PAI-1 Regulation of TGF-β1–induced Alveolar Type II Cell Senescence, SASP Secretion, and SASP-mediated Activation of Alveolar Macrophages

Rana, Tapasi; Jiang, Chunsun; Liu, Gang; Miyata, Toshio; Antony, Veena B.; Thannickal, Victor J.; Liu, Rui Ming

doi:10.1165/rcmb.2019-0071oc

Cited by 99 publications

(86 citation statements)

References 49 publications

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“…Furthermore, the senescent fibroblast phenotype co-exists with the proliferative phenotype. Senescent ATII cells and fibroblast are characterized by a metabolically active, hypersecretory and apoptosis-resistant phenotype in the lungs of IPF patients, contributing to the release of fibrotic growth factors, which promote the IPF progression [45][46][47]. Previously, we reported that the inhibition of MUC1-CT expression via siRNA-MUC1, or of MUC1-CT nuclear translocation using GO-201, blocked the ATII cell senescence, fibroblast senescence and lung fibroblast proliferation induced by TGF-β1 [19].…”

Section: Figure 3: Pirfenidone (Pfd) Inhibits Muc1-ct Co-localizationmentioning

confidence: 95%

Pirfenidone anti-fibrotic effects are partially mediated by the inhibition of MUC1 bioactivation

2020

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Pirfenidone is a pleiotropic molecule approved to treat idiopathic pulmonary fibrosis (IPF). Pirfenidone has demonstrated to downregulate transforming growth factor-β1 (TGF-β1) cellular effects. However, its anti-fibrotic mechanism remains unclear. Here, we aim to analyze the effects of pirfenidone on the TGF-β1 canonical and non-canonical pathways, as well as, on the most characteristic IPF cellular processes. Results observed in this work showed that TGF-β1-induced canonical SMAD3 and noncanonical ERK1/2 phosphorylations were not inhibited by pirfenidone in alveolar A549 and lung fibroblasts MRC5 cells. In contrast, pirfenidone inhibited TGF-β1-induced MUC1-CT Thr 41 (1224) and Tyr 46 (1229) phosphorylations, thus reducing the β-catenin activation. Additionally, immunoprecipitation and immunofluorescence studies in ATII cells and lung fibroblasts showed that pirfenidone inhibited the formation and nuclear translocation of the transcriptional fibrotic TGF-β1-induced phospho-SMAD3/MUC1-CT/active-β-catenin complex, and consequently the SMAD-binding element activation (SBE). This study provided also evidence of the inhibitory effect of pirfenidone on the TGF-β1-induced ATII to mesenchymal and fibroblast to myofibroblast transitions, fibroblast proliferation and ATII and fibroblast senescence. Therefore, it indicates that pirfenidone's inhibitory effect on TGF-β1-induced fibrotic cellular processes is mediated by the inhibition of MUC1-CT phosphorylation, β-catenin activation, nuclear complex formation of phospho-SMAD3/MUC1-CT/active β-catenin and SBE activation, which may be of value to further develop anti-fibrotic IPF therapies.

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Section: Figure 3: Pirfenidone (Pfd) Inhibits Muc1-ct Co-localizationmentioning

confidence: 95%

Pirfenidone anti-fibrotic effects are partially mediated by the inhibition of MUC1 bioactivation

2020

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“…Macrophages are recruited to the lung by SARS-CoV-2-infected cells expressing ACE2 (Qi et al, 2020). The stronger inflammatory state described in circulating monocytes from men compared to women (Marquez et al, 2020) suggests that senescent-like macrophages compound the inflammation induced by COVID-19 through the production of proinflammatory cytokines like IL-6 (Hall et al, 2017;Liu et al, 2019;Rana et al, 2020), in a combination that in older men is especially lethal.…”

Section: Older Men Show Accelerated Biological Agingmentioning

confidence: 99%

Inflamm-Aging: Why Older Men Are the Most Susceptible to SARS-Cov-2 Complicated Outcomes

Bonafè

Prattichizzo

Giuliani

et al. 2020

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterized by a high mortality of elderly men with age-related comorbidities. In most of these patients, uncontrolled local and systemic hyperinflammation induces severe and often lethal outcomes. The aging process is characterized by the gradual development of a chronic subclinical systemic inflammation (inflamm-aging) and by acquired immune system impairment (immune senescence). Here, we advance the hypothesis that some key features of aging contribute to the disproportionate SARS-CoV-2 mortality suffered by elderly men. At least four well-recognized aging-related characteristics that are strongly expressed in older men go some way towards explaining why these patients account for the vast majority of fatalities: i. the presence of subclinical systemic inflammation without overt disease, ii. a blunted acquired immune system and type I interferon response due to the chronic inflammation; iii. the downregulation of ACE2 (SARS-CoV-2 receptor), which triggers inflammation, particularly in patients with age-related comorbid diseases such as type II diabetes; and iv. accelerated biological aging, as measured by epigenetic and senescence markers (e.g. telomere shortening) associated to the chronic inflammatory state. Though typical of the aged, especially of elderly men, it is conceivable that these features are also shared by some subsets of the younger population. The high mortality rate of SARS-CoV-2 infection suggests that clarification of the mechanisms of inflamm-aging and immune senescence can help combat not only age-related disorders but also SARS-CoV-2 infection.

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“…The heterogeneity of the injury also complicates assessment of epithelial senescence from a whole organ perspective. As discussed above, instability generated by TERT, ABCA3, SP-A, and SP-C mutations or fibrogenic exposure is accompanied by an epithelial phenotype that aligns with age-induced senescence (cell cycle checkpoint disruption and SASP) (136)(137)(138). To date, only correlative evidence (epidemiological) links ambient pollution exposure to acute inflammatory exacerbations that rapidly accelerate lung function decline in IPF patients (102,139,140).…”

Section: Lung Epitheliummentioning

confidence: 99%

Senescence in Pulmonary Fibrosis: Between Aging and Exposure

Venosa

2020

Front. Med.

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PAI-1 Regulation of TGF-β1–induced Alveolar Type II Cell Senescence, SASP Secretion, and SASP-mediated Activation of Alveolar Macrophages

Cited by 99 publications

References 49 publications

Pirfenidone anti-fibrotic effects are partially mediated by the inhibition of MUC1 bioactivation

Pirfenidone anti-fibrotic effects are partially mediated by the inhibition of MUC1 bioactivation

Inflamm-Aging: Why Older Men Are the Most Susceptible to SARS-Cov-2 Complicated Outcomes

Senescence in Pulmonary Fibrosis: Between Aging and Exposure

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