Divergent Regulation of Alveolar Type 2 Cell and Fibroblast Apoptosis by Plasminogen Activator Inhibitor 1 in Lung Fibrosis

Jiang, Chunsun; Liu, Gang; Cai, Lu; Deshane, Jessy; Antony, Veena B.; Thannickal, Victor J.; Liu, Rui-Ming

doi:10.1016/j.ajpath.2021.04.003

Cited by 17 publications

(9 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A growing body of evidence demonstrates that IPF fibroblasts are resistant to apoptosis [7][8][9][10]. The mechanisms are unclear, but evidence indicates the participation of the extrinsic pathway of apoptosis, such as the inhibition of Fas-mediated apoptotic cell death [8].…”

Section: Discussionmentioning

confidence: 99%

“…During physiological regeneration, fibroblasts are eliminated by apoptosis, and evasion or resistance to this process has been associated with progressive fibrosis. In this context, it has been reported that fibroblasts and myofibroblasts from patients with IPF are resistant to apoptosis, although the molecular mechanisms involved are uncertain [7][8][9][10]. Due to the central role that mitochondria play in the implementation, amplification, and regulation of cellular apoptosis, this organelle would be involved in the apoptosis resistance of IPF fibroblasts, but this has not yet been studied in depth.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mitochondrial Dysfunction and Alterations in Mitochondrial Permeability Transition Pore (mPTP) Contribute to Apoptosis Resistance in Idiopathic Pulmonary Fibrosis Fibroblasts

Luis-García

Becerril

Salgado-Aguayo

et al. 2021

IJMS

View full text Add to dashboard Cite

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by increased activation of fibroblasts/myofibroblasts. Previous reports have shown that IPF fibroblasts are resistant to apoptosis, but the mechanisms remain unclear. Since inhibition of the mitochondrial permeability transition pore (mPTP) has been implicated in the resistance to apoptosis, in this study, we analyzed the role of mitochondrial function and the mPTP on the apoptosis resistance of IPF fibroblasts under basal conditions and after mitomycin C-induced apoptosis. We measured the release of cytochrome c, mPTP opening, mitochondrial calcium release, oxygen consumption, mitochondrial membrane potential, ADP/ATP ratio, ATP concentration, and mitochondrial morphology. We found that IPF fibroblasts were resistant to mitomycin C-induced apoptosis and that calcium, a well-established activator of mPTP, is decreased as well as the release of pro-apoptotic proteins such as cytochrome c. Likewise, IPF fibroblasts showed decreased mitochondrial function, while mPTP was less sensitive to ionomycin-induced opening. Although IPF fibroblasts did not present changes in the mitochondrial membrane potential, we found a fragmented mitochondrial network with scarce, thinned, and disordered mitochondria with reduced ATP levels. Our findings demonstrate that IPF fibroblasts are resistant to mitomycin C-induced apoptosis and that altered mPTP opening contributes to this resistance. In addition, IPF fibroblasts show mitochondrial dysfunction evidenced by a decrease in respiratory parameters.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mitochondrial Dysfunction and Alterations in Mitochondrial Permeability Transition Pore (mPTP) Contribute to Apoptosis Resistance in Idiopathic Pulmonary Fibrosis Fibroblasts

Luis-García

Becerril

Salgado-Aguayo

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…In previous studies, we showed that the increased expression of plasminogen activator inhibitor 1 (PAI-1), a serine protease inhibitor playing a critical role in the development of lung fibrosis [24][25][26][27], contributes importantly to ATII cell senescence in the fibrotic lung [15,28]. We also showed that PAI-1 expression increases with age in mouse ATII cells [29] and that PAI-1 positively regulates p53 expression and promotes ATII cell senescence through activating the p53-p21-pRb cell cycle repression pathway, although the mechanism underlying PAI-1 induction of p53 remains to be determined [15]. As p53 is a master cell cycle repressor and PAI-1 expression is increased in many senescent cells [15,28,[30][31][32][33][34], uncovering the molecular mechanism by which PAI-1 regulates p53 expression will have a significant impact on multiple diseases.…”

Section: Introductionmentioning

confidence: 99%

PAI-1 Regulation of p53 Expression and Senescence in Type II Alveolar Epithelial Cells

Rana,

Jiang,

Banerjee

et al. 2023

Cells

Self Cite

View full text Add to dashboard Cite

Cellular senescence contributes importantly to aging and aging-related diseases, including idiopathic pulmonary fibrosis (IPF). Alveolar epithelial type II (ATII) cells are progenitors of alveolar epithelium, and ATII cell senescence is evident in IPF. Previous studies from this lab have shown that increased expression of plasminogen activator inhibitor 1 (PAI-1), a serine protease inhibitor, promotes ATII cell senescence through inducing p53, a master cell cycle repressor, and activating p53-p21-pRb cell cycle repression pathway. In this study, we further show that PAI-1 binds to proteasome components and inhibits proteasome activity and p53 degradation in human lung epithelial A549 cells and primary mouse ATII cells. This is associated with a senescence phenotype of these cells, manifested as increased p53 and p21 expression, decreased phosphorylated retinoblastoma protein (pRb), and increased senescence-associated beta-galactose (SA-β-gal) activity. Moreover, we find that, although overexpression of wild-type PAI-1 (wtPAI-1) or a secretion-deficient, mature form of PAI-1 (sdPAI-1) alone induces ATII cell senescence (increases SA-β-gal activity), only wtPAI-1 induces p53, suggesting that the premature form of PAI-1 is required for the interaction with the proteasome. In summary, our data indicate that PAI-1 can bind to proteasome components and thus inhibit proteasome activity and p53 degradation in ATII cells. As p53 is a master cell cycle repressor and PAI-1 expression is increased in many senescent cells, the results from this study will have a significant impact not only on ATII cell senescence/lung fibrosis but also on the senescence of other types of cells in different diseases.

show abstract

“…For terminal patients, lung transplantation is often considered as a management strategy (4). Recent studies have suggested that small lipid molecules, such as fatty acids, cholesterol, arachidonic acid metabolites, and phospholipids, may play a signi cant role in the development of IPF (5)(6)(7)(8). However, the exact causal relationship between lipid metabolites and IPF is still not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Mendelian Randomization revealed a one-way causal association between increased Isovalerylcarnitine (C5) levels and the risk of idiopathic pulmonary fibrosis

He,

Liao,

Chen

et al. 2024

Preprint

View full text Add to dashboard Cite

Background There have been multiple observational studies that have established a link between metabolite levels in the body and idiopathic pulmonary fibrosis (IPF), specifically focusing on metabolites derived from fatty acids. However, a complete understanding of the precise molecular and biological factors, as well as the causality between them, remains elusive.Objective The main objective of our study was to evaluate the potential causal relationship between blood metabolites and IPF by using Mendelian randomisation (MR).Methods To achieve this goal, we utilized the most comprehensive genome-wide association study (GWAS) to date, which identified genetic variants associated with blood metabolites (1,091 blood metabolites and 309 metabolite ratios). Summary statistics of IPF were collected from Finngen R8 (1,812 IPF patients and 338,784 controls), Inverse Variance Weighted method (IVW) is used as the main method in determining causality.Results Isovalerylcarnitine (C5) levels (OR = 1.2435, 95%CI: 1.0494–1.4736, PIVW = 0.0119) was found significantly related to higher risk of IPF. There was no significant heterogeneity in our study (IVW method: Pval = 0.132; MR-Egger method: Pval = 0.105) and horizontal pleiotropy (β=-0.027; se = 0.0337; Pval = 0.4310). The sensitivity analysis did not reveal any potential abnormal drivers (0.1 < All < 0.3).Conclusion Two-sample MR Method demonstrated the causal relationship between blood metabolites and IPF, and further studies found that C5 levels, as a potential biological risk factor for IPF, may provide a new target for the treatment of IPF.

show abstract

Divergent Regulation of Alveolar Type 2 Cell and Fibroblast Apoptosis by Plasminogen Activator Inhibitor 1 in Lung Fibrosis

Cited by 17 publications

References 52 publications

Mitochondrial Dysfunction and Alterations in Mitochondrial Permeability Transition Pore (mPTP) Contribute to Apoptosis Resistance in Idiopathic Pulmonary Fibrosis Fibroblasts

Mitochondrial Dysfunction and Alterations in Mitochondrial Permeability Transition Pore (mPTP) Contribute to Apoptosis Resistance in Idiopathic Pulmonary Fibrosis Fibroblasts

PAI-1 Regulation of p53 Expression and Senescence in Type II Alveolar Epithelial Cells

Mendelian Randomization revealed a one-way causal association between increased Isovalerylcarnitine (C5) levels and the risk of idiopathic pulmonary fibrosis

Contact Info

Product

Resources

About