{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T08:08:32Z","timestamp":1792570112430,"version":"4.5.0"},"reference-count":38,"publisher":"American Physiological Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"published-print":{"date-parts":[[2011,3]]},"abstract":"<jats:p>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 \u03b2-galactosidase staining and immunohistochemical detection of p21 were performed to evaluate cellular senescence. As a model for transforming growth factor (TGF)-\u03b2-induced senescence of abnormal reepithelialization, we used primary human bronchial epithelial cells (HBEC). The changes of SIRT6, p21, and interleukin (IL)-1\u03b2 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-\u03b2 induced senescence in primary HBEC by increasing p21 expression, and, whereas TGF-\u03b2 also induced SIRT6, it was not sufficient to inhibit cellular senescence. However, overexpression of SIRT6 efficiently inhibited TGF-\u03b2-induced senescence via proteasomal degradation of p21. TGF-\u03b2-induced senescent HBEC secreted increased amounts of IL-1\u03b2, 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.<\/jats:p>","DOI":"10.1152\/ajplung.00097.2010","type":"journal-article","created":{"date-parts":[[2010,12,17]],"date-time":"2010-12-17T22:35:23Z","timestamp":1292625323000},"page":"L391-L401","source":"Crossref","is-referenced-by-count":301,"title":["Accelerated epithelial cell senescence in IPF and the inhibitory role of SIRT6 in TGF-\u03b2-induced senescence of human bronchial epithelial cells"],"prefix":"10.1152","volume":"300","author":[{"given":"Shunsuke","family":"Minagawa","sequence":"first","affiliation":[{"name":"Division of Respiratory Diseases, Department of Internal Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Araya","sequence":"additional","affiliation":[{"name":"Division of Respiratory Diseases, Department of Internal Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanori","family":"Numata","sequence":"additional","affiliation":[{"name":"Division of Respiratory Diseases, Department of Internal Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoko","family":"Nojiri","sequence":"additional","affiliation":[{"name":"Division of Respiratory Diseases, Department of Internal Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromichi","family":"Hara","sequence":"additional","affiliation":[{"name":"Division of Respiratory Diseases, Department of Internal Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Yumino","sequence":"additional","affiliation":[{"name":"Division of Respiratory Diseases, Department of Internal Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Kawaishi","sequence":"additional","affiliation":[{"name":"Division of Respiratory Diseases, Department of Internal Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Odaka","sequence":"additional","affiliation":[{"name":"Division of Chest Diseases, Department of Surgery, Jikei University School of Medicine, Tokyo, Japan; 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