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1.
Exp Toxicol Pathol ; 66(4): 169-77, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24480153

ABSTRACT

The airway epithelium serves as a biological barrier essential for host defense against inhaled pollutants. While chronic epithelial injury, commonly associated with chronic obstructive pulmonary disease and bronchiolitis obliterans syndrome, often results in airway fibrosis, limited animal models of airway fibrosis have been established. Club cells (Clara cells) in the small airways represent an important population of epithelial progenitor cells and also the principal site of localization of the cytochrome P-450 monooxygenase system, which metabolically activates xenobiotic chemicals such as naphthalene by converting them to toxic epoxide intermediates. We hypothesized that repeated exposure to naphthalene may cause prolonged loss of club cells, triggering aberrant local epithelial repair mechanisms that lead to peribronchial fibrosis. We administered intraperitoneal injections of naphthalene to C57/BL6J mice once a week for 14 consecutive weeks. Repeated club cell injury caused by naphthalene triggered regional hyperproliferation of epithelial progenitor cells, while other regions remained denuded or squamated, resulting in fibroblast proliferation and peribronchial collagen deposition associated with upregulation of the fibrogenic cytokines transforming growth factor-ß and connective tissue growth factor. The total collagen content of the lung assessed by measurement of the hydroxyproline content was also increased after repeated exposure to naphthalene. These results lend support to the relevance of repeated injury of airway epithelial cells as a trigger for resting fibroblast proliferation and airway fibrosis. This model of airway fibrosis is simple and easy to reproduce, and may be expected to advance our understanding of the pathogenesis and potential treatment of airway fibrotic disorders.


Subject(s)
Environmental Pollutants/toxicity , Naphthalenes/toxicity , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/pathology , Respiratory Mucosa/drug effects , Animals , Cell Proliferation/drug effects , Connective Tissue Growth Factor/biosynthesis , Connective Tissue Growth Factor/immunology , Disease Models, Animal , Dose-Response Relationship, Drug , Fibroblasts/drug effects , Fibroblasts/pathology , Injections, Intraperitoneal , Male , Mice , Mice, Inbred C57BL , Pulmonary Fibrosis/immunology , Respiratory Mucosa/immunology , Respiratory Mucosa/pathology , Transforming Growth Factor beta/biosynthesis , Transforming Growth Factor beta/immunology
2.
Exp Toxicol Pathol ; 65(7-8): 1053-62, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23688655

ABSTRACT

Bleomycin produces DNA damage, apoptosis and senescence, all of which play crucial roles in the development of pulmonary fibrosis. Recently, close attention has been paid to a DNA damage-induced phenotypic change (senescence-associated secretory phenotype; SASP) as a trigger for the secretion of various mediators which modify the processes of tissue injury, inflammation, repair and fibrosis. We characterized the SASP in a murine model of bleomycin-induced lung injury. Mice were intratracheally administered bleomycin or control saline, and the lungs were obtained on days 7, 14 and 21. The occurrence of DNA damage and the SASP in the lungs was examined by immunostaining. γH2AX immunostaining of the bleomycin-treated lungs revealed double-strand breaks (DSBs), largely within E-cadherin-positive, ß4-integirn-positive alveolar epithelial cells. The DSBs were associated with phosphorylation of ATM/ATR, a central signal transducer mediating the DNA damage response, and upregulation of the cyclin-dependent kinase inhibitor p21(CIP1). The DSBs persisted for at least 21 days after the bleomycin exposure, although it began to wane after 7 days. A subpopulation of the γH2AX-positive, DNA-damaged cells exhibited the SASP, characterized by overexpression of IL-6, TNFα, MMP-2 and MMP-9, in association with the phosphorylation of IKKα/ß and p38 MAPK. Persistent DNA damage and the SASP are induced in the process of bleomycin-induced lung injury and repair, suggesting that these events play an important role in the regulation of inflammation and tissue remodeling in bleomycin-induced pneumopathy.


Subject(s)
Antibiotics, Antineoplastic/toxicity , Bleomycin/toxicity , Cellular Senescence/drug effects , Lung Injury/metabolism , Animals , DNA Damage/drug effects , Disease Models, Animal , Immunohistochemistry , Male , Mice , Mice, Inbred C57BL , Phenotype
3.
J Med Case Rep ; 7: 71, 2013 Mar 14.
Article in English | MEDLINE | ID: mdl-23497480

ABSTRACT

INTRODUCTION: Although the brain is a common site of metastasis from lung cancer, pineal region metastasis from lung adenocarcinoma is rare. Most cases of pineal metastases are asymptomatic, and are diagnosed by autopsy. Therefore, the management of pineal region tumors remains controversial. Here, we present a rare case of lung carcinoma presenting with pineal region metastasis and obstructive hydrocephalus as the first manifestation of the lung adenocarcinoma. CASE PRESENTATION: A 63-year-old Japanese woman was referred to our hospital for treatment of a tumor of the pineal region associated with hydrocephalus. On admission, she was found to have a mass in her right lung on a chest radiograph. During the preoperative investigation, the patient began to show a progressively worsening level of altered consciousness. Therefore, neuroendoscopic surgery was performed as an emergency procedure, which resulted in improvement of the hydrocephalus and diagnosis of adenocarcinoma. A systematic investigation revealed adenocarcinoma of her right lung as the primary lesion. She was treated by a platinum-based chemotherapy regime. Stereotactic radiation to the pineal region was undertaken concurrently. After completion of the chemotherapy, the primary lesion and pineal region metastasis showed good partial response. CONCLUSION: The prognosis of pineal region metastasis is extremely poor, and only three patients with metastatic pineal region metastasis from lung cancer who were treated by chemotherapy have been reported. We performed neuroendoscopic surgery to obtain resolution of the obstructive hydrocephalus and the definite histological diagnosis. This resulted in improvement of the general condition of the patient, and the patient could be treated by chemotherapy and radiotherapy. We strongly believe that neuroendoscopic surgery was a good option in this case. This case report suggests that in the presence of an isolated pineal region tumor, metastasis should be considered a possible diagnosis, and careful examination for systemic malignant disease will be needed.

4.
Pulm Pharmacol Ther ; 24(4): 401-6, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21300166

ABSTRACT

BACKGROUND: Tacrolimus (TAC) was approved in Japan in 2005 for rheumatoid arthritis (RA) patients having inadequate response to other disease-modifying anti-rheumatic drugs. As of May 2007, spontaneous reports identified twenty-seven cases of exacerbation or new development of interstitial pneumonia among RA patients given TAC in Japan. OBJECTIVE: To describe the clinical and radiological characteristics of TAC-induced pulmonary injury (TIPI). PATIENTS AND METHODS: Eleven RA patients diagnosed with de novo pulmonary injury or exacerbation of IP during treatment with TAC were identified. Clinical, radiological, and laboratory data of ten of these cases were retrospectively analyzed. RESULTS: Baseline data for the ten patients were a mean age of 69.7 years; gender, 70% female; mean RA disease duration, 9.1 years; and pulmonary comorbidities, 90%. Six cases were classified as presumptive TAC-induced pulmonary injury (TIPI) and four as probable TIPI. Among the six presumptive cases, TIPI developed at an average of 84 days after initiation of treatment (n = 5) or four days after reinstitution of TAC (n = 1). Five cases were an exacerbation of pre-existing interstitial pneumonia and one was a de novo pulmonary injury. Radiological patterns of thoracic computed tomography (CT) scans of patients in the presumptive TIPI cases were hypersensitivity pneumonia like-pattern (n = 3), ground-glass opacity (n = 2), and organizing pneumonia-pattern (n = 1). All patients with presumptive TIPI were treated with high dosage glucocorticosteroids and one received concomitant immunosuppressants. Two of the six presumptive TIPI patients died. CONCLUSION: Rheumatologists should be aware of this rare but potentially life-threatening adverse event in RA patients receiving TAC.


Subject(s)
Arthritis, Rheumatoid/drug therapy , Immunosuppressive Agents/adverse effects , Lung/drug effects , Tacrolimus/adverse effects , Aged , Aged, 80 and over , Female , Humans , Lung/pathology , Male , Middle Aged , Radiography, Thoracic , Tomography, X-Ray Computed
5.
Nihon Kokyuki Gakkai Zasshi ; 47(1): 81-5, 2009 Jan.
Article in Japanese | MEDLINE | ID: mdl-19198243

ABSTRACT

The chest radiograph of a 57-year-old man, complaining of paroxysmal dyspnea, suggested the probably of a tumor. Chest CT showed a tumor containing calcification, behind the left crus of the diaphragm. Chest MRI suggested lipid components and a cystic lesion within the tumor. Their findings were clinically compatible with posterior mediastinal teratoma. The pathological diagnosis of the surgically resected tumor was mature teratoma with neither malignant components nor thymic tissue. Study of past case reports suggests that posterior mediastinal teratomas should have less malignant characteristics than anterior mediastainal teratomas. Our case is the fifteenth case report in the Japanese literature, and accumulation of more cases is required.


Subject(s)
Mediastinal Neoplasms/diagnosis , Teratoma/diagnosis , Humans , Male , Middle Aged
6.
Cancer Sci ; 98(7): 992-9, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17459058

ABSTRACT

Directed movement of normal cells occurs when actin-related protein 2 and 3 complex (Arp2/3 complex) triggers the actin polymerization that forms lamellipodia immediately after binding to WAVE2. In order to determine whether the same mechanism correlates with liver metastasis from colorectal cancer, paired mirror sections of 154 cancer specimens (29 cases with liver metastasis and 125 cases without liver metastasis in which T factor, gender, primary tumor site, and age at operation were matched) were examined immunohistochemically for the localization of Arp2 and WAVE2. Expression of both Arp2 and WAVE2 was detected in the same cancer cells in 55 (35.7%) of the 154 cases, but not detected in the normal colonic epithelial cells. Univariate analysis showed that the colocalization was significantly predictive of liver metastasis (risk ratio [RR] 8.760. Likewise, histological grade (RR 2.46), lymphatic invasion (RR 9.95), and tumor budding (RR 4.00) were significant predictors. Among these, colocalization and lymphatic invasion were shown to be independent risk factors by multivariate analysis. Another 59 colorectal specimens were examined for mRNA expression of Arp2 by real time polymerase chain reaction. High mRNA levels of Arp2, that in situ hybridization revealed to be expressed by the cancer cells, were significantly associated with liver metastasis. However, its effect was absorbed by the influence of risk of the colocalization that is closely related to high expression of Arp2. These results indicate that the colocalization of Arp2 and WAVE2 is an independent risk factor for liver metastasis of colorectal carcinoma.


Subject(s)
Actin-Related Protein 2/physiology , Actin-Related Protein 3/physiology , Colorectal Neoplasms/pathology , Liver Neoplasms/secondary , Wiskott-Aldrich Syndrome Protein Family/physiology , Actin-Related Protein 2/genetics , Actin-Related Protein 3/genetics , Actins/physiology , Adenocarcinoma/blood supply , Adenocarcinoma/pathology , Colorectal Neoplasms/blood supply , DNA Primers , Female , Humans , Immunohistochemistry , In Situ Hybridization , Liver Neoplasms/blood supply , Liver Neoplasms/pathology , Male , Neoplasm Invasiveness , Polymerase Chain Reaction , RNA, Messenger/genetics , Wiskott-Aldrich Syndrome Protein Family/genetics
7.
Clin Cancer Res ; 12(8): 2449-54, 2006 Apr 15.
Article in English | MEDLINE | ID: mdl-16638851

ABSTRACT

PURPOSE: Highly invasive and metastatic cancer cells, such as adenocarcinoma of the lung cells, form irregular protrusions by assembling a branched network of actin filaments. In mammalian cells, the actin-related protein 2 and 3 (Arp2/3) complex initiates actin assembly to form lamellipodial protrusions by binding to Wiskott-Aldrich syndrome (WASP)/WASP family verproline-homologous protein 2 (WAVE2). In this study, colocalization of Arp2 and WAVE2 in adenocarcinoma of the lung was investigated to elucidate its prognostic value. EXPERIMENTAL DESIGN: Immunohistochemical staining of Arp2 and WAVE2 was done on mirror sections of 115 adenocarcinomas of the lung from pathologic stage IA to IIIA classes. Kaplan-Meier disease-free survival and overall survival curves were analyzed to determine the prognostic significance of the coexpression of Arp2 and WAVE2. RESULTS: Immunoreactivity for both Arp2 and WAVE2 was detected in the same cancer cells in 78 (67.8%) of the 115 lung cancer specimens. The proportion of cancer cells expressing both Arp2 and WAVE2 was significantly higher in cases with lymph-node metastasis (P = 0.0046), and significantly lower in bronchioloalveolar carcinomas (P < 0.0001). The patients whose cancer cells coexpressed them had a shorter disease-free survival time (P < 0.0001) and overall survival time (P < 0.0001). Multivariate Cox regression analysis revealed that coexpression of Arp2 and WAVE2 is an independent risk factor for tumor recurrence. CONCLUSIONS: Coexpression of Arp2 and WAVE2 is correlated with poorer patient outcome, and may be involved in the mechanism of cancer metastasis.


Subject(s)
Actin-Related Protein 2/biosynthesis , Adenocarcinoma/pathology , Lung Neoplasms/pathology , Wiskott-Aldrich Syndrome Protein Family/biosynthesis , Adenocarcinoma/metabolism , Aged , Disease-Free Survival , Female , Humans , Immunohistochemistry , Lung Neoplasms/metabolism , Male , Multivariate Analysis , Neoplasm Staging , Prognosis , Survival Analysis
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