Molecular mechanisms of alveolar epithelial cell senescence and idiopathic pulmonary fibrosis: a narrative review

Tu, Mingjin; Wei, Ting; Jia, Yufang; Wang, Yajun; Wu, Jun

doi:10.21037/jtd-22-886

Cited by 9 publications

(5 citation statements)

References 179 publications

(168 reference statements)

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“…The WNT/β-catenin signaling pathway is essential for organ development and generation although its pathological activation is associated with several fibrotic diseases. Thus, targeted inhibition of this pathway results in antifibrotic effects in a variety of organs [ 133 , 134 , 135 ]. Under inactivation of WNT signaling, β-catenin is normally phosphorylated in NH2-terminal residues, in which a glycogen synthase kinase 3β (GSK-3β) consensus motif is present, with the aid of a scaffolding complex composed of axin and adenomatous polyposis proteins.…”

Section: Core Signaling Pathways and Their Crosstalk Involved In Deve...mentioning

confidence: 99%

Molecular Mechanisms and Risk Factors Related to the Pathogenesis of Peyronie’s Disease

Mitsui

Yamabe

Hori

et al. 2023

IJMS

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Peyronie’s disease (PD) is a benign condition caused by plaque formation on the tunica albuginea of the penis. It is associated with penile pain, curvature, and shortening, and contributes to erectile dysfunction, which worsens patient quality of life. In recent years, research into understanding of the detailed mechanisms and risk factors involved in the development of PD has been increasing. In this review, the pathological mechanisms and several closely related signaling pathways, including TGF-β, WNT/β-catenin, Hedgehog, YAP/TAZ, MAPK, ROCK, and PI3K/AKT, are described. Findings regarding cross-talk among these pathways are then discussed to elucidate the complicated cascade behind tunica albuginea fibrosis. Finally, various risk factors including the genes involved in the development of PD are presented and their association with the disease summarized. The purpose of this review is to provide a better understanding regarding the involvement of risk factors in the molecular mechanisms associated with PD pathogenesis, as well as to provide insight into disease prevention and novel therapeutic interventions.

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Section: Core Signaling Pathways and Their Crosstalk Involved In Deve...mentioning

confidence: 99%

Molecular Mechanisms and Risk Factors Related to the Pathogenesis of Peyronie’s Disease

Mitsui

Yamabe

Hori

et al. 2023

IJMS

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“…Fibroblast differentiation, collagen deposition, and epithelial to mesenchymal transition eventually lead to irreversible progressive respiratory insufficiency ( 1 , 39 , 40 ). The pathogenesis of IPF is not yet fully understood, increasingly, the accelerated aging mechanism, including cell senescence, is thought to play an important role in the pathogenesis of IPF ( 15 , 19 ). Through in vivo and in vitro experiments, we studied the mechanism of PGC-1α involved in the aging of AECs by regulating mitochondrial morphology and function and explored the protective effect of PGC-1α agonist ZLN005 on aging AECs.…”

Section: Discussionmentioning

confidence: 99%

“…Evidence suggests that AEC mitochondrial dysfunction plays an important role in mediating lung fibrosis signaling via mechanisms involving imbalances in the levels of ROS, the endoplasmic reticulum stress response, mitophagy, apoptosis, and/or senescence, and inflammatory signaling ( 17 ). Mitochondria dysfunction and metabolic reprogramming have been identified in different IPF lung cells (e.g., AECs, fibroblasts, and macrophages) and have been shown to promote low resilience and increase susceptibility to the activation of profibrotic responses ( 18 , 19 ).…”

Section: Introductionmentioning

confidence: 99%

ZLN005 improves the protective effect of mitochondrial function on alveolar epithelial cell aging by upregulating PGC-1α

Ma,

Gao,

Qiu

et al. 2023

J Thorac Dis

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Background Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal pulmonary interstitial disease that usually occurs in the elderly. The senescence of alveolar epithelial cells (AECs) is an important mechanism of IPF. The AECs of patients with IPF have lower expression of peroxisome proliferator-activated receptor-γ coactivator-1 alpha (PGC-1α), which has been shown to play an important role in maintaining mitochondrial morphology and energy metabolism. This study sought to explore the mechanism by which ZLN005 improves mitochondrial function by upregulating PGC-1α to protect AECs from aging. Methods Western blot was used to detect the expression of PGC-1α, mitochondrial synthesis protein nuclear respiratory factor-1 (NRF-1), and p21 WAF1 in the lung tissue of the IPF patients and the mice with bleomycin (BLM)-induced pulmonary fibrosis. A549 cells and mice AEC2 cells were treated with hydrogen peroxide (H 2 O 2 ) to construct cell senescence models. Cell senescence was detected by senescence-associated beta-galactosidase staining. The mitochondrial respiratory function was measured, including the adenosine triphosphate (ATP) generation, reactive oxygen species (ROS) level, changes in cell membrane potential, and energy metabolism. Using lentivirus as a vector and using gene editing technology to over express (upPGC-1α) and knockdown PGC-1α (shPGC-1α) in the A549 cells. The PGC-1α agonist ZLN005 was used to pretreat the A549 and shPGC-1α A549 cells, and cell aging and mitochondrial respiratory function were observed. Results The Western blot and immunofluorescence assays showed that the expression of PGC-1α and NRF-1 was decreased in the lung tissues of the IPF patients and BLM-induced mice pulmonary fibrosis model, while the expression of p21 WAF1 was increased. The results of the immunofluorescence and mitochondrial function experiments also indicated that the expression of PGC-1α and mitochondrial synthesis protein NRF-1 were decreased in the senescent cells. Further, the mitochondrial morphology was abnormal and the mitochondrial function was impaired. PGC-1α was involved in the AEC senescence by regulating mitochondrial morphology and function. Treatment with the agonist of PGC-1α (i.e., ZLN005) blocked the H 2 O 2 -induced cell senescence by enhancing the expression of PGC-1α. Conclusions These results provide preliminary insights into the potential clinical application of ZLN005 as a novel therapeutic agent for the treatment of IPF.

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“…Meanwhile, the induction of senescence in AECs by mitomycin was observed to be regulated through the enhancement of GSK3β phosphorylation [87]. Notably, the activation of the β-catenin signaling pathway initiates a DNA damage response, leading to the upregulation of senescence-related genes such as p16, p21, and p53 [88,89]. Consequently, the aberrant activation of Wnt/β-catenin signaling can promote lung cell senescence by inducing cell-cycle arrest, thereby contributing to the progression of PF.…”

Section: Wnt/β-catenin Regulatory Pathwaymentioning

confidence: 99%

Cellular Senescence: A Troy Horse in Pulmonary Fibrosis

Wan,

Wang,

Zhu

et al. 2023

IJMS

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Pulmonary fibrosis (PF) is a chronic interstitial lung disease characterized by myofibroblast abnormal activation and extracellular matrix deposition. However, the pathogenesis of PF remains unclear, and treatment options are limited. Epidemiological studies have shown that the average age of PF patients is estimated to be over 65 years, and the incidence of the disease increases with age. Therefore, PF is considered an age-related disease. A preliminary study on PF patients demonstrated that the combination therapy of the anti-senescence drugs dasatinib and quercetin improved physical functional indicators. Given the global aging population and the role of cellular senescence in tissue and organ aging, understanding the impact of cellular senescence on PF is of growing interest. This article systematically summarizes the causes and signaling pathways of cellular senescence in PF. It also objectively analyzes the impact of senescence in AECs and fibroblasts on PF development. Furthermore, potential intervention methods targeting cellular senescence in PF treatment are discussed. This review not only provides a strong theoretical foundation for understanding and manipulating cellular senescence, developing new therapies to improve age-related diseases, and extending a healthy lifespan but also offers hope for reversing the toxicity caused by the massive accumulation of senescence cells in humans.

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Molecular mechanisms of alveolar epithelial cell senescence and idiopathic pulmonary fibrosis: a narrative review

Cited by 9 publications

References 179 publications

Molecular Mechanisms and Risk Factors Related to the Pathogenesis of Peyronie’s Disease

Molecular Mechanisms and Risk Factors Related to the Pathogenesis of Peyronie’s Disease

ZLN005 improves the protective effect of mitochondrial function on alveolar epithelial cell aging by upregulating PGC-1α

Cellular Senescence: A Troy Horse in Pulmonary Fibrosis

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