YAP1 silencing attenuated lung injury/fibrosis but worsened diaphragmatic function by regulating oxidative stress and inflammation response in mice

Li, Shaoping; Zhou, Xianlong; Zeng, Rong; Lin, Lian Yu; Zou, Xingnan; Yan, Yu; Lu, Zengjun; Xia, Jian Chuan; Zhang, Lijuan; Ni, Shao-Zhou; Dai, Shifeng; Chen, Haihua; Zhao, Yan

doi:10.1016/j.freeradbiomed.2022.10.323

Cited by 15 publications

(5 citation statements)

References 39 publications

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“…3 ). The present data corroborate with previous in vivo findings that pulmonary redox imbalance triggers oxidative stress, which induces oxidative damage and drives a fibroproliferative response [ 59 ]. Furthermore, circulating redox imbalance has also been reported to correlate with COVID-19 severity [ 60 , 61 ].…”

Section: Discussionsupporting

confidence: 92%

Pulmonary redox imbalance drives early fibroproliferative response in moderate/severe coronavirus disease-19 acute respiratory distress syndrome and impacts long-term lung abnormalities

Yang,

Tan,

et al. 2024

Ann. Intensive Care

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Background COVID-19-associated pulmonary fibrosis remains frequent. This study aimed to investigate pulmonary redox balance in COVID-19 ARDS patients and possible relationship with pulmonary fibrosis and long-term lung abnormalities. Methods Baseline data, chest CT fibrosis scores, N-terminal peptide of alveolar collagen III (NT-PCP-III), transforming growth factor (TGF)-β1, superoxide dismutase (SOD), reduced glutathione (GSH), oxidized glutathione (GSSG) and malondialdehyde (MDA) in bronchoalveolar lavage fluid (BALF) were first collected and compared between SARS-CoV-2 RNA positive patients with moderate to severe ARDS (n = 65, COVID-19 ARDS) and SARS-CoV-2 RNA negative non-ARDS patients requiring mechanical ventilation (n = 63, non-ARDS). Then, correlations between fibroproliferative (NT-PCP-III and TGF-β1) and redox markers were analyzed within COVID-19 ARDS group, and comparisons between survivor and non-survivor subgroups were performed. Finally, follow-up of COVID-19 ARDS survivors was performed to analyze the relationship between pulmonary abnormalities, fibroproliferative and redox markers 3 months after discharge. Results Compared with non-ARDS group, COVID-19 ARDS group had significantly elevated chest CT fibrosis scores (p < 0.001) and NT-PCP-III (p < 0.001), TGF-β1 (p < 0.001), GSSG (p < 0.001), and MDA (p < 0.001) concentrations on admission, while decreased SOD (p < 0.001) and GSH (p < 0.001) levels were observed in BALF. Both NT-PCP-III and TGF-β1 in BALF from COVID-19 ARDS group were directly correlated with GSSG (p < 0.001) and MDA (p < 0.001) and were inversely correlated with SOD (p < 0.001) and GSH (p < 0.001). Within COVID-19 ARDS group, non-survivors (n = 28) showed significant pulmonary fibroproliferation (p < 0.001) with more severe redox imbalance (p < 0.001) than survivors (n = 37). Furthermore, according to data from COVID-19 ARDS survivor follow-up (n = 37), radiographic residual pulmonary fibrosis and lung function impairment improved 3 months after discharge compared with discharge (p < 0.001) and were associated with early pulmonary fibroproliferation and redox imbalance (p < 0.01). Conclusions Pulmonary redox imbalance occurring early in COVID-19 ARDS patients drives fibroproliferative response and increases the risk of death. Long-term lung abnormalities post-COVID-19 are associated with early pulmonary fibroproliferation and redox imbalance. Graphical abstract

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Section: Discussionsupporting

confidence: 92%

Pulmonary redox imbalance drives early fibroproliferative response in moderate/severe coronavirus disease-19 acute respiratory distress syndrome and impacts long-term lung abnormalities

Yang,

Tan,

et al. 2024

Ann. Intensive Care

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“…Interestingly, we found that the IL-6 protein level was reduced in both internal controls and VP treated samples, indicating that inhibition of YAP transcriptional activity may downregulate IL-6 protein independently of 30% cyclic stretch. Similar results of IL-6 induced by YAP were shown in cancer cells ( Zhou et al, 2018 ; Wang et al, 2019 ), while other studies reported that suppression of YAP might prolong and worsen the inflammation in lung tissue ( LaCanna et al, 2019 ; Li et al, 2022 ). A possible explanation for these different observations could be the crosstalk with other signaling pathways in YAP-IL-6 regulation.…”

Section: Discussionsupporting

confidence: 78%

Modulation of the hippo-YAP pathway by cyclic stretch in rat type 2 alveolar epithelial cells—a proof-of-concept study

Ran,

Müller,

Brunssen

et al. 2023

Front. Physiol.

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Background: Mechanical ventilation (MV) is a life supporting therapy but may also cause lung damage. This phenomenon is known as ventilator-induced lung injury (VILI). A potential pathomechanisms of ventilator-induced lung injury may be the stretch-induced production and release of cytokines and pro-inflammatory molecules from the alveolar epithelium. Yes-associated protein (YAP) might be regulated by mechanical forces and involved in the inflammation cascade. However, its role in stretch-induced damage of alveolar cells remains poorly understood. In this study, we explored the role of YAP in the response of alveolar epithelial type II cells (AEC II) to elevated cyclic stretch in vitro. We hypothesize that Yes-associated protein activates its downstream targets and regulates the interleukin-6 (IL-6) expression in response to 30% cyclic stretch in AEC II.Methods: The rat lung L2 cell line was exposed to 30% cyclic equibiaxial stretch for 1 or 4 h. Non-stretched conditions served as controls. The cytoskeleton remodeling and cell junction integrity were evaluated by F-actin and Pan-cadherin immunofluorescence, respectively. The gene expression and protein levels of IL-6, Yes-associated protein, Cysteine-rich angiogenic inducer 61 (Cyr61/CCN1), and connective tissue growth factor (CTGF/CCN2) were studied by real-time polymerase chain reaction (RT-qPCR) and Western blot, respectively. Verteporfin (VP) was used to inhibit Yes-associated protein activation. The effects of 30% cyclic stretch were assessed by two-way ANOVA. Statistical significance as accepted at p < 0.05.Results: Cyclic stretch of 30% induced YAP nuclear accumulation, activated the transcription of Yes-associated protein downstream targets Cyr61/CCN1 and CTGF/CCN2 and elevated IL-6 expression in AEC II after 1 hour, compared to static control. VP (2 µM) inhibited Yes-associated protein activation in response to 30% cyclic stretch and reduced IL-6 protein levels.Conclusion: In rat lung L2 AEC II, 30% cyclic stretch activated YAP, and its downstream targets Cyr61/CCN1 and CTGF/CCN2 and proinflammatory IL-6 expression. Target activation was blocked by a Yes-associated protein inhibitor. This novel YAP-dependent pathway could be involved in stretch-induced damage of alveolar cells.

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“…Yes-associated protein 1 (YAP) and WW domain-containing transcription factor (WWTR1 or TAZ) are major Hippo downstream effectors of canonical Hippo pathway [ 15 ]. The expression and activation of YAP can be rapidly regulated by biological processes such as oxidative stress [ 16 , 17 ], energy homeostasis [ 18 ], and mechanical pressure [ 19 ]. Two recent studies reported the increased expression of YAP and its downstream profibrotic factor connective tissue growth factor (Ctgf) in rodent PQ poisoning models, indicating the potential role of YAP in PQ-induced lung injury [ 17 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

“…The expression and activation of YAP can be rapidly regulated by biological processes such as oxidative stress [ 16 , 17 ], energy homeostasis [ 18 ], and mechanical pressure [ 19 ]. Two recent studies reported the increased expression of YAP and its downstream profibrotic factor connective tissue growth factor (Ctgf) in rodent PQ poisoning models, indicating the potential role of YAP in PQ-induced lung injury [ 17 , 20 ]. Moreover, in IPF models, YAP/TAZ is shown to contribute to pulmonary fibrosis and alveolar regeneration [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

YAP/TAZ activation mediates PQ-induced lung fibrosis by sustaining senescent pulmonary epithelial cells

Yu,

Chu,

Wang

et al. 2024

Respir Res

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Paraquat (PQ) is a widely used herbicide and a common cause of poisoning that leads to pulmonary fibrosis with a high mortality rate. However, the underlying mechanisms of PQ-induced pulmonary fibrosis and whether pulmonary epithelial cell senescence is involved in the process remain elusive. In this study, PQ-induced pulmonary epithelial cell senescence and Hippo-YAP/TAZ activation were observed in both C57BL/6 mice and human epithelial cells. PQ-induced senescent pulmonary epithelial cells promoted lung fibroblast transformation through secreting senescence-associated secretory phenotype (SASP) factors. Yap/Taz knockdown in mice lungs significantly decreased the expression of downstream profibrotic protein Ctgf and senescent markers p16 and p21, and alleviated PQ-induced pulmonary fibrosis. Interfering YAP/TAZ in senescent human pulmonary epithelial cells resulted in decreased expression of the anti-apoptosis protein survivin and elevated level of apoptosis. In conclusion, our findings reveal a novel mechanism by which the involvement of Hippo-YAP/TAZ activation in pulmonary epithelial cell senescence mediates the pathogenesis of PQ-induced pulmonary fibrosis, thereby offering novel insights and potential targets for the clinical management of PQ poisoning as well as providing the mechanistic insight of the involvement of Yap/Taz activation in cell senescence in pulmonary fibrosis and its related pulmonary disorders. The YIN YANG balance between cell senescence and apoptosis is important to maintain the homeostasis of the lung, the disruption of which will lead to disease.

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YAP1 silencing attenuated lung injury/fibrosis but worsened diaphragmatic function by regulating oxidative stress and inflammation response in mice

Cited by 15 publications

References 39 publications

Pulmonary redox imbalance drives early fibroproliferative response in moderate/severe coronavirus disease-19 acute respiratory distress syndrome and impacts long-term lung abnormalities

Pulmonary redox imbalance drives early fibroproliferative response in moderate/severe coronavirus disease-19 acute respiratory distress syndrome and impacts long-term lung abnormalities

Modulation of the hippo-YAP pathway by cyclic stretch in rat type 2 alveolar epithelial cells—a proof-of-concept study

YAP/TAZ activation mediates PQ-induced lung fibrosis by sustaining senescent pulmonary epithelial cells

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