24 results on '"Imaida K"'
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2. Association of longer telomere length in cancer cells and cancer-associated fibroblasts with worse prognosis.
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Matsuda Y, Ye J, Yamakawa K, Mukai Y, Azuma K, Wu L, Masutomi K, Yamashita T, Daigo Y, Miyagi Y, Yokose T, Oshima T, Ito H, Morinaga S, Kishida T, Minamoto T, Kojima M, Kaneko S, Haba R, Kontani K, Kanaji N, Okano K, Muto-Ishizuka M, Yokohira M, Saoo K, Imaida K, and Suizu F
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- Humans, In Situ Hybridization, Fluorescence, Prognosis, Telomere Shortening, Telomere, Telomere Homeostasis, Carcinoma, Renal Cell, Cancer-Associated Fibroblasts pathology, Carcinoma, Squamous Cell pathology, Liver Neoplasms pathology, Kidney Neoplasms
- Abstract
Background: Telomere dysfunction has been reported to be directly involved in carcinogenesis owing to chromosomal instability and immortalization; however, the clinicopathological significance of telomeres remains controversial. We have shown that telomere shortening occurs in normal-appearing duct cells at initiation and then continues during the progression of pancreatic cancer. In this study, we determined the clinicopathological and prognostic value of telomere length (TL) in cancer progression., Methods: TL in both cancer cells and cancer-associated fibroblasts (CAFs) was analyzed by high-throughput quantitative fluorescence in situ hybridization using a previously reported cohort comprising 1434 cases of adenocarcinoma (ADC), squamous cell carcinoma (SCC), adenosquamous carcinoma, hepatocellular carcinoma, and renal cell carcinoma (RCC), which are known cancers with a statistically significantly low incidence of alternative lengthening of telomeres. Cases were divided into 2 groups as follows: longer and shorter telomeres, according to the median TL of cancer cells and CAFs. The statistical significance of TL in cancer cells and CAFs on clinicopathological characteristics and prognosis was analyzed., Results: There was a close association between TL in cancer cells and CAFs. Longer telomeres in cancer cells and CAFs were associated with aggressive features such as advanced stage, high mitosis score and nuclear score, poorly differentiated cancer, and desmoplastic stroma in ADC. Furthermore, a longer TL was an independent prognostic factor for ADC, SCC, and RCC., Conclusions: Longer telomeres are associated with worse prognosis in ADC, SCC, and RCC. Thus, TL is a novel biomarker for the diagnosis of aggressive cancers with poor prognoses., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2023
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3. GAREM1 is involved in controlling body mass in mice and humans.
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Nishino T, Abe T, Kaneko M, Yokohira M, Yamakawa K, Imaida K, and Konishi H
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- Adaptor Proteins, Signal Transducing, Animals, Cell Cycle Proteins, Cell Line, Epidermal Growth Factor metabolism, Humans, MAP Kinase Signaling System, Mice, Phosphorylation, Ribosomal Protein S6 Kinases metabolism, Body Weight genetics, Dwarfism genetics, GRB2 Adaptor Protein metabolism
- Abstract
The adaptor protein GAREM has two subtypes. Each is involved in Erk activation signaling downstream of the cell growth factor receptor in cultured cells. Regarding their role in individual animals, we have previously reported that mice deficient in GAREM2, which is highly expressed in the brain, exhibit emotional changes. In this paper, we report an amino acid substitution mutation (K291R) in GAREM1, in a patient with idiopathic short stature, which indicates that the mutant exhibits dominant-negative properties. The GAREM K291R mutant did not promote Erk activation in EGF-stimulated cultured cells. Similar features were also observed in cells in which GAREM1 expression was suppressed by genome editing; along with Erk, phosphorylation of S6 kinase and 4EBP1, whose activation is necessary for cell proliferation and biological growth, were inhibited Furthermore, we generated mice deficient in GAREM1 and showed that the mutant mice are lighter in weight. Overall, the results of this paper suggest that GAREM1 is required for normal growth and for maintaing average body size in humans and mice., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hiroaki Konishi reports was provided by Shinshu University - Ina Campus., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2022
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4. An International Collaborative Animal Study of the Carcinogenicity of Mobile Phone Radiofrequency Radiation: Considerations for Preparation of a Global Project.
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Ahn YH, Imaida K, Kim YB, Han KH, Pack JK, Kim N, Jeon SB, Lee AK, Choi HD, Wang J, Kawabe M, and Kim HS
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- Animals, Brain, Carcinogenesis, Electromagnetic Fields, Male, Rats, Cell Phone, Radio Waves
- Abstract
Radiofrequency radiation (RFR) was classified as a "possible" human carcinogen in 2011, which caused great public concern. A carcinogenicity study by the National Toxicology Program (NTP) found Code Division Multiple Access-and Global System for Mobile Communications-modulated mobile phone RFR to be carcinogenic to the brain and heart of male rats. As part of an investigation of mobile phone carcinogenesis, and to verify the NTP study results, a 5-year collaborative animal project was started in Korea and Japan in 2019. An international animal study of this type has two prerequisites: use of the same study protocol and the same RF-exposure system. This article discusses our experience in the design of this global study on radiofrequency electromagnetic fields (RF-EMFs).© 2022 The Authors. Bioelectromagnetics published by Wiley Periodicals LLC on behalf of Bioelectromagnetics Society., (© 2022 The Authors. Bioelectromagnetics published by Wiley Periodicals LLC on behalf of Bioelectromagnetics Society.)
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- 2022
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5. Relationship between Lung Carcinogenesis and Chronic Inflammation in Rodents.
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Nakano-Narusawa Y, Yokohira M, Yamakawa K, Ye J, Tanimoto M, Wu L, Mukai Y, Imaida K, and Matsuda Y
- Abstract
Lung cancer remains the leading cause of cancer-related deaths, with an estimated 1.76 million deaths reported in 2018. Numerous studies have focused on the prevention and treatment of lung cancer using rodent models. Various chemicals, including tobacco-derived agents induce lung cancer and pre-cancerous lesions in rodents. In recent years, transgenic engineered rodents, in particular, those generated with a focus on the well-known gene mutations in human lung cancer ( KRAS , EGFR , and p53 mutations) have been widely studied. Animal studies have revealed that chronic inflammation significantly enhances lung carcinogenesis, and inhibition of inflammation suppresses cancer progression. Moreover, the reduction in tumor size by suppression of inflammation in animal experiments suggests that chronic inflammation influences the promotion of tumorigenesis. Here, we review rodent lung tumor models induced by various chemical carcinogens, including tobacco-related carcinogens, and transgenics, and discuss the roles of chronic inflammation in lung carcinogenesis.
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- 2021
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6. Pulmonary tumor thrombotic microangiopathy caused by urothelial carcinoma: An autopsy-proven case of a rare etiology.
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Parama JK, Hashimoto N, Murota M, Jinno K, Tsunemori H, Nakano-Narusawa Y, Yamakawa K, Saoo K, Yokohira M, Imaida K, Kuroda N, and Matsuda Y
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- Autopsy, Carcinoma pathology, Fatal Outcome, Humans, Lung diagnostic imaging, Lung pathology, Lung Neoplasms pathology, Male, Middle Aged, Thrombotic Microangiopathies pathology, Urothelium diagnostic imaging, Urothelium pathology, Carcinoma diagnostic imaging, Lung Neoplasms diagnostic imaging, Thrombotic Microangiopathies diagnostic imaging
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- 2020
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7. Lung proliferative lesion-promoting effects of left pulmonary ligation in A/J female mice.
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Yokohira M, Hashimoto N, Yamakawa K, Nakano-Narusawa Y, Matsuda Y, and Imaida K
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- Animals, Female, Ligation, Lung surgery, Mice, Carcinogens toxicity, Disease Models, Animal, Lung Neoplasms chemically induced, Nitrosamines toxicity
- Abstract
This present study was conducted in an attempt to examine proliferative lesion-promoting effect in the lung by compensatory lung growth after left pulmonary ligation. To examine a strong proliferative lesion-promoting effect in the lung, the effects of left pulmonary ligation on lung proliferative lesions induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were examined for 12 weeks. The number of proliferative lesions induced by NNK in the right lung after left pulmonary ligation increased significantly after 12 weeks, indicated by an increase in the weight of the right lung. In addition, several messenger RNA (mRNA) markers, including insulin growth factor 1, were highly expressed in the right lung on the seventh day after left ligation. These experiments demonstrated the clear proliferative lesion-promoting effects of pulmonary ligation on the induction of the expression of mRNAs related to the cell cycle, cell division and mitosis. However, the proliferative lesion-promoting effects were not strong enough to allow a shortened experimental period for the establishment of the lung bioassay model. The results also indicated the necessity to pay attention to the possibility of a recurrence of lung cancer in the residual lung after resection in humans., (© 2020 The Authors. Pathology International published by Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)
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- 2020
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8. Single Intratracheal Quartz Instillation Induced Chronic Inflammation and Tumourigenesis in Rat Lungs.
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Nakano-Narusawa Y, Yokohira M, Yamakawa K, Saoo K, Imaida K, and Matsuda Y
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- Adenocarcinoma immunology, Adenocarcinoma pathology, Animals, Cell Movement drug effects, Edema chemically induced, Edema immunology, Edema pathology, Granuloma chemically induced, Granuloma immunology, Granuloma pathology, Inflammation, Intubation, Intratracheal, Lung drug effects, Lung immunology, Lung pathology, Lung Neoplasms immunology, Lung Neoplasms pathology, Lymphocytes drug effects, Lymphocytes immunology, Lymphocytes pathology, Macrophages drug effects, Macrophages immunology, Macrophages pathology, Male, Neutrophils drug effects, Neutrophils immunology, Neutrophils pathology, Pulmonary Fibrosis immunology, Pulmonary Fibrosis pathology, Rats, Rats, Inbred F344, Silicosis immunology, Silicosis pathology, Adenocarcinoma chemically induced, Carcinogenesis drug effects, Lung Neoplasms chemically induced, Pulmonary Fibrosis chemically induced, Quartz administration & dosage, Silicosis etiology
- Abstract
Crystalline silica (quartz) is known to induce silicosis and cancer in the lungs. In the present study, we investigated the relationship between quartz-induced chronic inflammation and lung carcinogenesis in rat lungs after a single exposure to quartz. F344 rats were treated with a single intratracheal instillation (i.t.) of quartz (4 mg/rat), and control rats were treated with a single i.t. of saline. After 52 or 96 weeks, the animals were sacrificed, and the lungs and other organs were used for analyses. Quartz particles were observed in the lungs of all quartz-treated rats. According to our scoring system, the lungs of rats treated with quartz had higher scores for infiltration of lymphocytes, macrophages and neutrophils, oedema, fibrosis, and granuloma than the lungs of control rats. After 96 weeks, the quartz-treated rats had higher incidences of adenoma (85.7%) and adenocarcinoma (81.0%) than control rats (20% and 20%, respectively). Quartz-treated and control rats did not show lung neoplastic lesions at 52 weeks after treatment. The number of lung neoplastic lesions per rat positively correlated with the degree of macrophage and lymphocyte infiltration, oedema, fibrosis, and lymph follicle formation around the bronchioles. In conclusion, single i.t. of quartz may induce lung cancer in rat along with chronic inflammation.
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- 2020
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9. Preexisting diabetes mellitus had no effect on the no-observed-adverse-effect-level of acetaminophen in rats.
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Kishi S, Yamakawa K, Nakano-Narusawa Y, Kanie S, Hashimoto N, Saoo K, Yokohira M, Imaida K, and Matsuda Y
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- Animals, Hepatocytes drug effects, Hepatocytes pathology, Hypertrophy, Male, Rats, Wistar, Acetaminophen toxicity, Diabetes Mellitus, Type 2 physiopathology, No-Observed-Adverse-Effect Level
- Abstract
Information on the safety of chemical substances in patients with various preexisting conditions remains limited. Acetaminophen was added to the basal diet at 0, 80, 253, 800, 2530, or 8000 ppm and administered to type 2 diabetes mellitus rats (GK/Jcl) and the control male rats (Wistar) for 13 weeks. Both strains treated with 8000 ppm acetaminophen (561.4 and 567.7 mg/kg body weight/day, GK/Jcl and Wistar rats, respectively) showed decreased levels of red blood cell counts, blood urea nitrogen, creatinine, and total bilirubin compared to those of non-treated rats. Treatment with 8000 ppm of acetaminophen reduced the blood glucose and hemoglobin A1c levels of GK/Jcl rats. An increase in the relative weights of the kidneys and liver, and a decrease in the weight of the salivary glands were observed in both GK/Jcl and Wistar rats treated with 8000 ppm acetaminophen relative to those of non-treated control rats. Microscopically, both strains treated with 2530 (174.3 and 164.2 mg/kg body weight/day, GK/Jcl and Wistar rats, respectively) or 8000 ppm acetaminophen showed hepatocellular hypertrophy and degenerative lesions in the salivary glands, whereas similar lesions were not observed in non-treated rats. In conclusion, the no-observed-adverse-effect-level of acetaminophen was 800 ppm in both diabetic and control rats.
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- 2020
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10. Effects of the expectorant drug ambroxol hydrochloride on chemically induced lung inflammatory and neoplastic lesions in rodents.
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Yoshida S, Yokohira M, Yamakawa K, Nakano-Narusawa Y, Kanie S, Hashimoto N, and Imaida K
- Abstract
Ambroxol hydrochloride (AH) is an expectorant drug used to stimulate pulmonary surfactant and serous airway secretion. Surfactant proteins (SPs) are essential for maintaining respiratory structure and function, although SP expression has also been reported in lung inflammatory and proliferative lesions. To determine whether AH exerts modulatory effects on these lung lesions, we examined its effects on pleural thickening induced by intrathoracic administration of dipotassium titanate (TISMO) in A/JJmsSlc (A/J) mice. We also analyzed the modulatory effects of AH on neoplastic lung lesions induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice and by N-nitrosobis (2-hydroxypropyl) amine (DHPN) in F344/DuCrlCrj (F344) rats. A/J mice treated with TISMO showed decreased body weight, increased white blood cell (WBC) counts, and pleural thickening caused by pleuritis and poor general condition. However, A/J mice treated with TISMO + 120 ppm showed significant recovery of body weight and WBC counts to the same levels as those of A/J mice not treated with TISMO, although no significant differences were observed in histopathological changes including the immunohistopathological expression of IL-1β in the lung and maximum pleural thickness regardless of AH treatment. In the NNK and DHPN experiments, no significant differences in body weight, hematology, plasma biochemistry, and histopathological changes were associated with AH concentration. These results suggest that AH potentially exerts anti-inflammatory effects but does not have a direct suppressive effect on lung tumorigenesis in rodents.
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- 2018
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11. Characteristics of surfactant proteins in tumorigenic and inflammatory lung lesions in rodents.
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Yokohira M, Yamakawa K, Nakano-Narusawa Y, Hashimoto N, Kanie S, Yoshida S, and Imaida K
- Abstract
Surfactant proteins (SPs) are essential for the proper structure and respiratory function of the lungs. There are four subtypes of SPs: SP-A, SP-B, SP-C, and SP-D. The expectorant drug ambroxol hydrochloride is clinically used to stimulate pulmonary surfactant and airway serous secretion. In addition, previous studies showed that ambroxol regulated SP production and attenuated pulmonary inflammation, with ambroxol hydrochloride being found to suppress quartz-induced lung inflammation via stimulation of pulmonary surfactant and airway serous secretion. In this study, we investigated the expression of SP-A, SP-B, SP-C, and SP-D in neoplastic and inflammatory lung lesions in rodents, as well as their possible application as potential markers for diagnostic purposes. SP-B and SP-C showed strong expression in lung hyperplasia and adenoma, whereas SP-A and SP-D were expressed in the mucus or exudates of inflammatory alveoli. Rodent tumorigenic hyperplasic tissues induced by various carcinogens were positive for napsin A, an aspartic proteinase involved in the maturation of SP-B; this indicated a focal increase in type II pneumocytes in the lungs. Therefore, high expression of napsin A in the alveolar walls may serve as a useful marker for prediction of the tumorigenic potential of lung hyperplasia in rodents.
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- 2018
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12. γH2AX is immunohistochemically detectable until 7 days after exposure of N-bis (2-hydroxypropyl) nitrosamine (DHPN) in rat lung carcinogenesis.
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Ying JTX, Yokohira M, Nakano-Narusawa Y, Yamakawa K, Hashimoto N, and Imaida K
- Abstract
It is known that γH2AX, which is formed when there is a double-strand break in DNA, can act as a sensitive marker of genomic instability. In this experiment, the time-course manner of the expression of γH2AX in the lung was examined in the early phase after treatment with a lung carcinogen, N-bis (2-hydroxypropyl) nitrosamine (DHPN). The expression of γH2AX is expected to be one of the useful markers for lung carcinogenesis in early stages. Rats were separated into 10 groups of 5 rats. The DHPN groups were administered 0.1% DHPN in drinking tap water for two weeks, while the control group received drinking tap water. At 0, 1, 3, 7, and 14 days after finishing DHPN treatment, one group each from the DHPN and control groups was sacrificed. The removed lung tissues were examined for immunostaining of γH2AX and PCNA, and positive cells were counted. The γH2AX levels of the DHPN-treated groups were found to be increased significantly at 0, 1, 3, and 7 days (4.4 ± 1.4, 5.1 ± 2.7, 3.3 ± 1.0, and 4.1 ± 1.3%, respectively), and they dropped significantly on day 14 (1.1 ± 0.4%). The experiment showed that the γH2AX-positive score could be effectively measured for up to 7 days after exposure, as a significance difference was observed between the treated group and the control group. It can be deduced that γH2AX is an effective marker for DHPN-induced double-strand breaks in pulmonary epithelial cells.
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- 2018
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13. A 13-week subchronic toxicity study of acetaminophen using an obese rat model.
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Toyoda T, Cho YM, Akagi JI, Mizuta Y, Matsushita K, Nishikawa A, Imaida K, and Ogawa K
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- Acetaminophen administration & dosage, Acetaminophen metabolism, Administration, Oral, Animals, Antipyretics administration & dosage, Antipyretics metabolism, Disease Models, Animal, Dose-Response Relationship, Drug, Kidney drug effects, Kidney metabolism, Liver metabolism, Male, Organ Size drug effects, Rats, Inbred F344, Rats, Zucker, Time Factors, Acetaminophen adverse effects, Acetaminophen toxicity, Antipyretics adverse effects, Antipyretics toxicity, Liver drug effects, No-Observed-Adverse-Effect Level, Obesity metabolism
- Abstract
Although obesity is increasing worldwide, experimental studies examining the possible association between obesity and susceptibility to chemical toxicity are limited. In the present study, we performed a 13-week toxicity study for acetaminophen (APAP), a well-known drug that exhibits hepatotoxicity as an adverse effect, using an obese rat model to investigate the differences in susceptibility between obese and normal individuals. Male F344 and obese Zucker (lean and fatty) rats were administered 0, 80, 253, 800, 2,530, or 8,000 ppm APAP in the diet for 13 weeks. No significant toxicity related to APAP treatment was observed in terms of clinical signs and hematology in all three strains. Body weight gain in F344 and lean rats was significantly decreased by 8,000 ppm APAP treatment. Significant increases in serum total cholesterol level and relative liver weights were detected in F344 rats in the highest dose group. On histopathological assessment, centrilobular hepatocellular hypertrophy was observed in the 8,000 ppm groups of F344 and lean rats, whereas no histopathological changes were induced by APAP in fatty rats. The no-observed-adverse-effect levels (NOAELs) of APAP were evaluated to be 2,530 ppm in F344 and lean rats (142.1 and 152.8 mg/kg bw/day, respectively) and more than 8,000 ppm in fatty rats (> 539.9 mg/kg bw/day). These results suggested that obese Zucker rats may be less susceptible to APAP-dependent toxicity in the liver than their lean counterparts.
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- 2018
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14. Validating the use of napsin A as a marker for identifying tumorigenic potential of lung bronchiolo-alveolar hyperplasia in rodents.
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Yokohira M, Nakano-Narusawa Y, Yamakawa K, Hashimoto N, Yoshida S, Kanie S, and Imaida K
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- Adenocarcinoma, Bronchiolo-Alveolar metabolism, Animals, Bronchioles pathology, Carcinogenesis metabolism, Carcinogens toxicity, Female, Hyperplasia pathology, Lung Neoplasms metabolism, Male, Mice, Pulmonary Alveoli pathology, Rats, Inbred F344, Reproducibility of Results, Adenocarcinoma, Bronchiolo-Alveolar pathology, Aspartic Acid Endopeptidases metabolism, Biomarkers, Tumor metabolism, Carcinogenesis pathology, Lung Neoplasms pathology
- Abstract
There are two types of bronchiolo-alveolar hyperplasia (hyperplasia) in rodent lungs. The first is "inflammatory hyperplasia" that retains its ability to revert to normal epithelia upon removal of the stimulating insult. The second is "latent tumorigenic hyperplasia", which is irreversible and causes independent preneoplastic lesions that can progress to bronchiolo-alveolar adenocarcinoma. Previously, lung samples with hyperplastic lesions were obtained from rats exposed to N-bis (2-hydroxypropyl) nitrosamine (DHPN) and fine particles (e.g. quartz), and 19 specific markers were examined immunohistochemically to identify latent tumorigenic hyperplasia. In the cytoplasm of the cells that make up the alveolar wall, we found that napsin A was weakly expressed in the inflammatory hyperplastic lesions, and was strongly expressed in the latent tumorigenic hyperplastic lesions induced by DHPN. To validate the possibility that napsin A may serve as a tumorigenic hyperplastic marker, additional experiments were performed with rats and mice. Latent tumorigenic hyperplasia induced by various carcinogens were positive for napsin A, similar to hyperplasia induced by DHPN. Thus, high expression of napsin A in alveolar walls may serve as a useful marker for detecting the tumorigenic potential of lung hyperplasia in rodents., (Copyright © 2017 Elsevier GmbH. All rights reserved.)
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- 2017
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15. Hepatocyte growth factor produced in lung fibroblasts enhances non-small cell lung cancer cell survival and tumor progression.
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Kanaji N, Yokohira M, Nakano-Narusawa Y, Watanabe N, Imaida K, Kadowaki N, and Bandoh S
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- Animals, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Cell Survival physiology, Fibroblasts pathology, Humans, Lung metabolism, Lung pathology, Lung Neoplasms pathology, Mice, Mice, Inbred BALB C, Mice, Nude, Xenograft Model Antitumor Assays methods, Carcinoma, Non-Small-Cell Lung metabolism, Fibroblasts metabolism, Hepatocyte Growth Factor biosynthesis, Lung Neoplasms metabolism
- Abstract
Background: The influence of lung fibroblasts on lung cancer progression is not fully understood., Methods: Lung fibroblasts (HFL1, MRC5, and IMR90 cells) and non-small cell lung cancer (NSCLC)-derived cell lines (A549, EBC1, and HI1017) were cultured under serum-free conditions, and the resulting culture media were designated "cell-conditioned media". Cell survival (viability) was assessed by WST-1 assay. Concentrations of hepatocyte growth factor (HGF) were measured by ELISA. The BALB/c-nu mouse strain was used for the xenograft model., Results: Lung fibroblast-conditioned media enhanced the survival of the three NSCLC cell lines tested. HGF was produced to a greater extent by lung fibroblasts than NSCLC cells. Exogenous HGF enhanced the survival of NSCLC cells. Either an anti-HGF neutralizing antibody or the Met inhibitor PHA-665752 inhibited the fibroblast-conditioned media-enhanced survival of NSCLC cells. The co-inoculation of mice with NSCLC cells and fibroblasts enhanced tumorigenicity and tumor progression in a mouse xenograft model. PHA-665752 significantly inhibited tumor progression that occurred after the co-inoculation of NSCLC cells and fibroblasts. In addition, HGF production by fibroblasts was stimulated by NSCLC cells., Conclusions: The current study provides evidence for an interaction between fibroblasts and NSCLC cells via the HGF/Met signaling pathway, which affects NSCLC cell survival and tumor progression. These findings may contribute to the development of anti-cancer-associated fibroblast therapeutic strategies., Trial Registration: No trial registration is required because this study is not a clinical trial. This study does not include any participants or patients.
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- 2017
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16. Suppressive effects of the expectorant drug ambroxol hydrochloride on quartz-induced lung inflammation in F344 rats.
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Kanie S, Yokohira M, Yamakawa K, Nakano-Narusawa Y, Yoshida S, Hashimoto N, and Imaida K
- Abstract
Surfactant proteins (SPs) are essential to respiratory structure and function. The expectorant drug ambroxol hydrochloride is clinically prescribed to stimulate pulmonary surfactant and airway serous secretion. Therefore, ambroxol hydrochloride may affect SP production and pulmonary inflammation. Lung toxicity of fine particles of various materials has been examined previously in our in vivo bioassay using the intratracheal (i.t.) instillation approach. In the present study, we evaluated modulatory effects of ambroxol hydrochloride on quartz-induced lung inflammation in F344 rats. Male 6-week-old F344 rats were exposed by i.t. instillation to 2 mg of quartz particles suspended in 0.2 mL of saline. Ambroxol hydrochloride was administered at 0, 12, and 120 ppm in rat basal diet for 28 days, and then formalin-fixed paraffin-embedded lung, liver, and kidney samples were prepared. No changes in general condition, body and organ weights, or food consumption upon exposure to quartz were noted. The mean ambroxol intake in rats of the 12 ppm group was comparable to the human conventional dose. Histopathology of lung lesions was evaluated, and the degree of inflammation was scored. At 120 ppm, ambroxol hydrochloride significantly decreased individual lung inflammation scores for pulmonary edema and lymph follicle proliferation around the bronchiole, as well as the total inflammation score, in quartz-treated rats. Expression of SP-C in the type II alveolar cells and macrophages was greater in inflammatory lesions than in non-inflamed areas. Ambroxol treatment did not affect expression of SP-B and SP-C. In conclusion, we demonstrated that ambroxol hydrochloride relieves quartz-induced lung inflammation.
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- 2017
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17. Altered susceptibility of an obese rat model to 13-week subchronic toxicity induced by 3-monochloropropane-1,2-diol.
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Toyoda T, Cho YM, Akagi JI, Mizuta Y, Matsushita K, Nishikawa A, Imaida K, and Ogawa K
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- Animals, Disease Models, Animal, Epididymis drug effects, Epididymis pathology, Food Contamination, Hematologic Tests, Kidney drug effects, Kidney pathology, Male, No-Observed-Adverse-Effect Level, Rats, Inbred F344, Rats, Zucker, Toxicity Tests, Subchronic, Obesity blood, Obesity pathology, alpha-Chlorohydrin toxicity
- Abstract
3-Monochloropropane-1,2-diol (3-MCPD) is a heat-induced food contaminant that has been shown to be a nongenotoxic renal carcinogen. Although the toxicity of 3-MCPD has been widely investigated for decades, there is a further concern that 3-MCPD might exert more potent toxicity in high-risk population with underlying diseases such as hyperlipidemia associated with obesity. In the present study, we performed a 13-week subchronic toxicity study for 3-MCPD using an obesity rat model to investigate the differences in susceptibility between obese and normal individuals. Male F344 and obese Zucker (lean and fatty) rats were administered 0, 9, 28.5, 90, 285, or 900 ppm 3-MCPD in drinking water for 13 weeks. 3-MCPD treatment decreased body weight gain, increased relative kidney weights, induced anemia, and induced epithelial cell necrosis in epididymal ducts in all 3 strains. The degrees of epididymal damage were higher in F344 and lean rats than in fatty rats, while renal toxicity was most potent in F344 rats and comparable in lean and fatty rats. In contrast, the hematology data indicated that anemia was worse in fatty rats than in F344 and lean rats, and a significant decrease in hematopoietic cells in the bone marrow was observed only in fatty rats. The no-observed-adverse-effect level was estimated to be 28.5 ppm in all 3 strains for 3-MCPD. These results suggested that obese Zucker rats may be more susceptible to 3-MCPD-dependent toxicity in the hematopoietic tissues than their lean counterparts.
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- 2017
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18. Chronic mesothelial reaction and toxicity of potassium octatitanate fibers in the pleural cavity in mice and F344 rats.
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Yokohira M, Nakano-Narusawa Y, Yamakawa K, Hashimoto N, Yoshida S, Kanie S, and Imaida K
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- Animals, Body Weight drug effects, Female, Kidney drug effects, Kidney pathology, Liver drug effects, Liver pathology, Lung drug effects, Lung pathology, Male, Mesothelioma pathology, Mice, Mice, Inbred Strains, Nitrosamines toxicity, Organ Size drug effects, Particle Size, Pleural Cavity pathology, Rats, Rats, Inbred F344, Species Specificity, Titanium chemistry, Mesothelioma chemically induced, Pleural Cavity drug effects, Titanium toxicity
- Abstract
Fiber-shaped particles of potassium octatitanate (tradename TISMO; chemical formula K2 O·6TiO2 ), which are morphologically similar to asbestos particles, were shown to induce severe proliferative reactions in the pleural mesothelium in a previous experiment carried out over 21 weeks. The present study aims to determine whether these fibers induce malignant mesotheliomas in rodents, and to examine chronic toxicity induced. Additionally, we investigated the specific differences observable between the biological responses to the direct infusion of the fibers alone into the pleural cavity and those induced by the co-administration of the fibers with a known carcinogen. To detect the induction of malignant pleural mesotheliomas, two experiments were undertaken. In Experiment 1, four strains of mice, A/J, C3H, ICR, and C57BL, were examined for 52 weeks after experimental treatment with TISMO. In Experiment 2, the F344 rats were treated with TISMO alone, the lung carcinogen N-bis (2-hydroxypropyl) nitrosamine (DHPN) alone, both TISMO and DHPN, or left untreated and were then examined for 52 weeks. In this experiment, malignant lesion induction was expected in the co-administration group. TISMO fibers were observed in the alveoli, indicating penetration through the visceral pleura in mice and rats. The histopathological detection of TISMO fibers in the liver and kidneys of mice and rats indicated migration of the fibers out of the pleural cavity. Atypical mesothelial cells with severe pleural proliferation were observed, but malignant mesotheliomas were not detected. Among the rats, there were no observed malignant alterations in the mesothelium induced by DHPN-TISMO co-administration., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
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- 2016
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19. Activation of MEK1/2-ERK1/2 signaling during NNK-induced lung carcinogenesis in female A/J mice.
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Yamakawa K, Yokohira M, Nakano Y, Kishi S, Kanie S, and Imaida K
- Subjects
- Adenocarcinoma chemically induced, Adenocarcinoma enzymology, Adenocarcinoma genetics, Adenocarcinoma of Lung, Adenoma chemically induced, Adenoma enzymology, Adenoma genetics, Animals, Cell Transformation, Neoplastic, Enzyme Activation genetics, Female, Lung Neoplasms chemically induced, Lung Neoplasms genetics, MAP Kinase Kinase Kinase 1 metabolism, MAP Kinase Kinase Kinase 2 metabolism, MAP Kinase Signaling System genetics, Mice, Inbred A, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Mutation, Nitrosamines, Proliferating Cell Nuclear Antigen metabolism, Proto-Oncogene Proteins p21(ras) genetics, Lung Neoplasms enzymology, MAP Kinase Signaling System physiology
- Abstract
The extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway is activated by several growth factors and mitogens, and upregulation has been noted in many human cancers, including examples in the lung. In this study, to study the association of ERK1/2 activation with mutation of Kras encoding an upstream activator of ERK1/2 in lung premalignant lesions, we immunohistochemically examined expression of phosphorylated forms of ERK1/2 (pERK1/2) and MAP/ERK kinase 1/2 (pMEK1/2) proteins and correlation between ERK activation and mutation of Kras encoding an upstream activator of ERK1/2, in a mouse lung carcinogenesis model. Female 7-week-old A/J mice were administered a single dose of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), then maintained without additional treatment until sacrifice at week 52. Histopathologically, adenocarcinomas, adenomas and hyperplasias were observed in the lung. pMEK1/2 was expressed mostly in the cell cytoplasm in all three. In contrast, pERK1/2-positive cells were also relatively rare in any histological types as compared with level of pMEK1/2 expression. However, pERK1/2-positive cells in adenocarcinoma were still markedly more common than in hyperplasias and adenomas (~5-fold, ~4-fold; P < 0.01). Activating mutations of Kras gene at codons 12, 13 and 61 were detected in the majority of adenomas and adenocarcinomas, but without any significant relation to pERK1/2 expression. These results suggest that activation of ERK1/2 plays a key role in malignant transformation during lung carcinogenesis featuring Kras mutaion. Activation of ERK1/2 in lung premalignant lesions was little regardless of the mutation of Kras, and ERK1/2 activation in NNK-induced mouse lung carcinogenesis may be regulated not only by Kras mutation but also other signaling pathway or regulatory factor., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
- Published
- 2016
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20. An Autopsy Case of Rapidly Progressing Spindle Cell Carcinoma of the Lung Accompanied with Intratumor Hemorrhage.
- Author
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Kida J, Kanaji N, Kishi S, Imaida K, and Bandoh S
- Subjects
- Aged, Autopsy, Carcinoma blood supply, Carcinoma complications, Fatal Outcome, Hemorrhage diagnosis, Humans, Lung Neoplasms blood supply, Lung Neoplasms complications, Male, Neoplasm Staging, Tomography, X-Ray Computed, Carcinoma diagnosis, Hemorrhage etiology, Lung Neoplasms diagnosis
- Abstract
Background: Spindle cell carcinoma (SPCC) of the lung is a subset of sarcomatoid carcinoma. Its clinical features are unclear because of its rarity. Here, we report an autopsy case of SPCC and review CT findings and chemotherapeutic regimens based on previous reports of this disease. To our knowledge, this is the first reported case of pemetrexed used to treat SPCC., Case Report: A 74-year-old Japanese male presented with dyspnea and contrast-enhanced computed tomography (CT) showed abundant left pleural effusion and a mass in lower lobe of the left lung. By the tumor biopsy, he was diagnosed for SPCC of the lung, cT3N0M1a, stage IV. The tumor was resistant to chemotherapy with carboplatin and pemetrexed, and rapidly progressed. Autopsy revealed abundant hemorrhage within the tumor, which apparently reflects a low-density area in CT., Conclusions: Present case and the accumulation of cases indicate that low-density areas in CT and rapid tumor progression may be common SPCC findings.
- Published
- 2015
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21. Long-Term Chronic Toxicity and Mesothelial Cell Reactions Induced by Potassium Octatitanate Fibers (TISMO) in the Left Thoracic Cavity in A/J Female Mice.
- Author
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Yokohira M, Hashimoto N, Nakagawa T, Nakano Y, Yamakawa K, Kishi S, Kanie S, Ninomiya F, Saoo K, and Imaida K
- Subjects
- Animals, Epithelial Cells metabolism, Female, Kidney drug effects, Kidney metabolism, Liver cytology, Liver drug effects, Liver metabolism, Lung drug effects, Lung metabolism, Lung Neoplasms chemically induced, Lung Neoplasms diagnosis, Mesothelioma chemically induced, Mesothelioma diagnosis, Mesothelioma, Malignant, Mice, Mice, Inbred A, Organ Size drug effects, Spleen drug effects, Spleen metabolism, Thoracic Cavity metabolism, Toxicity Tests, Chronic, Epithelial Cells drug effects, Pleura drug effects, Thoracic Cavity drug effects, Titanium toxicity
- Abstract
The present study was conducted to examine the chronic effects of potassium octatitanate fibers (trade name TISMO; chemical formula K2O·6TiO2) on the mouse lung and thoracic cavity. This method of infusion was employed to examine the direct effects of the fibers to the pleura. In the present study, 52- and 65-week experiments were employed to examine the long-term chronic effects after infusion of fiber-shaped TISMO into the thoracic cavities of A/J mice. Following this infusion, TISMO fibers were observed in the alveoli, indicating penetration through the visceral pleura. The additional histopathological detection of TISMO fibers in the liver, spleen, kidneys, ovary, heart, bone marrow, and brain of TISMO-infused mice indicated migration of the fibers out from the thoracic cavity. Atypical mesothelial cells with severe pleural proliferation were observed, but malignant mesotheliomas were not detected. This study demonstrated that intrathoracic infusion of TISMO fiber did not cause malignant mesothelioma but did cause severe chronic inflammation and proliferation of pleural mesothelial cells., (© The Author(s) 2015.)
- Published
- 2015
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22. Significance of the progesterone receptor and epidermal growth factor receptor, but not the estrogen receptor, in chemically induced lung carcinogenesis in female A/J mice.
- Author
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Kishi S, Yokohira M, Yamakawa K, Saoo K, and Imaida K
- Abstract
In the present study, the expression levels of female hormone receptors, estrogen receptor (ER) and progesterone receptor (PR) and the epidermal growth factor receptor, (EGFR), as well as proliferating cell nuclear antigen (PCNA) were examined in lung tumors that were induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in female A/J mice. Each seven-week-old mouse was administered with 2 mg NNK via intraperitoneal injection and the mice were subsequently euthanized at week 52. Lung tumors, including adenomas, carcinomas in adenomas and adenocarcinomas, were obtained and analyzed by immunohistochemistry for the expression levels of the receptors, ER, PR and EGFR, and PCNA. The results were as follows: i) In mouse lung adenomas, a significant correlation was identified between the size of the tumor and PCNA expression, although not with the expression of the receptors (ER, PR and EGFR); ii) in the carcinoma components of the carcinomas in adenomas, the size of the tumor and PCNA expression were correlated, while EGFR expression demonstrated a significant correlation with PR expression; iii) in adenocarcinomas, the tumor size significantly correlated with PCNA, EGFR and PR expression; and iv) EGFR and PR expression was identified to be significantly correlated in adenocarcinomas, and to a certain extent in the carcinoma components of the carcinomas in adenomas, although not in the adenomas. Notably, ER expression was not associated with tumor growth or the other factors, particularly EGFR expression, and no significant differences were identified between the three types of lesion. These results indicate that PR, like EGFR, may be significant in lung carcinogenesis.
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- 2014
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23. Immunohistochemical characteristics of surfactant proteins a, B, C and d in inflammatory and tumorigenic lung lesions of f344 rats.
- Author
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Yokohira M, Yamakawa K, Nakano Y, Numano T, Furukawa F, Kishi S, Ninomiya F, Kanie S, Hitotsumachi H, Saoo K, and Imaida K
- Abstract
Surfactant proteins (SPs), originally known as human lung surfactants, are essential to respiratory structure and function. There are 4 subtypes, SP-A, SP-B, SP-C and SP-D, with SP-A and SP-D having immunological functions, and SP-B and SP-C having physicochemical properties that reduce the surface tension at biological interfaces. In this experiment, the expressions of SP-A, SP-B, SP-C and SP-D in lung neoplastic lesions induced by N-bis (2-hydroxypropyl) nitrosamine (DHPN) and inflammatory lesions due to quartz instillation were examined and compared immunohistochemically. Formalin fixed paraffin embedded (FFPE) lung samples featuring inflammation were obtained with a rat quartz instillation model, and neoplastic lesions, hyperplasias and adenomas, were obtained with the rat DHPN-induced lung carcinogenesis model. In the rat quartz instillation model, male 10-week old F344 rats were exposed by intratracheal instillation (IT) to quartz at a dose of 2 mg/rat suspended in saline (0.2 ml) on day 0, and sacrificed on day 28. Lung tumorigenesis in F344 male rats was initiated by DHPN in drinking water for 2 weeks, and the animals were then sacrificed in week 30. Lung proliferative lesions, hyperplasias and adenomas, were observed with DHPN, and inflammation was observed with quartz. The expressions of SP-A, SP-B, SP-C and SP-D were examined immunohistochemically. SP-B and SP-C showed strong expression in lung hyperplasias and adenomas, while SP-A and SP-D were observed in mucus or exudates in inflammatory alveoli. These results suggest the possibility that SP-B and SP-C are related to lung tumorigenesis.
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- 2014
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24. Rat strain differences in levels and effects of chronic inflammation due to intratracheal instillation of quartz on lung tumorigenesis induced by DHPN.
- Author
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Nakano Y, Yokohira M, Hashimoto N, Yamakawa K, Kishi S, Ninomiya F, Kanie S, Saoo K, and Imaida K
- Subjects
- Animals, Carcinogenesis chemically induced, Carcinogenesis pathology, Carcinogens toxicity, Lung drug effects, Lung Neoplasms genetics, Male, Nitrosamines toxicity, Rats, Rats, Inbred F344, Rats, Sprague-Dawley, Rats, Wistar, Carcinogenesis genetics, Inflammation chemically induced, Inflammation complications, Lung Neoplasms etiology, Quartz toxicity
- Abstract
Chronic inflammatory effects of single intratracheal instillation (i.t.) of quartz on rat lung tumorigenesis were examined using 4 different animal models. At first, in order to determine an appropriate dose of quartz i.t. to promote lung tumorigenesis, F344 male rats were administrated single 0, 0.5, 1, 2 or 4 mg quartz/rat after initiation by N-bis(2-hydroxypropyl) nitrosamine (DHPN). Further studies were performed to examine strain differences of the effects of chronic inflammation caused by quartz i.t. in 3 strains of rat, i.e. F344, Wistar-Hannover and SD. Each was instilled with 2mg quartz/rat after DHPN administration and sacrificed in week 24. In addition, strain differences in generation of inflammation were determined at days 1 and 28. Finally, for determination of long-term effects period, F344 and Wistar-Hannover rats were similarly treated, but the experiment was terminated at week 52. In F344 rats, the tumor areas in DHPN treated groups showed a tendency to increase along with the dose of quartz. F344 rats demonstrated the highest and Wistar-Hannover rats the lowest sensitivity to quartz in acute and chronic phases in the 3 strains. In 52 week, in F344 rats, the multiplicity of tumors and the serum concentration of IL-6 in the group treated with DHPN and quartz were significantly increased. The present experiments indicated that chronic inflammation due to quartz instillation exerted promoting effects on lung carcinogenesis in F344, SD and Wistar-Hannover rats. The strain differences in tumor promotion appeared to correlate with inflammatory reactions to quartz and increase of IL-6., (Copyright © 2014 Elsevier GmbH. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
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