Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 29
Filter
Add more filters










Publication year range
1.
Toxicol Res ; 40(2): 223-235, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38525129

ABSTRACT

Several patients with cutaneous adverse drug reactions exhibit extracutaneous organ damages, and it becomes severe in a few patients resulting in death due to multiorgan failure. Understanding the sequential changes in various organs in patients with cutaneous eruption following drug administration will help understand disease onset and progression, aiding the development of prevention strategies and interventions. Therefore, we aimed to understand the effects of abacavir (ABC) on various organs in patients with ABC-induced eruptions by evaluating its effects in a mouse model. We found pathological changes in various organs of HLA-B*57:01 transgenic mice (B*57:01-Tg) following oral administration of ABC (20 mg/body/day). B*57:01-Tg exhibited a significant body weight decrease from day 1 of ABC administration, and reddening of the auricle was observed from day 5, and approximately 2/3 mice died by day 7. Histopathological examination revealed severe thymic atrophy after day 3, infiltration of inflammatory cells, predominantly lymphocytes with neutrophils, not only in the skin but also in the liver, kidney, and lung after day 5, and an increased number of lymphocytes with enlarged nuclei and granulocytic hematopoiesis were observed in the spleen after day 5. Blood chemistry revealed that albumin/globulin ratio was below 1.0 on day 5, reflecting a systemic inflammatory response, and the aspartate aminotransferase concentration rose to 193 ± 93.0 U/L on day 7, suggesting that cell damage may have occurred in various organs including liver accompanying inflammatory cell infiltration. These examinations of a mouse model of ABC-induced skin eruption show that disorders in various organs other than the skin should be considered and provide insights into the unexpected early systemic responses dependent on HLA-B*57:01. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-023-00220-1.

2.
Mol Cancer Ther ; 21(4): 635-646, 2022 04 01.
Article in English | MEDLINE | ID: mdl-35149548

ABSTRACT

B7-H3 is overexpressed in various solid tumors and has been considered as an attractive target for cancer therapy. Here, we report the development of DS-7300a, a novel B7-H3-targeting antibody-drug conjugate with a potent DNA topoisomerase I inhibitor, and its in vitro profile, pharmacokinetic profiles, safety profiles, and in vivo antitumor activities in nonclinical species. The target specificity and species cross-reactivity of DS-7300a were assessed. Its pharmacologic activities were evaluated in several human cancer cell lines in vitro and xenograft mouse models, including patient-derived xenograft (PDX) mouse models in vivo. Pharmacokinetics was investigated in cynomolgus monkeys. Safety profiles in rats and cynomolgus monkeys were also assessed. DS-7300a specifically bound to B7-H3 and inhibited the growth of B7-H3-expressing cancer cells, but not that of B7-H3-negative cancer cells, in vitro. Additionally, treatment with DS-7300a and DXd induced phosphorylated checkpoint kinase 1, a DNA damage marker, and cleaved PARP, an apoptosis marker, in cancer cells. Moreover, DS-7300a demonstrated potent in vivo antitumor activities in high-B7-H3 tumor xenograft models, including various tumor types of high-B7-H3 PDX models. Furthermore, DS-7300a was stable in circulation with acceptable pharmacokinetic profiles in monkeys, and well tolerated in rats and monkeys. DS-7300a exerted potent antitumor activities against B7-H3-expressing tumors in in vitro and in vivo models, including PDX mouse models, and showed acceptable pharmacokinetic and safety profiles in nonclinical species. Therefore, DS-7300a may be effective in treating patients with B7-H3-expressing solid tumors in a clinical setting.


Subject(s)
Antineoplastic Agents , Immunoconjugates , Neoplasms , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Humans , Immunoconjugates/therapeutic use , Macaca fascicularis , Mice , Neoplasms/pathology , Rats , Topoisomerase I Inhibitors/pharmacology , Topoisomerase I Inhibitors/therapeutic use
3.
J Toxicol Pathol ; 34(2): 161-180, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33976473

ABSTRACT

With the aim of sharing information about the technical aspects of immunohistochemistry (IHC) and facilitating the selection of suitable antibodies for histopathological examination, this technical report describes the results of a questionnaire distributed during the period of 2018 to 2019 among members of the Conference on Experimental Animal Histopathology. Additionally, it describes the immunological properties and supplier details (clone, supplier, catalog number, species reactivity, etc.) as well as the IHC staining conditions (fixing solution, fixing time, embedding, antigen retrieval method, antibody dilution, incubation time, incubation temperature, positive control tissue, blocking condition, secondary antibody information, etc.) for a total of 509 primary antibodies (comprising 220 different types). These survey results were an update on the contents reported by CEAH in 2017.

4.
Sci Rep ; 10(1): 16146, 2020 09 30.
Article in English | MEDLINE | ID: mdl-32999394

ABSTRACT

MAS-related G protein coupled receptor-X2 (MRGPRX2), expressed in human mast cells, is associated with drug-induced pseudo-allergic reactions. Dogs are highly susceptible to drug-induced anaphylactoid reactions caused by various drugs; however, the distribution and physiological function of canine MRGPR family genes, including MRGPRX2, remain largely unknown. In the present study, we clarified the distribution of dog MRGPR family genes by real-time quantitative PCR and in situ hybridisation. We also investigated the stimulatory effects of various histamine-releasing agents, including fluoroquinolones, on HEK293 cells transiently transfected with dog MRGPR family genes to identify their physiological function. Dog MRGPRX2 and MRGPRG were distributed in a limited number of tissues, including the skin (from the eyelid, abdomen, and cheek), whereas MRGPRD and MRGPRF were extensively expressed in almost all tissues examined. Histochemical and in situ hybridisation analyses revealed that MRGPRX2 was expressed in dog connective tissue-type mast cells in the skin. Intracellular Ca2+ mobilisation assay revealed that HEK293 cells, expressing dog MRGPRX2 or human MRGPRX2, but not dog MRGPRD, MRGPRF, and MRGPRG, responded to histamine-releasing agents. Our results suggest that dog MRGPRX2 is the functional orthologue of human MRGPRX2 and plays an essential role in drug-induced anaphylactoid reactions in dogs.


Subject(s)
Anaphylaxis/genetics , Dogs/genetics , Nerve Tissue Proteins/genetics , Receptors, G-Protein-Coupled/genetics , Receptors, Neuropeptide/genetics , Anaphylaxis/metabolism , Animals , Calcium/metabolism , Cell Degranulation/drug effects , Drug Hypersensitivity/genetics , Drug Hypersensitivity/metabolism , HEK293 Cells , Humans , Mast Cells/metabolism , Nerve Tissue Proteins/metabolism , Receptors, G-Protein-Coupled/metabolism , Receptors, Neuropeptide/metabolism
5.
Cancer Sci ; 111(12): 4636-4645, 2020 Dec.
Article in English | MEDLINE | ID: mdl-33051938

ABSTRACT

Trastuzumab deruxtecan (T-DXd: DS-8201a) is an anti-human epidermal growth factor receptor 2 (HER2) Ab-drug conjugated with deruxtecan (DXd), a derivative of exatecan. The objective of this study was to characterize T-DXd-induced lung toxicity in cynomolgus monkeys. Trastuzumab deruxtecan was injected i.v. into monkeys once every 3 weeks for 6 weeks (10, 30, and 78.8 mg/kg) or for 3 months (3, 10, and 30 mg/kg). To evaluate the involvement of DXd alone in T-DXd-induced toxicity, DXd monohydrate was given i.v. to monkeys once a week for 4 weeks (1, 3, and 12 mg/kg). Interstitial pneumonitis was observed in monkeys given T-DXd at 30 mg/kg or more. The histopathological features of diffuse lymphocytic infiltrates and slight fibrosis were similar to interstitial lung diseases (ILD)/pneumonitis related to anticancer drugs in patients, with an incidence that was dose-dependent and dose-frequency-dependent. Monkeys receiving DXd monohydrate did not suffer lung toxicity, although the DXd exposure level was higher than that of DXd in the monkeys given T-DXd. The HER2 expression in monkey lungs was limited to the bronchial level, although the lesions were found at the alveolar level. Immunohistochemical analysis confirmed that T-DXd localization was mainly in alveolar macrophages, but not pulmonary epithelial cells. These findings indicate that monkeys are an appropriate model for investigating T-DXd-related ILD/pneumonitis. The results are also valuable for hypothesis generation regarding the possible mechanism of T-DXd-induced ILD/pneumonitis in which target-independent uptake of T-DXd into alveolar macrophages could be involved. Further evaluation is necessary to clarify the mechanism of ILD/pneumonitis in patients with T-DXd therapy.


Subject(s)
Camptothecin/analogs & derivatives , Immunoconjugates/adverse effects , Immunoconjugates/metabolism , Lung Diseases, Interstitial/chemically induced , Macaca fascicularis , Trastuzumab/adverse effects , Trastuzumab/metabolism , Animals , Camptothecin/administration & dosage , Camptothecin/adverse effects , Camptothecin/metabolism , Cathepsin B/analysis , Drug Administration Schedule , Female , Immunoconjugates/administration & dosage , Lung/drug effects , Lung/metabolism , Lung/pathology , Lung Diseases, Interstitial/metabolism , Lung Diseases, Interstitial/pathology , Male , Receptor, ErbB-2/metabolism , Time Factors , Trastuzumab/administration & dosage
6.
Biol Pharm Bull ; 43(6): 1007-1015, 2020.
Article in English | MEDLINE | ID: mdl-32475910

ABSTRACT

The interaction of human leukocyte antigen (HLA) with specific drugs is associated with delayed-type hypersensitivity reactions, which cause severe cutaneous toxicity. Such interactions induce structural alterations in HLA complexes via several different mechanisms such as the hapten theory, p-i concept, and altered peptide repertoire model, leading to the activation of cytotoxic T cells. To date, comprehensive detection of such structural alterations in preclinical studies has been difficult. Here, we evaluated structural alterations in HLA complexes focusing on the interaction between the HLA-B*57 : 01 allele and abacavir (an anti-human immunodeficiency virus drug), representing a model of abacavir hypersensitivity syndrome induced by changes in the peptide repertoire on the HLA molecule. We employed a phage display method using a commercially available antibody library to screen specific phage antibodies able to recognize HLA-B*57 : 01. The affinity of selected phage antibodies increased because of structural alterations in HLA-B*57 : 01 following exposure to abacavir, indicating that specific phage antibodies can identify drug-mediated structural changes in HLA complexes. We also identified an unreported structural change in HLA-B*57 : 01 using the phage display method, whereby abacavir increased the expression of peptide-deficient HLA-B*57 : 01 on the cell surface. These results suggest that phage display technology is a useful method for detecting structural changes in HLA complexes. This technology represents a potential novel strategy for predicting HLA-associated hypersensitivity reactions by drugs in pre-clinical studies.


Subject(s)
Anti-HIV Agents/pharmacology , Dideoxynucleosides/pharmacology , HLA-B Antigens/chemistry , Antibodies/immunology , Cell Surface Display Techniques , HLA-B Antigens/genetics , HLA-B Antigens/immunology , HeLa Cells , Humans
7.
J Toxicol Pathol ; 33(1): 21-24, 2020 Jan.
Article in English | MEDLINE | ID: mdl-32051661

ABSTRACT

A 40-week-old male spontaneous diabetic Torii rat, an animal model of type 2 diabetes mellitus, was found to have marked urinary calculi with hematuria in the urinary bladder on necropsy. Histological findings in the urinary bladder included a papillary growth pattern with a fibrovascular stroma without atypia. Fine granular materials in the bladder lumen were positive for Von Kossa staining but negative for periodic acid-Schiff or Gram staining, indicating no apparent bacterial infection in the urinary bladder. Scanning electron microscopy revealed that the urinary calculi were magnesium ammonium phosphate crystals (struvite). On the basis of the results, the lesion was diagnosed as urothelial hyperplasia with calculi (papillomatosis). Chronic inciting stimuli by struvite crystals were considered the primary cause of the bladder findings.

8.
Environ Int ; 137: 105560, 2020 04.
Article in English | MEDLINE | ID: mdl-32062438

ABSTRACT

Arsenic and benzo[a]pyrene (BaP) are among the most common environmental carcinogens causing lung cancer. Millions of people are exposed to arsenic through consuming arsenic-contaminated drinking water. High levels of BaP are found in well-done barbecued meat and other food in addition to cigarette smoke. Hence, arsenic and BaP co-exposure in humans is common. However, the combined health effect and the underlying mechanism of arsenic and BaP co-exposure have not been well-understood. In this study we investigate the combined tumorigenic effect of arsenic and BaP co-exposure and the mechanism using both cell culture and mouse models. It was found that arsenic (sodium arsenite, 1.0 µM) and BaP (2.5 µM) co-exposure for 30 weeks synergizes in inducing malignant transformation of immortalized non-tumorigenic human bronchial epithelial cells and cancer stem cell (CSC)-like property to enhance their tumorigenicity. In animal studies, A/J mice were exposed to arsenic in drinking water (sodium arsenite, 20 ppm) starting from gestation day 18. After birth, the dams continuously received arsenic water throughout lactation. At weaning (3 weeks of age), male offspring were exposed to either arsenic alone via drinking the same arsenic water or exposed to arsenic plus BaP. BaP was administered via oral gavage (3 µmol per mouse per week) once a week starting from 3 weeks of age for 8 weeks. All mice were euthanized 34-weeks after the first BaP exposure. It was found that mice in control and arsenic exposure alone group did not develop lung tumors. All mice in BaP exposure alone group developed lung adenomas. However, arsenic and BaP co-exposure synergized in increasing lung tumor multiplicity and tumor burden. Furthermore, 30% of mice in arsenic and BaP co-exposure group also developed lung adenocarcinomas. Mechanistic studies revealed that arsenic and BaP co-exposure does not produce more BPDE-DNA adducts than BaP exposure alone; but acts synergistically in activating aryl hydrocarbon receptor (AhR) to up-regulate the expression of a histone H3 lysine 9 methyltransferase SUV39H1 and increase the level of suppressive H3 lysine 9 dimethylation (H3K9me2), which down-regulates the expression of tumor suppressive SOCS3 leading to enhanced activation of Akt and Erk1/2 to promote cell transformation, CSC-like property and tumorigenesis. Together, these findings suggest that arsenic and BaP co-exposure synergizes in causing epigenetic dysregulation to enhance cell transformation, CSC-like property and tumorigenesis.


Subject(s)
Arsenic , Benzo(a)pyrene , Carcinogenesis , Carcinogens, Environmental , Epigenesis, Genetic , Suppressor of Cytokine Signaling 3 Protein , Animals , Arsenic/toxicity , Benzo(a)pyrene/toxicity , Carcinogenesis/chemically induced , Carcinogens, Environmental/toxicity , Cell Transformation, Neoplastic , Down-Regulation , Female , Humans , Male , Mice , Neoplastic Stem Cells , Suppressor of Cytokine Signaling 3 Protein/metabolism
10.
Toxicol Pathol ; 46(3): 302-311, 2018 04.
Article in English | MEDLINE | ID: mdl-29587622

ABSTRACT

Diacylglycerol acyltransferase 1 (DGAT1) catalyzes the final step in triglyceride synthesis. Since Dgat1-/- mice fed a high-fat diet (HFD) are resistant to hepatic steatosis, DGAT1 inhibitors are expected to have antifatty liver effects. To evaluate the hepatic effects of DS-7250, a selective DGAT1 inhibitor, vehicle or 10 mg/kg of DS-7250 was administered orally to male Fisher 344 (F344) and Zucker fatty (ZF) rats fed a standard diet or HFD for 14 or 28 days. ZF rats showed slight hepatic steatosis regardless of feeding conditions. DS-7250 exacerbated hepatic steatosis in ZF rats fed an HFD compared with the vehicle control. Hepatic steatosis did not occur in F344 rats fed an HFD, in which systemic exposures of DS-7250 were comparable to those in ZF rats. There was a higher expression of genes involved in lipid uptake and fatty acid synthesis in ZF rats compared to F344 rats under HFD conditions. DS-7250 upregulated key genes involved in de novo lipogenesis, which causes hepatic steatosis independently of DGAT1, in ZF rats fed an HFD compared with the vehicle control. These data suggest that ZF rats were more susceptible to hepatic steatosis due to their genetic characteristics and DS-7250 exacerbated hepatic steatosis independently of DGAT1.


Subject(s)
Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Fatty Acids/biosynthesis , Fatty Liver/metabolism , Animals , Diet, High-Fat , Lipogenesis/drug effects , Lipogenesis/physiology , Male , Rats , Rats, Inbred F344 , Rats, Zucker , Up-Regulation
11.
Toxicol Pathol ; 45(6): 692-704, 2017 08.
Article in English | MEDLINE | ID: mdl-28891433

ABSTRACT

Exposure to elevated levels of ambient ozone in photochemical smog is associated with eosinophilic airway inflammation and nonatopic asthma in children. In the present study, we determined the role of innate lymphoid cells (ILCs) in the pathogenesis of ozone-induced nonatopic asthma by using lymphoid cell-sufficient C57BL/6 mice, ILC-sufficient Rag2-/- mice (devoid of T and B cells), and ILC-deficient Rag2-/-Il2rg-/- mice (depleted of all lymphoid cells including ILCs). Mice were exposed to 0 or 0.8 parts per million ozone for 1 day or 9 consecutive weekdays (4 hr/day). A single exposure to ozone caused neutrophilic inflammation, airway epithelial injury, and reparative DNA synthesis in all strains of mice, irrespective of the presence or absence of ILCs. In contrast, 9-day exposures induced eosinophilic inflammation and mucous cell metaplasia only in the lungs of ILC-sufficient mice. Repeated ozone exposures also elicited increased messenger RNA expression of transcripts associated with type 2 immunity and airway mucus production in ILC-sufficient mice. ILC-deficient mice repeatedly exposed to ozone had no pulmonary pathology or increased gene expression related to type 2 immunity. These results suggest a new paradigm for the biologic mechanisms underlying the development of a phenotype of childhood nonatopic asthma that has been linked to ambient ozone exposures.


Subject(s)
Air Pollutants/toxicity , Immunity, Innate/drug effects , Lymphocytes/drug effects , Ozone/toxicity , Pulmonary Eosinophilia/chemically induced , Respiratory Mucosa/drug effects , Animals , DNA-Binding Proteins/genetics , Immunity, Mucosal/drug effects , Inhalation Exposure , Interleukin Receptor Common gamma Subunit/genetics , Lymphocytes/pathology , Male , Metaplasia , Mice, Inbred C57BL , Mice, Knockout , Pulmonary Eosinophilia/immunology , Pulmonary Eosinophilia/pathology , Respiratory Mucosa/immunology , Respiratory Mucosa/pathology
12.
Sci Rep ; 7(1): 5921, 2017 07 19.
Article in English | MEDLINE | ID: mdl-28725001

ABSTRACT

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant which elicits hepatotoxicity through activation of the aryl hydrocarbon receptor (AhR). Male C57BL/6 mice orally gavaged with TCDD (0.01-30 µg/kg) every 4 days for 28 days exhibited bile duct proliferation and pericholangitis. Mass spectrometry analysis detected a 4.6-fold increase in total hepatic bile acid levels, despite the coordinated repression of genes involved in cholesterol and primary bile acid biosynthesis including Cyp7a1. Specifically, TCDD elicited a >200-fold increase in taurolithocholic acid (TLCA), a potent G protein-coupled bile acid receptor 1 (GPBAR1) agonist associated with bile duct proliferation. Increased levels of microbial bile acid metabolism loci (bsh, baiCD) are consistent with accumulation of TLCA and other secondary bile acids. Fecal bile acids decreased 2.8-fold, suggesting enhanced intestinal reabsorption due to induction of ileal transporters (Slc10a2, Slc51a) and increases in whole gut transit time and intestinal permeability. Moreover, serum bile acids were increased 45.4-fold, consistent with blood-to-hepatocyte transporter repression (Slco1a1, Slc10a1, Slco2b1, Slco1b2, Slco1a4) and hepatocyte-to-blood transporter induction (Abcc4, Abcc3). These results suggest that systemic alterations in enterohepatic circulation, as well as host and microbiota bile acid metabolism, favor bile acid accumulation that contributes to AhR-mediated hepatotoxicity.


Subject(s)
Bacteria/metabolism , Bile Acids and Salts/metabolism , Enterohepatic Circulation/drug effects , Homeostasis/drug effects , Polychlorinated Dibenzodioxins/toxicity , Animals , Bacteria/drug effects , Bacteria/genetics , Bile Acids and Salts/blood , Cholesterol/metabolism , Feces/chemistry , Female , Genes, Bacterial , Hydrophobic and Hydrophilic Interactions , Intestinal Absorption/drug effects , Liver/drug effects , Liver/metabolism , Male , Mice, Inbred C57BL
14.
PLoS One ; 11(8): e0160622, 2016.
Article in English | MEDLINE | ID: mdl-27513935

ABSTRACT

Occupational exposure to respirable crystalline silica (cSiO2, quartz) is etiologically linked to systemic lupus erythematosus (lupus) and other human autoimmune diseases (ADs). In the female NZBWF1 mouse, a widely used animal model that is genetically prone to lupus, short-term repeated intranasal exposure to cSiO2 triggers premature initiation of autoimmune responses in the lungs and kidneys. In contrast to cSiO2's triggering action, consumption of the ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) prevents spontaneous onset of autoimmunity in this mouse strain. The aim of this study was to test the hypothesis that consumption of DHA will prevent cSiO2-triggered autoimmunity in the female NZBWF1 mouse. Mice (6 wk old) were fed isocaloric AIN-93G diets containing 0.0, 0.4, 1.2 or 2.4% DHA. Two wk after initiating feeding, mice were intranasally instilled with 1 mg cSiO2 once per wk for 4 wk and maintained on experimental diets for an additional 12 wk. Mice were then sacrificed and the lung, blood and kidney assessed for markers of inflammation and autoimmunity. DHA was incorporated into lung, red blood cells and kidney from diet in a concentration-dependent fashion. Dietary DHA dose-dependently suppressed cSiO2-triggered perivascular leukocyte infiltration and ectopic lymphoid tissue neogenesis in the lung. DHA consumption concurrently inhibited cSiO2-driven elevation of proinflammatory cytokines, B-cell proliferation factors, IgG and anti-dsDNA Ig in both bronchoalveolar lavage fluid and plasma. DHA's prophylactic effects were further mirrored in reduced proteinuria and glomerulonephritis in cSiO2-treated mice. Taken together, these results reveal that DHA consumption suppresses cSiO2 triggering of autoimmunity in female NZBWF1 mice as manifested in the lung, blood and kidney. Our findings provide novel insight into how dietary modulation of the lipidome might be used to prevent or delay triggering of AD by cSiO2. Such knowledge opens the possibility of developing practical, low-cost preventative strategies to reduce the risk of initiating AD and subsequent flaring in cSiO2-exposed individuals. Additional research in this model is required to establish the mechanisms by which DHA suppresses cSiO2-induced autoimmunity and to ascertain unique lipidome signatures predictive of susceptibility to cSiO2-triggered AD.


Subject(s)
Docosahexaenoic Acids/pharmacology , Lupus Erythematosus, Systemic/immunology , Silicon Dioxide/immunology , Animals , Bronchoalveolar Lavage Fluid , Immunity, Cellular , Kidney/drug effects , Mice , Models, Theoretical , Occupational Exposure/adverse effects
15.
Toxicol Sci ; 154(2): 253-266, 2016 12.
Article in English | MEDLINE | ID: mdl-27562557

ABSTRACT

We have previously shown that in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-elicited NAFLD progression, central carbon, glutaminolysis, and serine/folate metabolism are reprogrammed to support NADPH production and ROS defenses. To further investigate underlying dose-dependent responses associated with TCDD-induced fibrosis, female C57BL/6 mice were gavaged with TCDD every 4 days (d) for 28 d or 92 d. RNA-Seq, ChIP-Seq (2 h), and 28 d metabolomic (urine, serum, and hepatic extract) analyses were conducted with complementary serum marker assessments at 92 d. Additional vehicle and 30 µg/kg treatment groups were allowed to recover for 36 d following the 92-d treatment regimen to examine recovery from TCDD-elicited fibrosis. Histopathology revealed dose-dependent increases in hepatic fat accumulation, inflammation, and periportal collagen deposition at 92 days, with increased fibrotic severity in the recovery group. Serum proinflammatory and profibrotic interleukins-1ß, -2, -4, -6, and -10, as well as TNF-α and IFN-γ, exhibited dose-dependent induction. An increase in glucose tolerance was observed with a concomitant 3.0-fold decrease in hepatic glycogen linked to increased ascorbic acid biosynthesis and proline metabolism, consistent with increased fibrosis. RNA-Seq identified differential expression of numerous matrisome genes including an 8.8-fold increase in Tgfb2 indicating myofibroblast activation. Further analysis suggests reprogramming of glycogen, ascorbic acid, and amino acid metabolism in support of collagen deposition and the use of proline as a substrate for ATP production via the proline cycle. In summary, we demonstrate that glycogen, ascorbic acid, and amino acid metabolism are also reorganized to support remodeling of the extracellular matrix, progressing to hepatic fibrosis in response to chronic injury from TCDD.


Subject(s)
Cellular Reprogramming/drug effects , Chemical and Drug Induced Liver Injury/etiology , Energy Metabolism/drug effects , Liver Cirrhosis/chemically induced , Liver/drug effects , Non-alcoholic Fatty Liver Disease/chemically induced , Polychlorinated Dibenzodioxins/toxicity , Transcriptome/drug effects , Animals , Ascorbic Acid/metabolism , Chemical and Drug Induced Liver Injury/genetics , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/pathology , Collagen/metabolism , Cytokines/metabolism , Dose-Response Relationship, Drug , Extracellular Matrix/drug effects , Extracellular Matrix/metabolism , Extracellular Matrix/pathology , Female , Gene Expression Regulation/drug effects , Glucose/metabolism , Glycogen/metabolism , Inflammation Mediators/metabolism , Liver/metabolism , Liver/pathology , Liver Cirrhosis/genetics , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Proline/metabolism , Time Factors
16.
Am J Respir Cell Mol Biol ; 54(6): 782-91, 2016 06.
Article in English | MEDLINE | ID: mdl-26559808

ABSTRACT

Epidemiological studies suggest that elevated ambient concentrations of ozone are associated with activation of eosinophils in the nasal airways of atopic and nonatopic children. Mice repeatedly exposed to ozone develop eosinophilic rhinitis and type 2 immune responses. In this study, we determined the role of innate lymphoid cells (ILCs) in the pathogenesis of ozone-induced eosinophilic rhinitis by using lymphoid-sufficient C57BL/6 mice, Rag2(-/-) mice that are devoid of T cells and B cells, and Rag2(-/-)Il2rg(-/-) mice that are depleted of all lymphoid cells including ILCs. The animals were exposed to 0 or 0.8 ppm ozone for 9 consecutive weekdays (4 h/d). Mice were killed 24 hours after exposure, and nasal tissues were selected for histopathology and gene expression analysis. ILC-sufficient C57BL/6 and Rag2(-/-) mice exposed to ozone developed marked eosinophilic rhinitis and epithelial remodeling (e.g., epithelial hyperplasia and mucous cell metaplasia). Chitinase-like proteins and alarmins (IL-33, IL-25, and thymic stromal lymphopoietin) were also increased morphometrically in the nasal epithelium of ozone-exposed C57BL/6 and Rag2(-/-) mice. Ozone exposure elicited increased expression of Il4, Il5, Il13, St2, eotaxin, MCP-2, Gob5, Arg1, Fizz1, and Ym2 mRNA in C57BL/6 and Rag2(-/-) mice. In contrast, ozone-exposed ILC-deficient Rag2(-/-)Il2rg(-/-) mice had no nasal lesions or overexpression of Th2- or ILC2-related transcripts. These results indicate that ozone-induced eosinophilic rhinitis, nasal epithelial remodeling, and type 2 immune activation are dependent on ILCs. To the best of our knowledge, this is the first study to demonstrate that ILCs play an important role in the nasal pathology induced by repeated ozone exposure.


Subject(s)
Immunity, Innate/drug effects , Lymphocytes/immunology , Nasal Mucosa/immunology , Ozone/pharmacology , Alarmins/metabolism , Animals , Eosinophils/drug effects , Eosinophils/pathology , Inflammation/complications , Inflammation/pathology , Interleukins/metabolism , Lymphocytes/drug effects , Male , Mice, Inbred C57BL , Nasal Mucosa/drug effects , Nasal Mucosa/injuries , Nasal Mucosa/pathology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rhinitis/complications , Rhinitis/immunology , Rhinitis/pathology
17.
Am J Respir Cell Mol Biol ; 54(3): 331-40, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26203683

ABSTRACT

Inhalation exposures to ozone commonly encountered in photochemical smog cause airway injury and inflammation. Elevated ambient ozone concentrations have been epidemiologically associated with nasal airway activation of neutrophils and eosinophils. In the present study, we elucidated the temporal onset and lymphoid cell dependency of eosinophilic rhinitis and associated epithelial changes in mice repeatedly exposed to ozone. Lymphoid cell-sufficient C57BL/6 mice were exposed to 0 or 0.5 parts per million (ppm) ozone for 1, 2, 4, or 9 consecutive weekdays (4 h/d). Lymphoid cell-deficient, Rag2(-/-)Il2rg(-/-) mice were similarly exposed for 9 weekdays. Nasal tissues were taken at 2 or 24 hours after exposure for morphometric and gene expression analyses. C57BL/6 mice exposed to ozone for 1 day had acute neutrophilic rhinitis, with airway epithelial necrosis and overexpression of mucosal Ccl2 (MCP-1), Ccl11 (eotaxin), Cxcl1 (KC), Cxcl2 (MIP-2), Hmox1, Il1b, Il5, Il6, Il13, and Tnf mRNA. In contrast, 9-day ozone exposure elicited type 2 immune responses in C57BL/6 mice, with mucosal mRNA overexpression of Arg1, Ccl8 (MCP-2), Ccl11, Chil4 (Ym2), Clca1 (Gob5), Il5, Il10, and Il13; increased density of mucosal eosinophils; and nasal epithelial remodeling (e.g., hyperplasia/hypertrophy, mucous cell metaplasia, hyalinosis, and increased YM1/YM2 proteins). Rag2(-/-)Il2rg(-/-) mice exposed to ozone for 9 days, however, had no nasal pathology or overexpression of transcripts related to type 2 immunity. These results provide a plausible paradigm for the activation of eosinophilic inflammation and type 2 immunity found in the nasal airways of nonatopic individuals subjected to episodic exposures to high ambient ozone.


Subject(s)
Eosinophilia/immunology , Immunity, Mucosal , Lymphocytes/immunology , Nasal Mucosa/immunology , Ozone , Rhinitis/immunology , Animals , Cytokines/genetics , Cytokines/metabolism , DNA-Binding Proteins/deficiency , DNA-Binding Proteins/genetics , Disease Models, Animal , Eosinophilia/chemically induced , Eosinophilia/genetics , Eosinophilia/metabolism , Gene Expression Regulation , Genotype , Inflammation Mediators/metabolism , Inhalation Exposure , Interleukin Receptor Common gamma Subunit/deficiency , Interleukin Receptor Common gamma Subunit/genetics , Lymphocytes/metabolism , Male , Mice, Inbred C57BL , Mice, Knockout , Nasal Mucosa/metabolism , Phenotype , RNA, Messenger/metabolism , Rhinitis/chemically induced , Rhinitis/genetics , Rhinitis/metabolism , Signal Transduction , Time Factors
18.
PLoS One ; 10(5): e0125481, 2015.
Article in English | MEDLINE | ID: mdl-25978333

ABSTRACT

Genetic predisposition and environmental factors influence the development of human autoimmune disease. Occupational exposure to crystalline silica (cSiO2) has been etiologically linked to increased incidence of autoimmunity, including systemic lupus erythematosus (SLE), but the underlying mechanisms are poorly understood. The purpose of this study was to test the hypothesis that early repeated short-term cSiO2 exposure will modulate both latency and severity of autoimmunity in the lupus-prone female NZBWF1 mouse. Weekly intranasal exposure to cSiO2 (0.25 and 1.0 mg) for 4 wk beginning at 9 wk of age both reduced latency and increased intensity of glomerulonephritis. cSiO2 elicited robust inflammatory responses in the lungs as evidenced by extensive perivascular and peribronchial lymphoplasmacytic infiltration consisting of IgG-producing plasma cells, and CD45R+ and CD3+ lymphocytes that were highly suggestive of ectopic lymphoid tissue (ELT). In addition, there were elevated concentrations of immunoglobulins and the cytokines MCP-1, TNF-α and IL-6 in bronchoalveolar lavage fluid. cSiO2-associated kidney and lung effects paralleled dose-dependent elevations of autoantibodies and proinflammatory cytokines in plasma. Taken together, cSiO2-induced pulmonary inflammation and ectopic lymphoid neogenesis in the NZBWF1 mouse corresponded closely to systemic inflammatory and autoimmune responses as well as the early initiation of pathological outcomes in the kidney. These findings suggest that following airway exposure to crystalline silica, in mice genetically prone to SLE, the lung serves as a platform for triggering systemic autoimmunity and glomerulonephritis.


Subject(s)
Autoimmunity/drug effects , Glomerulonephritis/chemically induced , Inflammation/chemically induced , Lung/drug effects , Lung/metabolism , Lupus Erythematosus, Systemic/metabolism , Silicon Dioxide/toxicity , Animals , Bronchoalveolar Lavage Fluid/chemistry , Chemokine CCL2/metabolism , Female , Glomerulonephritis/metabolism , Inflammation/metabolism , Interleukin-6/metabolism , Lung/immunology , Male , Mice , Tumor Necrosis Factor-alpha/metabolism
19.
Toxicol Pathol ; 40(5): 807-9, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22552389

ABSTRACT

A nodule was observed in the adrenal medulla of a twenty-week-old male Wistar Hannover rat. The nodule was predominantly (over 80%) composed of neural components, with ganglion cells scattered in sparse supporting tissue containing nerve fibers and Schwann cells. In the peripheral area of the tumor, atypical chromaffin cells were also observed. Accumulation of eosinophilic serous fluid was also noted in the stromal tissue. There were neither mitotic figures in the ganglion cells nor necrotic foci. In immunohistochemistry, the ganglion cells were positive for neuronal nuclei (NeuN), and negative for proliferating cell nuclear antigen, S-100, and chromogranin A. There were some NeuN-positive small cells in the peripheral area of the tumor. These findings indicate that this tumor was a ganglioneuroma. This seems to be an extremely rare case, as the spontaneous occurrence of ganglioneuroma in rats is very low, even in two-year carcinogenicity studies.


Subject(s)
Adrenal Medulla/pathology , Ganglioneuroma/pathology , Neurons/pathology , Animals , Chromaffin Cells/pathology , Chromogranin A/metabolism , Immunohistochemistry , Male , Neurons/cytology , Rats , Rats, Wistar
20.
J Toxicol Pathol ; 24(3): 169-72, 2011 Sep.
Article in English | MEDLINE | ID: mdl-22272057

ABSTRACT

Multiple whitish nodules in the thoracic cavity at the site of the thymus were observed in a 101-week-old male ICR mouse. In a histopathological examination, the neoplastic cells were predominantly fusiform in shape and proliferated in sarcomatoid growth patterns. Some neoplastic cells showed epithelial growth patterns, such as the ductal structures. Mitotic figures were frequently seen, and small necrotic foci and invasion to adjacent thoracic organs were noted. In Alcian blue staining, bluish materials were observed between fusiform-shaped cells and in some of the lumens of the ductal structures. In immunohistochemistry, both fusiform-shaped and ductal structure-forming cells were positive for vimentin and weakly positive to positive for cytokeratin. Based on the aforementioned findings, the thoracic nodules were diagnosed as a mixed type of malignant mesothelioma. This case was thought to be rare because of the very low occurrence of spontaneous mesothelioma in mice.

SELECTION OF CITATIONS
SEARCH DETAIL
...