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1.
J Vet Med Sci ; 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32161252

RESUMO

An 11-year-old female French Bulldog was presented with a mass at the base of the heart, detected by X-ray and echocardiography. Clinical abnormality included abdominal retention by ascites. Radiation therapy was performed for 5 weeks. The mass volume didn't change during the radiotherapy. The condition became worse and the dog died 6 months after the initial presentation and necropsy was performed. Grossly, the mass, 12.5×6.5×6.0 cm in size, was found at the base of the heart. Histopathological examination revealed that cardiac mass was composed of alveolar, bundle and diffuse proliferation of neoplastic cells. Most of the neoplastic cells showed a spindle morphology; in some areas small round or polyhedral neoplastic cells were observed. Occasional cartilage metaplasia was seen multifocal in the mass, and it was surrounded by the sarcomatoid proliferation. Electron microscopy revealed a few neuroendocrine granules in the cytoplasm of spindle and polyhedral neoplastic cells. Metastatic cells in the lungs which had not irradiated demonstrated typical morphology of aortic body tumors. Based on these findings, the case was diagnosed as an aortic body carcinoma with sarcomatoid morphology and chondroid metaplasia.

2.
Toxicol Pathol ; : 192623320906817, 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32122285

RESUMO

A3, generated as a monoclonal antibody against rat malignant fibrous histiocytoma cells, recognizes somatic stem cells in rats. We analyzed the distribution of A3-positive cells in dextran sulfate sodium (DSS)-induced colonic lesions consisting of regenerating mucosa and fibrosis. Male 6-week-old F344 rats were administered 5% DSS in drinking water for 5 to 7 days, and lesions at recovery stage were also examined. In untreated control adult colons, A3-positive cells are localized around the crypts where stem cell niche is formed. Histopathologically, in colons of DSS-administered rats, mucosal atrophy, inflammatory cell infiltration, and fibrosis were observed in the lamina propria; thereafter, mucosal epithelia were desquamated, and crypts were decreased gradually with decrease in surrounding A3-positive cells. At the early recovery stage, crypts showed regeneration with reappearance of A3-positive cells. Interestingly, A3-positive cells aggregated in desquamated mucosa surface of fibrosis. Aggregated A3-positive cells coexpressed with vimentin, Thy-1, and partly CK19 but did not react simultaneously with α-SMA. Likely, aggregated A3-positive cells may be rescue cells with nature of both mesenchymal and epithelial cells to maintain self-renewal after injury in the colon. A3 antibody would become a useful tool to investigate the participation of stem cells in rat colonic lesions.

3.
Toxicol Pathol ; 48(3): 509-523, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31896309

RESUMO

Macrophages and myofibroblasts are important in fibrogenesis. The cellular characteristics in pancreatic fibrosis remain to be investigated. Pancreatic fibrosis was induced in F344 rats by a single intravenous injection of dibutyltin dichloride. Histopathologically, the induced pancreatic fibrosis was divided into 3 grades (1+, 2+, and 3+), based on collagen deposition. Immunohistochemically, CD68-expressing M1 macrophages increased with grade and CD163-expressing M2 macrophages also increased later than M1 macrophage appearance. Double immunofluorescence showed that there were macrophages coexpressing CD68 and CD163, suggesting a possible shift from M1 to M2 types; similarly, increased major histocompatibility complex class II- and CD204-expressing macrophages were polarized toward M1 and M2 types, respectively. These findings indicated the participation of M1- and M2-polarized macrophages. Mesenchymal cells staining positive for vimentin, desmin, and α-smooth muscle actin (α-SMA) increased with grade. There were mesenchymal cells coexpressing vimentin/α-SMA, desmin/α-SMA, and glial fibrillary acidic protein (GFAP)/α-SMA; Thy-1-expressing immature mesenchymal cells also increased in fibrotic lesions. Because α-SMA expression is a reliable marker for myofibroblasts, α-SMA-expressing pancreatic myofibroblasts might be originated from GFAP-expressing pancreatic stellate cells or Thy-1-expressing immature mesenchymal cells; the myofibroblasts could simultaneously express cytoskeletal proteins such as vimentin and desmin. The present findings would provide useful information for analyses based on features of macrophages and myofibroblasts in chemically induced pancreatic fibrosis.

4.
Exp Anim ; 69(1): 11-17, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31292305

RESUMO

Hyperpolarization-activated cyclic nucleotide-gated potassium channel 1 (HCN1) contribute to spontaneous rhythmic activity in different tissues, including the heart and brain. Deficiency in HCN1 function is associated with sick sinus syndrome in mice and epilepsy in humans. We recently developed Hcn1-deficient rats and found that they exhibit absence epilepsy. While rearing Hcn1-deficient rats, we noticed loose muscle tension and abnormal gait. We therefore evaluated the muscle strength and motor functions of Hcn1-deficient rats. When subjected to the wire hang test, Hcn1-deficient rats fell down more easily than control F344 rats. Grip strength of Hcn1-deficient rats was significantly smaller than F344 rats. In the inclined plane test, they exhibited a smaller maximum angle. In the rotarod test, the latency to fall was shorter for Hcn1-deficient rats than F344 rats. In the footprint analysis, Hcn1-deficient rats exhibited smaller step length and wider step width than F344 rats. Instead of poor motor coordination ability and muscle weakness, Hcn1-deficient rats exhibited normal electromyograms, muscle histology, and deep tendon reflex. These findings suggest that HCN1 channels contribute to motor coordination and muscle strength, and that the muscle weakness of Hcn1-deficient rats results from the involvement not of the peripheral but of the central nervous system.

5.
Exp Anim ; 69(1): 26-33, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31341137

RESUMO

Spontaneous hhy mice show hydrocephalus and subcortical heterotopia, and a mutation in the Ccdc85c gene has been identified. To contribute to the comparison of the role of Ccdc85c in different species, we established a Ccdc85c KO rat and investigated its pathological phenotypes. Ccdc85c KO rats were produced by genomic engineering using transcription activator-like effector nuclease (TALEN). The KO rats had an approximately 350-bp deletion in Ccdc85c and lacked CCDC85C protein expression. The KO rats showed non-obstructive hydrocephalus, subcortical heterotopia, and intracranial hemorrhage. The KO rats had many pathological characteristics similar to those in hhy mice. These results indicate that CCDC85C plays an important role in cerebral development in rats, and the function of CCDC85C in the cerebrum are similar in rats and mice.

6.
J Vet Med Sci ; 82(2): 139-142, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-31852861

RESUMO

Leiomyoma is the most common mesenchymal tumor in the gastrointestinal (GI) tract. Leiomyomas usually have a single or multinodular mass of various sizes, and affected animals can develop alimentary symptoms depending on the location and size. A 3-year old female miniature dachshund died after a history of refractory rectal prolapse, esophagectasis and aspiration pneumonia. At necropsy, the GI wall at the gastroesophageal and anorectal junctions was circumferentially thickened. Histologically, both GI lesions were composed of bundles of well-differentiated smooth muscles without mass formation or invasive growth. The neoplastic cells had little cellular atypia and low proliferative activity, and were positive for α-smooth muscle actin. The lesions were diagnosed as diffuse leiomyomatosis with circumferential thickening of the GI wall and has not been described in the veterinary literature.

7.
Nihon Yakurigaku Zasshi ; 154(2): 61-65, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31406044

RESUMO

Non-alcoholic steatohepatitis (NASH), one of the most common chronic liver diseases (CLD), is getting the most important cause of cirrhosis and hepatocellular carcinoma. Iron is an essential micronutrient for organisms. Once excess iron is accumulated in vital organs, dysfunctions of these organs can occur via the generation of reactive oxygen species. Hepatic iron overload is often seen in CLD patients. In NASH patients, iron accumulation in the liver is positively correlated with histological severity. Thus iron overload can contribute to progression of nonalcoholic fatty liver disease (NAFLD) to NASH. In a rat model of NASH, feeding of high-fat and high-iron diet increases hepatic inflammation with increased hepatic cytokine expression compared with feeding of high-fat diet only. In this model, iron is intensely accumulated in Kupffer cells/macrophages within the lesion, raising the possibility that iron-laden Kupffer cells/macrophages can play a key role in the enhancement of hepatic inflammation in NASH condition. On the other hand, in a rat model of liver cirrhosis, dietary iron overload clearly abrogates the development and progression of liver cirrhosis induced by repeated administration of thioacetamide (TAA). These findings suggest that iron overload can promote or suppress chronic liver diseases depending on the tissue microenvironment. Here we review and introduce the recent findings on the pathological roles of iron overload in the development and progression of NAFLD/NASH.


Assuntos
Sobrecarga de Ferro/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Animais , Progressão da Doença , Humanos , Ferro , Ratos
8.
Vet Pathol ; 56(6): 889-894, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31170892

RESUMO

An 11-year-old female miniature Dachshund dog presented with a solid, soft, gray mass on the hepatic lateral left lobe. Histologically, the mass consisted of neoplastic proliferation of cells with round nuclei and eosinophilic and vacuolated cytoplasm arranged in alveolar, trabecular, and solid patterns. Immunohistochemically, the neoplastic cells were positive for pancytokeratin (CK AE1/AE3), CK5, CK14, vimentin, Sox9, and myoepithelial markers (α-smooth muscle actin, p63, and calponin). The morphological and immunohistochemical findings indicated a diagnosis of myoepithelial carcinoma. We conducted immunohistochemical studies on other representative canine hepatic tumors. Although the myoepithelial phenotype was not observed in the hepatocellular carcinoma, some tumor cells in cholangiocarcinoma showed immunohistochemical features of myoepithelium, suggesting that some neoplastic cells in cholangiocarcinoma may have the potential to differentiate into myoepithelial cells. To our knowledge, this is the first report in veterinary medicine of a hepatic carcinoma with a myoepithelial phenotype.

9.
Brain Res ; 1718: 169-175, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31100216

RESUMO

OBJECTIVE: The dmy rat is an autosomal recessive mutant that exhibits severe rapid myelin breakdown throughout the central nervous system at 7-8 weeks of age. The dmy rat has a point mutation in Mrs2 gene, which encodes an essential component of the major electrophoretic Mg2+ influx system in the mitochondria. However, it remains unknown how mitochondrial dysfunction leads to the myelin breakdown. METHODS: We focused on the aspartoacylase (ASPA) and mitochondrion-related metabolites to clarify the mechanism of myelin pathology in dmy rats. Aspa mRNA was significantly decreased in both the gray matter and the ventral white matter of spinal cord in the dmy rats from 4 to 8 weeks of age. Very faint immunohistochemical expression for ASPA was noted in the gray and white matter of the affected dmy rats at 8 weeks. Liquid chromatography mass spectrometry revealed no different amount of N-acetylaspartate (NAA), which is synthesized from aspartate and acetyl-coenzyme A (CoA) in neurons, in the brain and spinal cord between the dmy and control rats. CONCLUSION: Our results indicated that the pyruvate dehydrogenase activity might be reduced due to the loss of Mg2+ transport activity in the mitochondria of the dmy rats, suggesting acetyl CoA production might be reduced. The number of oligodendrocytes was well preserved until 7 weeks. It is intriguing that prior to the myelin destruction at 7-8 weeks, disrupted expression of Aspa mRNA and ASPA protein undergoes from early stage of myelinogenesis. These data indicate that ASPA expression would be a useful index to evaluate a function of oligodendrocyte in the dmy rat.

10.
J Vet Med Sci ; 81(5): 750-752, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-30956256

RESUMO

An 8-year-old female Magellanic penguin (Spheniscus magellanicus) started to show epilepsy-like seizures. Subsequent magnetic resonance imaging (MRI) examinations did not reveal any responsible lesions. The neurological symptoms worsened at the age of 10. This penguin became recumbent and died 6 months later after the apparition of the recumbency. At necropsy, only multiple yellowish necrotic lesions in the air sacs and lungs were found. Histopathological evaluation of the brain showed a marked loss of Purkinje cells and many hypertrophied parvalbumin-positive basket/stellate cells were seen in the cerebellar cortex. Calbindin immunohistochemistry demonstrated disrupted arrangement of dendrites in the Purkinje cells. This case was diagnosed as cerebellar cortical degeneration with a very late onset and a slow progression in a Magellanic penguin.


Assuntos
Doenças Cerebelares/veterinária , Spheniscidae , Sacos Aéreos/patologia , Animais , Encéfalo/diagnóstico por imagem , Doenças Cerebelares/patologia , Feminino , Pulmão/patologia , Imagem por Ressonância Magnética/veterinária , Células de Purkinje/citologia
11.
J Vet Med Sci ; 81(5): 744-746, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-30842355

RESUMO

This study represents cases with spontaneous neuritis of peripheral nerves in electric eels. Two electric eels were presented with abnormal swimming behavior and loss of appetite. Electric eels had extensive histopathologic lesions in the splenic and cardiac nerves. The lesions were characterized by swelling of neuronal cells, central chromatolysis and marked inflammatory cell infiltration consisting mainly of lymphocytes around the affected nerves. To the best of our knowledge, this is the first case report of spontaneous neuritis of peripheral nerves in electric eels.


Assuntos
Electrophorus , Neurite (Inflamação)/veterinária , Animais , Feminino , Doenças dos Peixes/patologia , Neurite (Inflamação)/patologia , Natação
12.
J Toxicol Pathol ; 32(1): 37-48, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30739994

RESUMO

A3, generated as a monoclonal antibody against rat malignant fibrous histiocytoma (MFH)-derived cloned cells, recognizes somatic stem cells (bone-marrow/hair follicle stem cells). We investigated the distribution of cells immunoreactive to A3 in the developing rat intestine (particularly, the colon), focusing on the ontogenic kinetics of A3-positive cells. In the rat intestine, A3 labeled spindle-shaped stromal cells localized in the submucosa and labeled endothelial cells of capillaries in the lamina propria forming villi in the early development stage. With development progression, A3-positive cells were exclusively localized around the crypts of the colon. Double immunofluorescence revealed that A3-positive cells around the crypts reacted to vimentin (for mesenchymal cells) and Thy-1 (for mesenchymal stromal cells) but not to α-SMA (for mesenchymal myofibroblastic cells) or CD34 (for hematopoietic stem cells), indicating that A3-positive cells around the crypts may have characteristics of immature mesenchymal cells. In addition, A3 labeled a few epithelial cells at the base of colon crypts. Furthermore, immunoelectron microscopy revealed that A3-positive cells lay inside myofibroblasts adjacent to the epithelium of the crypts. A3-positive cells were regarded as a new type of immature mesenchymal cells around the crypts. Collectively, A3-positive cells might take part in the stem cell niche in the colon, which is formed through epithelial-mesenchymal interaction.

13.
J Cell Physiol ; 234(5): 6667-6678, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30317589

RESUMO

Organ-organ crosstalk is involved in homeostasis. Gastrointestinal symptoms are common in patients with renal failure. The aim of this study was to elucidate the relationship between gastrointestinal motility and gastrointestinal symptoms in chronic kidney disease. We performed studies in C57BL/6 mice with chronic kidney disease after 5/6 nephrectomy. Gastrointestinal motility was evaluated by assessing the ex vivo responses of ileum and distal colon strips to electrical field stimulation. Feces were collected from mice, and the composition of the gut microbiota was analyzed using 16S ribosomal RNA sequencing. Mice with chronic kidney disease after 5/6 nephrectomy showed a decreased amount of stool, and this constipation was correlated with a suppressed contraction response in ileum motility and decreased relaxation response in distal colon motility. Spermine, one of the uremic toxins, inhibited the contraction response in ileum motility, but four types of uremic toxins showed no effect on the relaxation response in distal colon motility. The 5/6 nephrectomy procedure disturbed the balance of the gut microbiota in the mice. The motility dysregulation and constipation were resolved by antibiotic treatments. The expression levels of interleukin 6, tumor necrosis factor-α, and iNOS in 5/6 nephrectomy mice were increased in the distal colon but not in the ileum. In addition, macrophage infiltration in 5/6 nephrectomy mice was increased in the distal colon but not in the ileum. We found that 5/6 nephrectomy altered gastrointestinal motility and caused constipation by changing the gut microbiota and causing colonic inflammation. These findings indicate that renal failure was remarkably associated with gastrointestinal dysregulation.

14.
J Vet Med Sci ; 81(1): 127-133, 2019 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-30464077

RESUMO

Fibrotic lesion is formed by myofibroblasts capable of producing collagens. The myofibroblasts are characterized by immunoexpressions of vimentin, desmin and α-smooth muscle actin (α-SMA) in varying degrees. The cellular characteristics remain investigated in myocardial fibrosis. We analyzed immunophenotypes of myofibroblasts appearing in isoproterenol-induced myocardial fibrosis in rats until 28 days after injection (10 mg/kg body weight); the lesions developed as interstitial edema and inflammatory cell reaction on 8 hr and days 1 and 3, and fibrosis occurred on days 1, 3, 7, 14, and 21 by gradual deposition of collagens, showing the greatest grade on day 14; the lesions gradually reduced with sporadic scar until day 28. Myofibroblasts expressing vimentin and α-SMA increased with a peak on day 3, and then, gradually decreased onwards. Interestingly, Thy-1 expressing cells appeared in the affected areas, apparently being corresponding to the grade similar to vimentin- and α-SMA-positive cells. Thy-1 is expressed in immature mesenchymal cells such as pericytes with pluripotent nature. The immunoreactivity for A3-antigen, a marker for immature mesenchymal cells, was seen in some surrounding cells. There were no cells reacting with antibodies to nestin or glial fibrillary acidic protein, although hepatic myofibroblats have been reported to react with these antibodies. Collectively, myofibroblasts appearing in rat myocardial fibrosis may have been derived from immature mesenchymal cells positive for Thy-1 or A3-antigen, with thereafter showing expressions of vimentin and α-SMA in differentiation.


Assuntos
Cardiomiopatias/induzido quimicamente , Fibrose Endomiocárdica/induzido quimicamente , Isoproterenol/toxicidade , Miofibroblastos/efeitos dos fármacos , Agonistas Adrenérgicos beta/toxicidade , Animais , Fibrose Endomiocárdica/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Imuno-Histoquímica , Masculino , Miofibroblastos/metabolismo , RNA Mensageiro , Ratos , Ratos Sprague-Dawley
15.
J Toxicol Pathol ; 31(4): 301-306, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30393434

RESUMO

In neonatal rats, glutamate could induce retinal thinning depending on the development stage, and the severity peaked at treatment on postnatal day (PND) 8. To elucidate the molecular mechanism of retinal thinning induced by L-glutamate in neonatal rats, we investigated the time-course gene expression profile in the developing retina in addition to initial histopathological changes. Histopathologically, apoptotic cells in the inner retina were observed at 6 hours after treatment on PNDs 4, 6 and 8, and inflammatory cell infiltration was noted at 24 hours. Comprehensive gene expression analysis conducted on PNDs 4 and 8 indicated that cell death/proliferation- and inflammation-related genes were upregulated and that neuron development- and neurotransmitter-related genes were downregulated. Furthermore, quantitative RT-PCR analysis of apoptosis- and inflammation-related genes performed on PNDs 4, 6, 8, 10 and 12 showed that the time-course changes of the gene expression ratios of Gadd45b and Ccl3 seemed to be related to histopathological changes of the retina induced by L-glutamate. These results revealed that the association of initial histopathological changes with the gene expression profile in the retina induced by L-glutamate and that Gadd45b and Ccl3 are considered to participate in retinal thinning induced by L-glutamate in neonatal rats.

16.
Nutrients ; 10(10)2018 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-30279328

RESUMO

Chronic liver disease is an intractable disease, which can progress to cirrhosis and hepatocellular carcinoma. Hepatic iron overload is considered to be involved in the progression of chronic liver diseases; however, the mechanism remains to be elucidated. Here we investigate the role of dietary iron overload using chemically-induced liver cirrhosis model. Rats were fed a high-iron or standard diet and were injected intraperitoneally with thioacetamide (TAA) or saline twice a week for 20 weeks. Rats with TAA treatment (TAA group) had progressive liver cirrhosis characterized by persistent hepatocellular injury, mononuclear cell inflammation and bridging fibrosis; these lesions were markedly reduced in rats with iron feeding and TAA treatment (Fe-TAA group). Rats with iron feeding alone (Fe group) had no evidence of liver injury. Hepatic expression of cleaved caspase-3, but not phospho-RIP3, was decreased in Fe-TAA group compared with that in TAA group. The number of TUNEL-positive (terminal deoxynucleotidyl transferase dUTP nick end labeling) apoptotic hepatocytes was lower in the Fe-TAA group than in the TAA group. Hepatic xenobiotic metabolism and lipid peroxidation were shown to be less related to the abrogation of liver cirrhosis. Our results suggested that dietary hepatic iron overload abrogates chemically-induced liver cirrhosis in rats, which could partly involve decreased hepatocellular apoptosis.


Assuntos
Dieta/efeitos adversos , Sobrecarga de Ferro/etiologia , Ferro na Dieta/efeitos adversos , Cirrose Hepática Experimental/induzido quimicamente , Tioacetamida/efeitos adversos , Animais , Hepatócitos/metabolismo , Fígado/metabolismo , Masculino , Ratos
17.
Stem Cells Dev ; 27(22): 1577-1586, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30215317

RESUMO

Canine induced pluripotent stem cells (ciPSCs) can be used in regenerative medicine. However, there are no reports on the generation of genome integration-free and completely exogenous gene-silenced (footprint free) ciPSCs that are tolerant to enzymatic single-cell passage. In this study, we reprogrammed canine embryonic fibroblasts using the auto-erasable replication-defective and persistent Sendai virus vector, SeVdp(KOSM)302L, and generated two ciPSC lines. The ciPSCs were positive for pluripotent markers, including alkaline phosphatase activity as well as OCT3/4, SOX2, and NANOG transcripts, and NANOG, stage-specific embryonic antigen-1, and partial TRA-1-60 protein expression, even after SeVdp(KOSM)302L removal. The ciPSCs were induced to differentiate into all the three germ layers as embryoid bodies in vitro and as teratomas in vivo. Furthermore, SeVdp(KOSM)302L-free ciPSCs maintained a normal karyotype even after repeated enzymatic single-cell passaging. Therefore, to our knowledge, for the first time, we demonstrated the generation of footprint-free and high-quality ciPSCs that can be passaged at the single-cell stage using enzymatic methods. Our method for generation of ciPSCs is a good step toward the development of clinical application of ciPSCs.


Assuntos
Diferenciação Celular/genética , Corpos Embrioides/citologia , Células-Tronco Pluripotentes Induzidas/citologia , Vírus Sendai/genética , Animais , Reprogramação Celular/genética , Cães , Fibroblastos/citologia , Regulação da Expressão Gênica no Desenvolvimento , Vetores Genéticos/genética , Humanos
18.
Toxicol Pathol ; 46(7): 764-776, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30253710

RESUMO

d-galactosamine (d-GalN) is a well-known hepatotoxic agent that causes liver injury. Conversely, hepatic macrophages play a crucial role in maintaining liver tissue integrity. Macrophage functions were investigated in hepatic lesions induced by a single intraperitoneal injection of d-GalN (800 mg/kg body weight [BW]) in 6-week-old F344 rats. Blood and liver samples were examined at 8 hr and on 1, 2, 3, and 5 days postsingle injection (PSI). Hepatic lesions consisting of degeneration/sporadic foci of coagulation necrosis, inflammatory cell reaction, and reparative fibrosis were seen on PSI days 1 and 2, reflected by significantly increased serum levels of aspartate transaminase and alanine transaminase and upregulation of CD68 M1 (tumor necrosis factor-α, interleukin [IL]-6, and interferon-γ) and CD163 M2 (transforming growth factor-ß1, IL-10, monocyte chemoattractant protein-1, and IL-4) macrophage-related factors. Double immunofluorescence staining on PSI day 2 demonstrated that 82% of hepatic macrophages expressed of CD163/CD68 simultaneously; 65-75% of MHC class II macrophages showed co-expression of CD163 or CD68 and 95% CD204-expressing macrophages reacted to CD163 or CD68. These findings showed that both M1- and M2-macrophages contributed to the development of hepatic lesions induced by d-GalN and provided information about macrophage activation, indicating the importance of analysis of macrophage phenotypes for hepatotoxicity based on M1/M2-polarization.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Galactosamina/toxicidade , Fígado/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Animais , Antígenos CD/genética , Antígenos de Diferenciação Mielomonocítica/genética , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocinas/genética , Fígado/imunologia , Fígado/patologia , Testes de Função Hepática , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Necrose , Ratos Endogâmicos F344 , Receptores de Superfície Celular/genética
19.
Biochem Biophys Res Commun ; 505(1): 267-273, 2018 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-30245134

RESUMO

Type I collagen is one of the most abundant proteins in mammals and plays important roles in maintaining the integrity of many tissues. Although fibroblasts are the main source of type I collagen, other cells also produce it; however, these cells are not well-defined owing to the lack of a specific marker. A transgenic (Tg) mouse line has been generated in which type I collagen-producing cells are labeled with enhanced green fluorescent protein (EGFP), which enables the monitoring of these cells without requiring an additional cell marker. This Tg mouse line has since been widely used to study type I collagen-producing cells and fibrosis; one study revealed that podocytes, which were not previously considered to produce type I collagen, expressed EGFP. This raises a question regarding the specificity of EGFP expression in this Tg mouse line. To exclude the possibility of non-specific EGFP expression in the existing Tg mouse line and specifically monitor type I collagen-producing cells, we generated a new Tg mouse line and histologically confirmed the specificity of EGFP expression throughout the body. Moreover, we explored type I collagen-producing cells other than fibroblasts and revealed for the first time that Leydig cells have the ability to produce type I collagen. Because of its highly specific and physiologically accurate expression, our new Tg mouse line will help to accurately elucidate not only type I collagen-producing cells in normal tissues but also the potential cells in fibrotic tissues, providing new insights into the pathology of fibrosis.


Assuntos
Colágeno Tipo I/metabolismo , Fibroblastos/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Células Intersticiais do Testículo/metabolismo , Animais , Colágeno Tipo I/genética , Feminino , Fibrose , Proteínas de Fluorescência Verde/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Microscopia de Fluorescência
20.
J Toxicol Pathol ; 31(3): 207-212, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30093791

RESUMO

Macrophages are required during kidney development and appear in the initiation and propagation of renal injury. To establish baseline data, we analyzed the kinetics of the macrophage with different immunophenotypes in the developing rat kidney (fetus at 18 and 20 days, neonate at 1-21 days, and adult at 7-weeks old). Macrophages reacting to CD68, CD163, and MHC class II were identified in the cortex and medulla of the developing rat kidney. CD68+ macrophages appeared in the fetal kidney as early as fetal day 18, and the number increased gradually in the neonatal kidney, whereas MHC class II+ and CD163+ macrophages first appeared on neonatal days 4 and 8, respectively. Apoptotic bodies were seen in the fetal kidney and early stages of the neonatal kidney (days 1-4), and simultaneously CD68+ macrophages appeared, indicating that CD68+ macrophages may have roles in phagocytosis of apoptotic bodies and contribute to renal tissue maturation. Colony stimulating factor 1 and insulin growth factor 1 mRNAs were increased in the late stage of renal development (neonatal day 12 or later), and simultaneously CD163+ and MHC class II+ cells appeared, suggesting that these cells may be a source of these growth factors and participate in renal tissue modeling. Generally, the CD163+ and MHC class II+ cell number was much smaller than that of CD68+ cells in the developing neonatal kidney. Therefore, the obtained findings provide valuable information on the participation of macrophages in the developing rat kidney. This information may be useful for evaluation of renal toxicity when macrophages are involved in the development of renal injury.

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