PAI-1 Regulation of TGF-β1-induced ATII Cell Senescence, SASP Secretion, and SASP-mediated Activation of Alveolar Macrophages.

08:00 EDT 12th September 2019 | BioPortfolio

Summary of "PAI-1 Regulation of TGF-β1-induced ATII Cell Senescence, SASP Secretion, and SASP-mediated Activation of Alveolar Macrophages."

Senescence of alveolar type II (ATII) cells, progenitors of the alveolar epithelium, is a pathological feature and contributes importantly to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Despite recognition of the importance of ATII cell senescence in IPF pathogenesis, how ATII cell senescence is regulated and how senescent ATII cells contribute to lung fibrogenesis remain unclear. In this study, we show that TGF-β1, a most ubiquitous and potent profibrotic cytokine, induces plasminogen activator inhibitor 1 (PAI-1), a cell senescence and fibrosis mediator, and p16 as well as senescence, but not apoptosis, in primary mouse ATII cells. We also found that senescent ATII cells secretes various cytokines and chemokines, including interleukin 4 (IL-4) and 13 (IL-13), which stimulate the expression of genes associated with a pro-fibrotic phenotype in alveolar macrophages. Similar responses were also observed in TGF-β1-treated rat ATII (L2) and rat macrophage NR8383 cells. Deletion of PAI-1 or inhibition of PAI-1 activity with a small molecule PAI-1 inhibitor, on the other hand, blocks TGF-β1-induced senescence as well as senescence associated secretion phenotype (SASP) in ATII and L2 cells and, consequently, the stimulatory effects of the conditional medium from senescent ATII/L2 cells on macrophages. Moreover, we show that silencing p16 ameliorates PAI-1 protein-induced ATII cell senescence and secretion of pro-fibrotic mediators. Our data suggest that PAI-1 mediates TGF-β 1-induced ATII cell senescence and secretion of pro-fibrotic mediators through inducing p16 and that senescent ATII cells contribute to lung fibrogenesis in part by activating alveolar macrophages through secreting pro-fibrotic and pro-inflammatory mediators.


Journal Details

This article was published in the following journal.

Name: American journal of respiratory cell and molecular biology
ISSN: 1535-4989


DeepDyve research library

PubMed Articles [28241 Associated PubMed Articles listed on BioPortfolio]

Notch Signaling Mediates Secondary Senescence.

Oncogene-induced senescence (OIS) is a tumor suppressive response to oncogene activation that can be transmitted to neighboring cells through secreted factors of the senescence-associated secretory ph...

The senescence-associated secretory phenotype and its regulation.

The senescence-associated secretory phenotype (SASP) defines the ability of senescent cells to express and secrete a variety of extracellular modulators that includes cytokines, chemokines, proteases,...

The senescence-associated secretory phenotype (SASP) from mesenchymal stromal cells impairs growth of immortalized prostate cells but has no effect on metastatic prostatic cancer cells.

Senescent cells secrete inflammatory cytokines, proteases, and other factors, which are indicated as senescence-associated secretory phenotype (SASP). There are contrasting studies on the role of the ...

Endothelial senescence-associated secretory phenotype (SASP) is regulated by Makorin-1 ubiquitin E3 ligase.

Disturbed flow (d-flow)-induced senescence and activation of endothelial cells (ECs) have been suggested to have critical roles in promoting atherosclerosis. Telomeric repeat-binding factor 2 (TERF2)-...

Cellular Senescence in the Lung Across the Age Spectrum.

Cellular senescence results in cell cycle arrest with secretion of cytokines, chemokines, growth factors and remodeling proteins (senescence associated secretory phenotype; SASP) that have autocrine a...

Clinical Trials [11803 Associated Clinical Trials listed on BioPortfolio]

Exercise and Low-Dose Rapamycin in Older Adults With CAD:Cardiac Rehabilitation And Rapamycin in Elderly (CARE) Trial

The investigators will do the study in two phases. The first phase will be a pilot study on up to 18 participants [patients 60 years or older with coronary artery disease (CAD) undergoing ...

Induction of Sensecence Using Dexamethasone to Re-sensitize NSCLC to Anti-PD1 Therapy

Lung cancer accounts for 30% of all cancers among American war Veterans and remains the leading cause of cancer related deaths. Half of all lung cancers are metastatic non-small cell lung ...

PROGENitors, TELomeres and ARTerial Aging

The prevailing view in telomere epidemiology is that leukocyte telomere length (LTL) is associated with atherosclerotic cardiovascular disease (ACVD) since it serves as a biomarker of the ...

Anti-thymocyte Globulin-induced Immune Senescence

The aim of the study is to investigate the impact of Anti-Thymocyte Globulin (ATG) on immune senescence. Markers of immune senescence expression is assessed in a prospective cohort of rena...

Cognitive Changes Associated With Breast Cancer Treatment

Patients with cancer often complain that their "mind does not seem to be clear." This can be due to stress, depression, anxiety, or physical problems caused by cancer or the treatments use...

Medical and Biotech [MESH] Definitions

Process by which cells irreversibly stop dividing and enter a state of permanent growth arrest without undergoing CELL DEATH. Senescence can be induced by DNA DAMAGE or other cellular stresses, such as OXIDATIVE STRESS.

PKC beta encodes two proteins (PKCB1 and PKCBII) generated by alternative splicing of C-terminal exons. It is widely distributed with wide-ranging roles in processes such as B-cell receptor regulation, oxidative stress-induced apoptosis, androgen receptor-dependent transcriptional regulation, insulin signaling, and endothelial cell proliferation.

Na-K-Cl transporter ubiquitously expressed. It plays a key role in salt secretion in epithelial cells and cell volume regulation in nonepithelial cells.

A forkhead box transcription factor and transcriptional activator which triggers type 1 programmed cell death (APOPTOSIS) in the absence of APOPTOSIS INHIBITING PROTEINS, including neuronal cell death induced by OXIDATIVE STRESS. It recognizes and binds to the DNA sequence 5'-(AG)TAAA(TC)A-3' and also functions in post-transcriptional regulation of the c-MYC PROTO-ONCOGENE.

A family of structurally related proteins that were originally discovered for their role in cell-cycle regulation in CAENORHABDITIS ELEGANS. They play important roles in regulation of the CELL CYCLE and as components of UBIQUITIN-PROTEIN LIGASES.

Quick Search

DeepDyve research library

Relevant Topic

Pulmonary relating to or associated with the lungs eg Asthma, chronic bronchitis, emphysema, COPD, Cystic Fibrosis, Influenza,  Lung Cancer, Pneumonia, Pulmonary Arterial Hypertension, Sleep Disorders etc Follow and track Lung Cancer News ...

Searches Linking to this Article