Accelerated epithelial cell senescence in IPF and the inhibitory role of SIRT6 in TGF-ß-induced senescence of human bronchial epithelial cells.

Reepithelialization of remodeled air spaces with bronchial epithelial cells is a prominent pathological finding in idiopathic pulmonary fibrosis (IPF) and is implicated in IPF pathogenesis. Recent studies suggest that epithelial senescence is a risk factor for development of IPF, indicating such reepithelialization may be influenced by the acceleration of cellular senescence. Among the sirtuin (SIRT) family, SIRT6, a class III histone deacetylase, has been demonstrated to antagonize senescence. We evaluated the senescence of bronchiolization in association with SIRT6 expression in IPF lung. Senescence-associated ß-galactosidase staining and immunohistochemical detection of p21 were performed to evaluate cellular senescence. As a model for transforming growth factor (TGF)-ß-induced senescence of abnormal reepithelialization, we used primary human bronchial epithelial cells (HBEC). The changes of SIRT6, p21, and interleukin (IL)-1ß expression levels in HBEC, as well as type I collagen expression levels in fibroblasts, were evaluated. In IPF lung samples, an increase in markers of senescence and SIRT6 expression was found in the bronchial epithelial cells lining cystically remodeled air spaces. We found that TGF-ß induced senescence in primary HBEC by increasing p21 expression, and, whereas TGF-ß also induced SIRT6, it was not sufficient to inhibit cellular senescence. However, overexpression of SIRT6 efficiently inhibited TGF-ß-induced senescence via proteasomal degradation of p21. TGF-ß-induced senescent HBEC secreted increased amounts of IL-1ß, which was sufficient to induce myofibroblast differentiation in fibroblasts. These findings suggest that accelerated epithelial senescence plays a role in IPF pathogenesis through perpetuating abnormal epithelial-mesenchymal interactions, which can be antagonized by SIRT6.

[A case of pericardial malignant mesothelioma accompanied by primary lung adenocarcinoma].

A 63-year-old man was admitted to Jikei University Hospital, with anasarca, and dyspnea in May, 2004. Echocardiograms and CT scans showed massive pericardial effusion, nodules on the pericardium and a tumor in the lower lobe of the left lung. Pathological examination of the punctured pericardial effusions yielded a diagnosis of pericardial malignant mesothelioma. However, no pathogen or malignant cells were identified from multiple biopsy specimens of the lung tumor, which were obtained by brochoscopic techniques. Since he worked as a fisherman in a diesel-powered fishing boat, he was possibly exposed to asbestos. On autopsy, the lung tumor was diagnosed as a primary lung adenocaricinoma. Exposure to asbestos is an important risk factor for both mesothelioma and lung cancer. However, pericardial malignant mesothelioma in itself is rare among mesothelioma. This is only the second report of malignant mesothelioma with primary lung adenocarcinoma, to date.

[Case of agranulocytosis associated with thymoma].

A 75-year-old-woman had undergone extended thymectomy, right upper and middle lobe resection, and radiation therapy (40 Gy) for thymoma at the age of 63. She visited our hospital complaining of low grade fever, cough, anorexia and a sore throat. Peripheral blood count revealed agranulocytosis. Agranulocytosis associated with thymoma was diagnosed, because there were no other possible causes of agranulocytosis such as drugs, infection, recent radiation therapy, or bone marrow invasion. In spite of giving G-CSF, steroid therapy and immunosuppressants, she died of pneumonia caused by agranulocytosis. We consider that agranulocytosis is a very rare complication of thymoma.