Autophagy Reprograms Alveolar Progenitor Cell Metabolism in Response to Lung Injury

Li, Xue; Wu, Junping; Sun, Xin; Wu, Qi; Li, Yue; Li, Kuan; Zhang, Qiuyang; Liu, Yu; Abel, E. Dale; Chen, Huaiyong

doi:10.1016/j.stemcr.2020.01.008

Cited by 48 publications

(38 citation statements)

References 32 publications

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“…Previously, Li et al showed that after lung injury with bleomycin (under SD conditions), glycolytic and pentose phosphate pathways are promoted, whereas fatty acid synthesis is repressed in mouse AT2 cells, which eventually results in fibrosis resolution and epithelial repair [31]. Therefore, we propose that in the presence of the HFD-induced excess in fatty acids, AT2 stem cells are pushed toward FAO as an energy source, rather than the classic glycolysis, thus impairing its repair capacity.…”

Section: Discussionmentioning

confidence: 99%

Effect of High Fat Diet on the Severity and Repair of Lung Fibrosis in Mice

Hegab

Ozaki

Kagawa

et al. 2021

Stem Cells and Development

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Lung fibrosis is a progressive fatal disease, and the underlying mechanisms remain unclear. These involve a combination of altered fibroblasts, excessive accumulation of extracellular matrix, inflammation, and aberrant activation of epithelial cells. Previously, we showed that high-fat diet (HFD) induces lung inflammation, aberrant activation of stem cells, and lung mitochondria impairment. Therefore, we hypothesized that HFD-induced changes would influence lung fibrosis. Mice were fed standard diet (SD) or HFD, administered bleomycin, then examined for fibrosis severity and the start of repair 3 weeks after injury, and for fibrosis repair/resolution 6-9 weeks after injury. At 3 weeks, no significant differences in inflammation and fibrosis severity were observed between SD-and HFD-fed mice. However, infiltration of alveolar type (AT)-2 cells and bronchioalveolar stem cells (BASCs) into the fibrotic areas (the start of repair) was impaired in HFD-fed mice. At 6 weeks, SD-fed mice showed near-complete resolution/repair of fibrosis and inflammation, while HFD-fed mice still showed residual fibrosis and inflammation. Infiltration of the fibrotic areas with AT2 cells was observed, but very few BASCs were detectable. At 9 weeks, mice from both groups showed complete resolution/repair of fibrosis and inflammation, indicating that HFD induced delayed, rather than failed, resolution of fibrosis and alveolar repair. To further confirm the direct role of enhanced fatty-acid oxidation (FAO) in delayed resolution/repair, we administered etomoxir, a FAO inhibitor, to HFD-fed mice for 3-6 weeks after bleomycin injury. Inhibition of FAO abolished the HFD-induced delay in alveolar repair and fibrosis resolution at both time points. In conclusion, after a fibrosis-inducing injury, HFD slows resolution of fibrosis/inflammation and delays alveolar repair by slowing the contribution of AT2 stem cells and abolishing the contribution of BASCs in the repair process. FAO activation appears to be involved in this delay mechanism; thus, inhibiting FAO may be useful in the treatment of lung injury and fibrosis.

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Section: Discussionmentioning

confidence: 99%

Effect of High Fat Diet on the Severity and Repair of Lung Fibrosis in Mice

Hegab

Ozaki

Kagawa

et al. 2021

Stem Cells and Development

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“…Moreover, activation of MTORC1 in macrophages by selective deletion of Tsc2 leads to excessive granuloma formation, a clinical implication for sarcoidosis (Linke et al , 2017 ). In addition, defective autophagy in progenitor alveolar type 2 (AT2) cells aggravates bleomycin‐induced lung injury, as it reduces AT2 cell stemness by reprogramming their metabolism (Li et al , 2020a ). Consistently, bleomycin‐induced upregulation of ANXA2 (Annexin A2) perturbs the autophagic flux by limiting TFEB nuclear translocation (Wang et al , 2018a ).…”

Section: Pulmonary Disordersmentioning

confidence: 99%

Autophagy in major human diseases

et al. 2021

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Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.

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“…The lungs are frequently exposed to microbes and pollutants, thus establishing environmental adaptation that sustains immune tolerance, alleviates tissue injury, and secures gas exchange [ 7 ]. Given the clonal analysis and organoid culture together with lineage tracing mouse models, an increasing body of evidence has shown that there exist heterogeneous and complex resident epithelial progenitor or stem cells in the lung [ 69 , 70 , 71 , 72 , 73 ]. They generally divide rarely and are quiescent but proliferate and differentiate rapidly to accelerate the restoration of the surrounding epithelium since the lung is injured [ 74 ].…”

Section: Macrophages and Lung Repairmentioning

confidence: 99%

Macrophages in Lung Injury, Repair, and Fibrosis

Cheng

Chen

2021

Cells

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245

107

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Fibrosis progression in the lung commonly results in impaired functional gas exchange, respiratory failure, or even death. In addition to the aberrant activation and differentiation of lung fibroblasts, persistent alveolar injury and incomplete repair are the driving factors of lung fibrotic response. Macrophages are activated and polarized in response to lipopolysaccharide- or bleomycin-induced lung injury. The classically activated macrophage (M1) and alternatively activated macrophage (M2) have been extensively investigated in lung injury, repair, and fibrosis. In the present review, we summarized the current data on monocyte-derived macrophages that are recruited to the lung, as well as alveolar resident macrophages and their polarization, pyroptosis, and phagocytosis in acute lung injury (ALI). Additionally, we described how macrophages interact with lung epithelial cells during lung repair. Finally, we emphasized the role of macrophage polarization in the pulmonary fibrotic response, and elucidated the potential benefits of targeting macrophage in alleviating pulmonary fibrosis.

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Autophagy Reprograms Alveolar Progenitor Cell Metabolism in Response to Lung Injury

Cited by 48 publications

References 32 publications

Effect of High Fat Diet on the Severity and Repair of Lung Fibrosis in Mice

Effect of High Fat Diet on the Severity and Repair of Lung Fibrosis in Mice

Autophagy in major human diseases

Macrophages in Lung Injury, Repair, and Fibrosis

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