iatropoulos Michael
Published: September 2009

The genotoxic and oncogenic potentials of methotrexate were studied in Sprague-Dawley rats. The rats received 0.1, 0.2, or 0.4 mg/kg of methotrexate as dietary admixtures on a 5 days on, 9 days off, regimen for 23 months. In the females of the high-dose group, there was a significant increase in mortality starting at 18 months. Significant increases in the number of rats with focal pulmonary interstitial fibrosis were seen in both sexes at the high-dose level. At the mid-and high-dose levels of both sexes, there was a significantly increased number of rats with myeloid and erythroid bone marrow hypoplasia. There was no evidence of either early onset or increased incidence of any tumor type in the treatment groups. Therefore, it is concluded that methotrexate does not have oncogenic potential. Also, at terminal sacrifice, bone marrow cells were harvested from selected animals on the last day of the 5-day dosing cycle and cytogenetic evaluation was performed. No significant increase in chromosomal aberrations was seen in any dose group relative to the control group. This observation further substantiates the absence of oncogenic potential due to methotrexate in rats.
Effects of Variation of Necropsy Time and Fasting on Liver Weights and Liver Components in Rats
Authors: Rothacker Dana L. , Kanerva Robert L. , Wyder William E. , Alden Carl L. , Maurer James K.
Published: September 2009

In rats, percent liver weight loss is greater than percent body weight loss within the 8 a.m.-4 p.m. period of the working day. The liver weight loss is principally the result of decreased water content, either carbohydrate (glycogen) bound water in rats with access to feed, or protein bound water in rats fasted overnight. During this period, percent kidney weight loss is approximately equal to percent body weight loss. To optimize the sensitivity of kidney and liver weight evaluation, it is recommended that rats be fasted overnight and that relative liver and kidney weights be expressed based on body weights taken immediately prior to necropsy. Since these procedures will not entirely eliminate necropsy time-related organ weight differences, the animal necropsy sequence must be randomized to distribute the remaining differences across all treatment groups.
Amplification of Chloroform Hepatotoxicity and Lethality by Dietary Chlordecone (Kepone®) in Mice
Authors: Purushotham Karnam R. , Lockard Virginia G. , Mehendale Harihara M.
Published: September 2009

Male Swiss Webster mice (25-30 g) maintained on powdered control diet, or on diets containing chlordecone (CD, 10 ppm), mirex (M, 10 ppm), or phenobarbital (PB, 225 ppm) were used in this study. At these low levels, chlorinated hydrocarbon pesticides are not toxic, they neither affect food or water consumption, nor the body weight of mice. After a 15-day dietary protocol, a single challenge dose of CHCl3(0.1 ml/kg) was administered intraperitoneally in corn oil vehicle. Liver damage was assessed 24 hours later using serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, histopathology, and lethality. For comparison, serum enzymes were measured in a separate group of mice receiving a high dose of CHCl3(1.0 ml/kg) alone. None of the dietary treatments alone affected any of the serum transaminases. The serum enzymes were remarkably elevated in the mice treated with CD and CHCl3. A high dose of CHCl3(1.0 ml/kg) elevated the serum enzymes more than 10-fold over those in the mice fed normal diet receiving only the corn oil vehicle. The histopathology of the liver indicated midzonal necrosis typical of liver injury from CHCl3and depletion of PAS positive glycogen deposits. These effects were not evident in mice treated with 0.1 ml/kg CHCl3alone. Additional histological alterations in the livers of the CD + CHCl3group include the degenerated cells, loss of basophilic staining characteristics, and an increased degree of cytoplasmic vacuolation. The amplification of CHCl3hepatotoxicity by CD was also reflected by a 4.2-fold increase in lethality determined by 48-hour LD50. Dietary exposure of mice to either the structurally related M (10 ppm) or a high dose of PB (225 ppm) in a similar dietary protocol did not cause potentiation of hepatotoxicity or lethality. These results indicate enhanced hepatocellular sensitivity to the hepatotoxic and lethal effects of CHCl3by dietary CD regimen even when the 2 interactants are administered at subtoxic doses.
Disposition of Xenobiotics: Species Differences
Authors: Rozman Karl
Published: September 2009

Species differences are a major obstacle in predicting toxicity of xenobiotics from one species to another. Species differences in toxicity of drugs and other chemicals may be due to differences in pharmacokinetics or pharmacodynamics. This paper illustrates the point that species differences in pharmacokinetics of xenobiotics may be the result of differences in any of the processes contributing to the disposition of a xenobiotic. This is an important point because biotransformation as a cause of species differences for the disposition of xenobiotics has been overemphasized in the past, whereas only scant attention has been paid to the other 3 major contributing processes to disposition, viz. absorption, distribution, and excretion. This brief overview presents a balanced examination of all 4 major processes (absorption, distribution, biotransformation and excretion) as they affect the pharmocokinetics of xenobiotics in various species.
Interactions of the Gut Microflora and the Host in Toxicology
Authors: Rowland Ian R.
Published: September 2009

Food components and ingested chemicals may be metabolized in the gut, not only by digestive and intestinal mucosal enzymes, but also by the resident bacteria, which are found in greatest numbers in the large intestine. The gut microflora is a large (about 1011organisms per g colon contents) and diverse (over 400 species) population of organisms and possesses a correspondingly diverse range of metabolic activities, including reductions, hydrolyses and degradations. In many cases, these reactions both complement and antagonize those of the liver, which are mainly oxidative and synthetic. The metabolism, by the gut flora, of chemicals ingested in food or secreted in bile can have numerous toxicological sequelae, including activation to more toxic, mutagenic or carcinogenic derivatives, detoxication and enterohepatic circulation. These toxicological consequences may be modified by changes in the flora due to diet, drugs and interindividual differences. Examples presented of the interaction between the gut flora and its host are the influence of intestinal bacteria on hepatic tumor incidence in mice, the effect of bacterial hydrolysis of rutin on the activity of hepatic enzymes which activate dietary carcinogens, and the role of the gut flora in demethylation and detoxication of methylmercury.
Immunological Functions of the Gut–Role of the Mucosal Immune System
Authors: Nagura Hiroshi , Sumi Yukiko
Published: September 2009

This review summarizes recent information about immune responses in the intestinal mucosa, with emphasis on the role of orally-administered antigens from the external environment. The intestinal mucosa provides an extensive surface for potential absorption of pathogenic environmental antigens, such as microbes, chemicals, and food. The intestinal mucosa is densely populated by IgA-producing plasma cells. The humoral immune responses to antigens in the intestinal mucosa are largely of the IgA class in secretory form (sIgA). This sIgA provides an immunological barrier to absorption of antigens on the mucosal epithelium and to penetration into the body. The cell-mediated immune mechanism is also equipped in the mucosal sites. In addition, the mucosal immune response induces hyporesponsiveness of nonmucosal (systemic) immune reactions, and the liver is an integral part of the mucosal immune system. Thus we consider that the mucosal immune system plays a central role in the maintenance of the homeostasis of the total immune system.
Morphological Characteristics of Prostaglandin Cytoprotection
Authors: Schmidt Karmen L. , Miller Thomas A.
Published: September 2009

The term “cytoprotection” originally described the ability of prostaglandins, independent of their known antisecretory activity, to prevent macroscopic evidence of gastric injury induced in different animal models under various experimental conditions. Several recent reports have challenged this concept because the apparent macroscopic protection could not be confirmed microscopically. To determine whether prostaglandins do indeed possess cytoprotective properties, and if such effects are dependent on the dose and the route of prostaglandin administration, studies were performed using 16,16 dimethyl prostaglandin E2 (PGE2) and the known gastric damaging agent, ethanol. Fasted rats received either oral or subcutaneous PGE2 in doses of 10 or 20 μg/kg or equal volumes of saline. Thirty minutes later, animals were given a 1-ml oral bolus of 50% or 100% ethanol or an equal volume of saline. At 5 minutes to 24 hours following ethanol, animals were sacrificed, and tissues from the glandular portion of the stomach were removed for histologic quantification of injury. At 5 minutes following ethanol, PGE2 reduced the depth of injury, but had no protective effects against surface cell damage when compared with control animals. By 24 hours after ethanol, most of the PGE2-treated mucosa was repaired. Oral administration of 10 μg/kg PGE2 was more cytoprotective at 5 minutes after ethanol than when administered by subcutaneous injection. This relationship was not true for the 20 μg/kg dose. We conclude that cytoprotection can be confirmed histologically, but is limited primarily to the deep mucosa. The ability of PGE2 to enhance healing is probably related to the prevention of deep mucosal injury, which thereby allows epithelial reconstitution to occur. Lastly, the effectiveness of PGE2 as a cytoprotective agent is dose- and route-dependent.
Structural Changes of the Gastrointestinal Mucosa Induced by Prostaglandins
Authors: Levin Stuart
Published: September 2009

Prostaglandins of the E series, which have been proposed as therapeutic agents for the treatment of peptic ulcers and other gastrointestinal diseases, cause hyperplasia of the gastrointestinal mucosa in experimental animals. The changes are most evident in the stomach, especially the antrum, in which the wall is thickened by hyperplasia of surface mucous cells and/or submucosal edema. In rodents, the non-glandular forestomach becomes hyperplastic and hyperkeratotic. Affected stomachs are heavier and may have a larger surface area than control stomachs. Small intestines may be heavier and have a thicker mucosa, with elongation of villi and crypts. Colonic mucosa may exhibit mild hyperplasia at very high dosages. Conflicting data exist as to whether the gastrointestinal mucosal hyperplasia is more related to increased production or decreased loss of epithelial cells.
The Propionic Acids. Gastrointestinal Toxicity in Various Species
Authors: Elliott George A. , Purmalis Andrejs , Vandermeer Donald A. , Denlinger Robert H.
Published: September 2009

The propionic acids represent the largest chemical class of nonsteroidal anti-inflammatory agents (NSAID). Several of them are widely used, both in the United States and internationally. This paper discusses observations made on fenoprofen, flurbiprofen, ibuprofen and naproxen. Of these compounds, three are racemates; the fourth, naproxen, is an enantiomer. As a group, the propionic acids, along with most members of the other classes of NSAID, produce gastrointestinal damage in most species. These lesions vary from erythema, hemorrhage and erosion to ulceration and peritonitis. As might be expected, the degree of gastrointestinal intolerance depends on many factors: the individual compound, the dose-level, the duration of the period of drug administration, and the pharmacokinetics and metabolism in a given species. For example, in our experience the rat is less tolerant of NSAID than is the monkey, and the dog is less tolerant than the rat. Gastrointestinal lesions have been seen following both parenteral and oral administration; these findings suggest that factors other than local irritation play a role in the development of lesions. Most NSAID inhibit prostaglandin cyclo-oxygenase activity, which results in a prostaglandin deficiency at the tissue level. The administration of relevant exogenous prostaglandins, such as 16,16-dimethyl PGE2, has been shown to inhibit the gastrointestinal toxicity accompanying the administration of several NSAID, including some of the propionic acids.
Gastrointestinal Damage from Nonsteroidal Anti-Inflammatory Drugs
Authors: Rainsford Kim D.
Published: September 2009

The mechanisms underlying the development of gastrointestinal (GI) damage by the NSAIDs differ considerably from drug to drug. Aside from environmental or intersubject influence (e.g., concurrent disease, physical or sociopsychologic stress, dietary and genetic status), the intrinsic pharmacokinetic and physico-chemical differences in these drugs account for variations in their rate of absorption or uptake from the circulation into the GI mucosa. Differences in the preference for absorption in the different regions of the GI tract account for the propensity of these drugs to cause injury in those regions wherein they accumulate. Bacterial flora and food antigens may be particularly important in promoting injury in the lower intestinal tract, whereas in the sterile environment of the normal stomach these may have less significance (except in achlorhydric states). The multiple cellular actions of NSAIDs are reviewed and the consequences of inhibiting prostaglandin cyclo-oxygenase considered. Under some conditions, the excess production of vasoconstrictor leukotrienes/HETES relative to effects of cyclo-oxygenase inhibition is postulated to have particularly important consequences in the pathogenesis of mucosal injury by NSAIDs. These consequences are separate from the concept of prostaglandin deficiency previously suggested by others.
The Pathophysiological and Pharmacological Basis of Peptic Ulcer Therapy
Authors: Freston James W.
Published: September 2009

Both genetic and nongenetic factors predispose to ulcer diathesis. At the mucosal level ulcers result from an imbalance between aggressive factors and mucosal defense. Ulcer therapy reduces aggressive forces, bolsters defense, or both. Gastric acid, the major aggressive factor, may have its secretion inhibited or it may be partially neutralized by antacids. H2 receptor antagonists competitively block histamine occupancy of H2 receptors on parietal cells, thereby preventing stimulation of adenylate cyclase, cAMP rises, and activation of protein kinase and H+/K+ATPase. Prostaglandins inhibit acid secretion largely by preventing histamine-induced cAMP rises. Proton pump inhibitors bind H+/K+ATPase. Antimuscarinics inhibit acetylcholine receptors on the parietal cell, thereby blocking Ca2+ entry and subsequent activation of protein kinase and the proton pump. Mucosal defense is enhanced by certain prostaglandins, colloidal bismuth subcitrate and sucralfate. Prostaglandins stimulate secretion of bicarbonate and mucus, among other effects. Colloidal bismuth and sucralfate bind to proteins in the ulcer base and stimulate bicarbonate and mucus secretion, partially, in the case of sucralfate, by increasing endogenous prostanoid synthesis. Sucralfate also binds pepsin and bile acids. Colloidal bismuth temporarily eradicates mucosal colonization by Campylobacter pylori, another putative agent in ulcer diathesis.
Gastric Enterochromaffin-Like Cell Hyperplasia and Neoplasia in the Rat: An Indirect Effect of the Histamine H2-Receptor Antagonist, BL-6341
Authors: Hirth Robert S. , Evans Lorraine D. , Buroker Robert A. , Oleson Frederick B.
Published: September 2009

Oral administration of BL-6341 hydrochloride, a long-acting histamine H2-receptor antagonist, to rats for 2 years at doses of 10, 55 or 300 mg/kg/day resulted in several changes in the fundic (oxyntic) mucosa of the glandular stomach. The most significant alteration was a proliferation of argyrophil endocrine cells that was demonstrated to be enterochromamn-like (ECL) cells. The ECL cell proliferation consisted of a continuum of changes involving diffuse hyperplasia, focal adenomatous hyperplasia, and carcinoid tumor formation at the highest dose level of 300 mg/kg. At 55 mg/kg only ECL cell hyperplasia occurred, and at the low dose of 10 mg/kg there were no remarkable proliferative changes. The reference compound, cimetidine (950 mg/ kg), produced a degree of ECL cell proliferation that was slightly less, but not significantly different than, that observed with 55 mg/kg of BL-6341. Dose-related elevations of serum gastrin were observed with BL-6341, while cimetidine produced hypergastrinemia that was generally intermediate between that produced by the middle and low doses of BL-6341. The hypergastrinemia resulted from the pharmacologic inhibition of acid secretion, which is the negative feedback mechanism controlling the production of gastrin. Only the 300 mg/kg dose of BL-6341 produced a significant, sustained (24 hours) hypergastrinemia and carcinoid tumors. The chronic, sustained hypergastrinemia was considered to be the primary cause of the ECL cell carcinoid neoplasia. All genetic toxicology tests performed with BL-6341 were negative. It was concluded that the demonstrated hypergastrinemia represents an indirect, hormonal, epigenetic mechanism of tumori-genesis.
Some Endocrine and Morphological Aspects of the Acute Toxicity of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD)
Authors: Gorski Joel R. , Muzi Giacomo , Weber Lutz W. D. , Pereira David W. , Arceo Ray J. , Iatropoulos Michael J. , Rozman Karl
Published: September 2009

Hormonal status was evaluated in TCDD-treated rats and in pair-fed and ad libitum- fed controls in order to separate hormonal changes resulting from the toxic insult of TCDD from those arising from progressive feed deprivation as it occurs in pair-fed controls. TCDD-treated rats received either a usually non-lethal (25 μg/kg) or a usually lethal (125 μg/kg) dose of TCDD whereas pair-fed and ad libitum- fed controls were given vehicle alone. Animals were terminated at predetermined time intervals and several hormones measured in serum or plasma. In addition, the morphology of the thyroid, pancreas, and pituitary was also examined. In both dosage groups, TCDD-treatment had the following effects: decreased TT4, FT4, insulin, and glucagon; mixed effects upon TT3, FT3, TSH, and GH. Pair-feeding to the non-lethal dose of TCDD had no effect on any of the hormones measured. Pair-feeding to the lethal dose of TCDD had the following effects: slightly decreased TT4, FT4, TT3, TSH, and insulin; no effect on FT3 and glucagon. It is concluded that the endocrine status of TCDD-treated rats was different from that of pair-fed rats suggesting that some hormonal changes represent responses to an insult other than that due to starvation stress alone. A differential response between TCDD-treated and pair-fed rats was also observable morphologically in the corresponding endocrine glands indicating the importance of this additional control for morphologic observations in instances when reduced-feed intake and body weight loss are prominent features of toxicity.
Gingival Hyperplasia in Dogs Induced by Oxodipine, a Calcium Channel Blocking Agent
Authors: Waner Trevor , Nyska Avraham , Nyska Meir , Pirak Michael , Sela Mordechai , Galiano Alvaro
Published: September 2009

Subchronic oral exposure of dogs to Oxodipine, a new calcium channel blocker of the dihydropyridine-type, resulted in dose-related gingival hyperplastic changes. The doses at which an effect was elicited were 24 and 73 times the intended therapeutic dose for man. The effeçts were first noted after 7 weeks of treatment, and were limited to the high and intermediate dose groups of both sexes. Macroscopically, a generalized enlargement of the maxillary and mandibular facial and lingual gingivae were noted. The histological changes were similar to those described in man for Nifedipine and hydantoin-related drugs. An increase in the activity of alkaline phosphatase and a decrease in alanine aminotransferase was demonstrated. This article is the first to describe gingival hyperplasia in dogs induced in a dose-dependent manner by a calcium channel blocker.
Mechanism of Death in Syrian Hamsters Gavaged Potato Sprout Material
Authors: Baker Dale C. , Keeler Richard F. , Gaffield William P.
Published: September 2009

Greened or sprouted potatoes contain increased concentrations of steroidal alkaloids that have caused intoxication and death in a wide variety of animal species, however, the cause of death in these animals has not been determined. Potato alkaloids can cause death when parenterally administered, and is attributed to the acetylcholinesterase inhibitory activity of solanine and chaconine. To determine the cause of death in animals ingesting potato sprout material, 40 Syrian hamsters were divided into 4 equal groups and gavaged once on day 0 either water, 300 mg of potato sprout material, 400 mg of potato sprout material, or 500 mg of potato sprout material. Tissues were examined grossly and microscopically at 72 hr post-gavaging and brain acetylcholinesterase activity of each hamster was measured. The 300-mg dose group had increased mean acetylcholinesterase activity compared with control hamster mean activity, and the 400-mg and 500-mg dose groups had 90% and 84% of the mean acetylcholinesterase activity of the control hamster mean activity. There was severe gastric and proximal small intestinal mucosal necrosis in those hamsters which died prior to euthanasia. Additionally, several hamsters had valvular endocarditis and infarcts. Death could not be attributed to the slight acetylcholinesterase inhibition in the 2 higher dose hamster groups and was related to the severe gastrointestinal necrosis which occurred in hamsters of these groups.
Mucosal Lesions Induced in the Rat Intestinal Tract by the Anti-Inflammatory Drug, Wy-41,770, a Weak Inhibitor of Prostaglandin Synthesis, Contrasted with Those from the Potent Prostaglandin Inhibitor, Indomethacin
Authors: Rainsford K. D.
Published: September 2009

The intestinal ulcerogenic activity of the weak prostaglandin synthesis inhibitor drug Wy-41,770 [5H-dibenzo(a,d)-cyclohepten-5-ylidine] was contrasted with the potent synthesis inhibitor, indomethacin, in rats to establish the relationship of inhibition of prostaglandin synthesis to the intestinal damage. Wy-41,770 induced superficial erosions only in the cecum 26 hr after a single oral dose of 250 or 500 mg/kg of the drug, progressing to ulcers after 5 days dosing with ultrastructural evidence of bacteria in the mucosa. Indomethacin (5 or 10 mg/kg po) induced mucosal erosions in the ileum, initially at 26 hr progressing to ulcers after 5 days. Fewer bacteria were seen in the ileal mucosa of indomethacin-treated rats. Both drugs reduced prostaglandin E in those regions of the intestine coincident with the known accumulation of these drugs at sites of mucosal injury. Site-specific intestinal damage from these 2 drugs is associated with inhibition of the synthesis of mucosal-protective prostanoids, followed by pronounced bacterial invasion through the damaged mucosae with consequent appearance of local immuno-inflammatory reactions.
An Immunocytochemical Study of Pituitary Adenomas and Focal Hyperplasia in Old Sprague-Dawley and Fischer 344 Rats
Authors: Sandusky George E. , Van Pelt Carolyn S. , Todd Glen C. , Wightman Karen
Published: September 2009

Spontaneous pituitary tumors occurring in groups of 100 Sprague-Dawley (SD) and 100 Fischer 344 (F344) rats of each sex on a 2-year aging study were characterized by immunocytochemistry. The SD strain had a total of 75 tumors with 10% in males and 65% in females. Tumors immunoreactive for prolactin (PRL) alone were the most common tumor (64%) with the immunonegative tumor being the second most common (17.3%). F344 rats had a total of 62 tumors with 26% in males and 36% in females. The majority of the tumors were reactive for prolactin alone (56.5%) and tumors reactive for both growth hormone (GH) and PRL were the second most common (21%). Most tumors were immunoreactive for only 1 hormone; however, both strains had tumors that expressed multiple hormones in unusual combinations.
Magnetic Resonance Imaging (MRI): A New Tool in Experimental Toxicologic Pathology
Authors: Dixon Darlene , Johnson G. Allan , Cofer Gary P. , Hedlund Lawrence W. , Maronpot Robert R.
Published: September 2009

Magnetic Resonance Imaging (MRI) is a noninvasive imaging technique that provides multidimensional images of the soft tissues of the body. This imaging technique has proven to be an excellent diagnostic and experimental tool for the detection of pathologic alterations in soft tissues, as well as an adjunct screening method for following the genesis, progression, or regression of chemically induced lesions in the same live animal. Future applications of MRI technology in small animals include MRI microscopy, mapping of vascular or circulatory alterations, measurement of perfusion and diffusion rates of body fluids, and acquisition of cell metabolic states in combination with Nuclear Magnetic Resonance (NMR) spectroscopy, all of which will contribute immensely to the advancement of toxicologic and biomolecular research.
Morphometric Evaluation of Hepatocellular Proliferative Lesions in the Rat Liver
Authors: Broxup Brian R. , Valli Victor E. O. , Losos George L. , Percy Dean H. , Farber Emmanuel , Mcmillan Ian
Published: September 2009

Classification of rat hepatocellular proliferative lesions can vary between pathologists as the many qualitative histologic criteria have not been satisfactorily evaluated and ranked for prognostic value. Computer-assisted morphometry offers an objective method to evaluate certain cellular features. The Solt-Farber resistant hepatocyte model was used in this study to produce populations of rats with a full range of hepatocellular proliferative lesions. Cellular features within the lesions were then measured morphometrically and the data were analyzed by animal age and by subjective lesion diagnosis. The nuclear/cytoplasmic ratio followed by the cell area and nuclear area were found to be the most important parameters for separating microscopic foci and islands of cellular alteration, an early hyperplastic lesion, from other hepatocellular proliferative lesions. The coefficient of variation, as a relative measure of heterogeneity, increased in a linear manner for cell, nuclear and nucleolar areas as the animals aged and was significantly higher for cell and nuclear area in hepatocellular carcinoma compared to other hepatocellular proliferative lesions. Hepatocyte nodules (representing primarily late hyperplastic lesions) and persistent hepatocyte nodules (lesions with similarities to hepatocellular adenoma) could not be satisfactorily seaprated within the limits of this study. As these borderline lesions show a continuum of cytologic change, other features, such as architectural change, are necessary to satisfactorily classify them on a subjective basis. An alternative approach is to use discriminant functions derived from morphometric studies.