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

Division of Respiratory Diseases, Dept. of Internal Medicine, Jikei Univ. School of Medicine, Tokyo, Japan.
AJP Lung Cellular and Molecular Physiology (Impact Factor: 4.08). 12/2010; 300(3):L391-401. DOI: 10.1152/ajplung.00097.2010
Source: PubMed


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 β-galactosidase staining and immunohistochemical detection of p21 were performed to evaluate cellular senescence. As a model for transforming growth factor (TGF)-β-induced senescence of abnormal reepithelialization, we used primary human bronchial epithelial cells (HBEC). The changes of SIRT6, p21, and interleukin (IL)-1β 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-β induced senescence in primary HBEC by increasing p21 expression, and, whereas TGF-β also induced SIRT6, it was not sufficient to inhibit cellular senescence. However, overexpression of SIRT6 efficiently inhibited TGF-β-induced senescence via proteasomal degradation of p21. TGF-β-induced senescent HBEC secreted increased amounts of IL-1β, 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.

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    • "Of note, there was no effect of LPS or SIRT6 inhibition on the expression of VCAM-1 or P-selection. Although there are no studies on SIRT6 and adhesion molecules, these studies are in support of the few other studies demonstrating that SIRT6 regulates inflammatory cytokines [26, 27]. "
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    ABSTRACT: A prominent feature of inflammatory diseases is endothelial dysfunction. Factors associated with endothelial dysfunction include proinflammatory cytokines, adhesion molecules, and matrix degrading enzymes. At the transcriptional level, they are regulated by the histone deacetylase sirtuin (SIRT) 1 via its actions on the proinflammatory transcription factor nuclear factor-κB (NF-κB). The role of SIRT6, also a histone deacetylase, in regulating inflammation in endothelial cells is not known. The aim of this study was to determine the effect of SIRT6 knockdown on inflammatory markers in human umbilical vein endothelial cells (HUVECs) in the presence of lipopolysaccharide (LPS). LPS decreased expression of SIRT6 in HUVECs. Knockdown of SIRT6 increased the expression of proinflammatory cytokines (IL-1β, IL-6, IL-8), COX-prostaglandin system, ECM remodelling enzymes (MMP-2, MMP-9 and PAI-1), the adhesion molecule ICAM-1, and proangiogenic growth factors VEGF and FGF-2; cell migration; cell adhesion to leukocytes. Loss of SIRT6 increased the expression of NF-κB, whereas overexpression of SIRT6 was associated with decreased NF-κB transcriptional activity. Taken together, these results demonstrate that the loss of SIRT6 in endothelial cells is associated with upregulation of genes involved in inflammation, vascular remodelling, and angiogenesis. SIRT6 may be a potential pharmacological target for inflammatory vascular diseases.
    Mediators of Inflammation 10/2012; 2012(10):597514. DOI:10.1155/2012/597514 · 3.24 Impact Factor
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    • "In a recent study by Minagawa et al. [72], β-gal-positive senescent epithelial cells and increased levels of p21 were demonstrated in lung biopsies of IPF patients, and also established, in vitro, that TGFβ plays a pivotal role in inducing lung epithelial cell senescence, and that the DNA repair specific sirtuin (SIRT), SIRT6 inhibited TGFβ-induced senescence. TGFβ is a pleiotropic growth factor involved in airway remodeling and fibrosis and has been shown to be an integral component of the pathologic network of lung diseases such as asthma and IPF [73, 74]. "
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    ABSTRACT: Streptococcus pneumonia, (Spn, the pneumococcus), is the leading cause of community-acquired pneumonia (CAP) and is responsible for 15-40% deaths in the elderly worldwide. A primed inflammatory status is a significant risk factor for the increased severity of infectious diseases among the elderly (≥65 years of age). Studies have shown that expression of host receptors that the pneumococci bind to invade the tissues are increased thereby increasing the susceptibility to pneumococcal challenge in aged mice. Cellular senescence, an age-related phenomenon that leads to cell cycle arrest may also contribute to increased inflammation in aged mice. Evidence of cellular senescence in aged lungs of humans and mice adds credits to the concept of inflammaging and enhanced bacterial ligands expression during aging. Furthermore, cell senescence has been shown to occur in age-associated lung pathologies such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) that may predispose the elderly to pathogenic assaults, including S. pneumoniae. This review highlights the aspects of: chronic inflammation in the aged population; contribution of cellular senescence to age-associated inflammation and their impact on host receptor expression; and, increased susceptibility of fibrosis and emphysematous lesions-bearing lungs to microbial infections.
    05/2012; 2012:267101. DOI:10.5402/2012/267101
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    • "Fibroblast transition to myofibroblast is a common denominator for pathologic fibrosis1 and tumor stroma9–11. In addition, pathological organ fibrosis share several common pathways and biological processes, like TGF-β, MAPK, and PDGF activation; epithelial-to-mesenchymal transition (EMT); metalloproteinase (MMP) activation; mechanical tension; oxidative stress; and inflammation5,6,12–18. "
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    ABSTRACT: Unlabelled: Fibroproliferative diseases of organs are poorly understood and generally lack effective anti-fibrotic treatments. Our goal was to identify the key regulatory factors in pathologic fibrosis, common between organ-based fibrotic disease. We analyzed 9 microarray datasets publicly available in the GEO datasets from lung, heart, liver and kidney fibrotic disease tissue (489 microarrays total, disease and control). We identified a set of 90 genes differentially expressed in at least five microarray datasets. We used IPA and DAVID analysis to identify gene networks and their molecular functions. A mutual information based network work activity analysis showed that a connective tissue disorders network was the most active for all types of fibrosis included in this analysis. Conclusion: Our analysis indicates that despite different disease manifestation, organ fibrosis share a specific set of genes suggesting the potential for a common origin.
    03/2012; 2012:106-15.
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