The Role of Aging in Idiopathic Pulmonary Fibrosis

Leung, Joseph C.K.; Cho, Young; Lockey, Richard F.; Kolliputi, Narasaiah

doi:10.1007/s00408-015-9729-3

Cited by 34 publications

(24 citation statements)

References 57 publications

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“…To test whether deletion of PAI‐1 specifically in ATII cells in mice will protect ATII cells from bleomycin‐induced senescence in vivo (Leung et al ., ), CKO and wild‐type (PAI‐1 fl/f ) mice were intraperitoneally injected with tamoxifen and then challenged with 2 U/kg bleomycin. Mice were euthanized 14 days after challenge, lung tissue collected, and ATII cells isolated.…”

Section: Resultsmentioning

confidence: 99%

Serpine 1 induces alveolar type II cell senescence through activating p53‐p21‐Rb pathway in fibrotic lung disease

et al. 2017

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SummarySenescence of alveolar type 2 (ATII) cells, progenitors of the alveolar epithelium, is implicated in the pathogeneses of idiopathic pulmonary fibrosis (IPF), an aging‐related progressive fatal lung disorder with unknown etiology. The mechanism underlying ATII cell senescence in fibrotic lung diseases, however, remains poorly understood. In this study, we report that ATII cells in IPF lungs express higher levels of serpine 1, also known as plasminogen activator inhibitor 1 (PAI‐1), and cell senescence markers p21 and p16, compared to ATII cells in control lungs. Silencing PAI‐1 or inhibition of PAI‐1 activity in cultured rat ATII (L2) cells leads to decreases in p53 serine 18 phosphorylation (p53S18P), p53 and p21 protein expressions; an increase in retinoblastoma protein phosphorylation (ppRb); and a reduction in the sensitivity to bleomycin‐ and doxorubicin‐induced senescence. Silencing p53, on the other hand, abrogates PAI‐1 protein‐stimulated p21 expression and cell senescence. In vivo studies, using ATII cell‐specific PAI‐1 conditional knockout mouse model generated recently in this laboratory, further support the role of PAI‐1 in the activation of p53‐p21‐Rb cell cycle repression pathway, ATII cell senescence, and lung fibrosis induced by bleomycin. This study reveals a novel function of PAI‐1 in regulation of cell cycle and suggests that elevation of PAI‐1 contributes importantly to ATII cell senescence in fibrotic lung diseases.

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Section: Resultsmentioning

confidence: 99%

Serpine 1 induces alveolar type II cell senescence through activating p53‐p21‐Rb pathway in fibrotic lung disease

et al. 2017

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“…Epigenetic changes are mediated by external factors and defined as alterations in gene expression without modifications of the DNA sequence. 21 Rabinovich et al have shown that the global methylation pattern in IPF is modified and there is evidence that several genes involved in the pathogenesis of IPF exhibit abnormal DNA methylation. 22 In IPF, the hypermethylation of the Thy-1 promoter region causes a reduced expression of the related glycoprotein Thy-1 that is normally expressed by fibroblasts.…”

Section: Role Of Risk Factorsmentioning

confidence: 99%

What We Know About the Pathogenesis of Idiopathic Pulmonary Fibrosis

Puglisi

Torrisi

Giuliano

et al. 2016

Semin Respir Crit Care Med

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Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease of unknown cause, occurring in adults, limited to the lungs and associated with the pathologic and radiologic pattern of usual interstitial pneumonia. Prognosis is poor, and most patients die of respiratory failure within 3 to 6 years from the onset of symptoms. Although our understanding of the pathogenesis of IPF has improved over the past two decades, the mechanisms responsible for this disorder have not been clearly defined. Aging is the single most important risk factor, but genetic, environmental, and diverse exogenous factors such as smoking, viral infections, chronic tissue injury (i.e., gastroesophageal reflux disease, traction injury) play contributory roles. In this review, we focus on pathogenetic mechanisms that we think are crucial for the initiation of the fibrotic process and for its progressive evolution. In the early stage of the disease, in the context of the permissive genetic background combined with the presence of specific risk factors, alveolar epithelial cells play a leading role. Subsequent evolution of the fibrotic process and its lethal progression is likely due to the abnormal tissue repair process that takes place in the lung and to the inability to counteract this process. In this phase of the disease, fibroblasts assume a crucial role. Current pharmacological treatment strategies for IPF have only modest value, principally by slowing the course of disease progression. Unfortunately, improvement or cure has not yet been achieved with pharmacological agents. The challenge for the future is to improve the comprehension of the mechanisms involved in the inception and evolution of IPF and their articulated interactions. This is fundamental not only to conceive and develop new drugs against this dreadful disease but also to apply different therapeutic approaches such as drug repositioning and personalized therapies in the management of IPF.

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“…[3] Accelerated senescence of lung tissue is involved in the pathogenesis of COPD and IPF. [4][5][6] Recent comprehension of the biology of aging has made significant progress summarized as critical function but also alter the functional direction of other cellular events including autophagy and ubiquitinproteasome system. [11] ROS affect the protein quality and function through post-translational modification of amino acid residues [12] resulting in conformational alterations to the tertiary and quaternary structures of these proteins and decreased activities of modified proteins.…”

Section: Introductionmentioning

confidence: 99%