Alveolar Epithelial Type 2 Cell Dysfunction in Idiopathic Pulmonary Fibrosis

Zhu, Weiwei; Tan, Che-Kim; Zhang, Jie

doi:10.1007/s00408-022-00571-w

Cited by 16 publications

(8 citation statements)

References 75 publications

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“…Although our ex vivo and in vitro experiments suggest that inhibiting myofibroblast differentiation is a primary antifibrotic mechanism, the inhibition of lactate transporters expressed by other cell types may also contribute to their therapeutic effect. For example, MCT4 expression is upregulated as part of a HIF-1α gene expression signature in transitional AT2 cells that accumulate in pulmonary fibrosis and contribute to aberrant repair processes ( 66, 67 ). Future work will explore the cell-type-specific effects of these transporters in conditional knockout mice.…”

Section: Discussionmentioning

confidence: 99%

Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis

Ziehr,

Li,

Mark Parnell

et al. 2024

Preprint

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Myofibroblast differentiation, essential for driving extracellular matrix synthesis in pulmonary fibrosis, requires increased glycolysis. While glycolytic cells must export lactate, the contributions of lactate transporters to myofibroblast differentiation are unknown. In this study, we investigated how MCT1 and MCT4, key lactate transporters, influence myofibroblast differentiation and experimental pulmonary fibrosis. Our findings reveal that inhibiting MCT1 or MCT4 reduces TGFβ-stimulated pulmonary myofibroblast differentiationin vitroand decreases bleomycin-induced pulmonary fibrosisin vivo. Through comprehensive metabolic analyses, including bioenergetics, stable isotope tracing, metabolomics, and imaging mass spectrometry in both cells and mice, we demonstrate that inhibiting lactate transport enhances oxidative phosphorylation, reduces reactive oxygen species production, and diminishes glucose metabolite incorporation into fibrotic lung regions. Furthermore, we introduce VB253, a novel MCT4 inhibitor, which ameliorates pulmonary fibrosis in both young and aged mice, with comparable efficacy to established antifibrotic therapies. These results underscore the necessity of lactate transport for myofibroblast differentiation, identify MCT1 and MCT4 as promising pharmacologic targets in pulmonary fibrosis, and support further evaluation of lactate transport inhibitors for patients for whom limited therapeutic options currently exist.

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Section: Discussionmentioning

confidence: 99%

Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis

Ziehr,

Li,

Mark Parnell

et al. 2024

Preprint

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“…ИЛФ характеризуется разрушением альвеолярного эпителия и уменьшением воздушного пространства, занимаемого фибробластами, которые образуют фиброзные очаги, характеризующиеся накоплением богатого коллагеном внеклеточного матрикса [39]. Дисфункция и апоптоз альвеолоцитов 2 типа (ATII) инициируют возникновение и прогрессирование ИЛФ [40]. Апоптоз и истощение клеток ATII при ИЛФ приводят к снижению синтеза ЛС, который необходим для предотвращения роста других клеток, таких как фибробласты, которые рекрутируются после повреждения эпителия.…”

Section: идиопатический легочный фиброзunclassified

“…Апоптоз и истощение клеток ATII при ИЛФ приводят к снижению синтеза ЛС, который необходим для предотвращения роста других клеток, таких как фибробласты, которые рекрутируются после повреждения эпителия. Апоптоз связан с изменениями в метаболизме фосфолипидов, высвобождаю щими жирные кислоты, такие как арахидоновая кислота, что сопровождается снижением жизнеспособности клеток [40]. Чрезмерный рост фибробластов приводит к накоплению коллагена и активации факторов роста, таких как трансформирующий фактор роста β (TGF-β).…”

Section: идиопатический легочный фиброзunclassified

The use of exogenous surfactant in pulmonological practice

Ignatova,

Antonov,

Zakharova

2024

Medicinskij sovet

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A lung surfactant is a complex mixture of lipids and proteins necessary to maintain proper lung function. Drug changes play an important role in chronic lung diseases such as chronic obstructive pulmonary disease, bronchial asthma and idiopathic pulmonary fibrosis. The purpose of this article is to substantiate the use of exogenous surfactant in various respiratory diseases, based on the analysis of publications in domestic and international medical journals, as well as their own experience of application in real clinical practice. This review primarily discusses the contribution of pulmonary surfactants to maintaining homeostasis of the respiratory system; optimal delivery routes; differences between natural and synthetic surfactant; diseases associated with impaired surfactant production, such as idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, acute respiratory distress syndrome, pulmonary alveolar proteinosis, cystic fibrosis. Special attention is paid to the immunological properties of specific proteins of surfactants A and D, their effect on protection against respiratory viral infection. Data on the direct effect of exogenous surfactant on pulmonary function, an increase in post-bronchodilation FEV1 and FVC are presented. Special attention is paid to the use of surfactant in the new coronavirus infection COVID-19. Pharmacological and therapeutic strategies to improve pulmonary surfactant dysfunction can prevent alveolar collapse, reduce the proinflammatory response, and limit viral infection. Currently, the use of surfactant preparations for the treatment of various respiratory diseases is being studied in several clinical trials, which will significantly revise the understanding of the therapeutic possibilities of an exogenous surfactant and expand its application areas.

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“…Damage to alveolar epithelial cells (AECs) is known to play a critical role in the development and progression of IPF. 2 AEC injury leads to impaired epithelial barrier integrity, which in turn triggers a feedback mechanism that leads to aberrant production of profibrotic factors such as transforming growth factor-beta 1 (TGF-β1). 3 Furthermore, persistent or irreparable damage to AECs may further induce cell apoptosis or trigger the progression of stress-induced senescence.…”

Section: Introductionmentioning

confidence: 99%

Influence of miR-142-3p on Pulmonary Fibrosis Through Regulation of p53/NF-κB

Şen

Zhang

et al. 2023

Journal of Pharmacology and Pharmacotherapeutics

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Objectives To investigate the role of miR-142-3p in the bleomycin-induced idiopathic pulmonary fibrosis (IPF) mouse model and elucidate its targets. Methods In vitro model: Alveolar epithelial cells (AECs) were isolated and treated with bleomycin (50 µg/mL) or PBS for 12 h. In vivo model: Bleomycin (5 mg/kg) was injected into the trachea under anesthesia and aseptic conditions, and controls were treated with equal saline. After the completion of modeling, proteins and RNA were extracted. p53/NF-κB signaling factors were evaluated by western blot or immunohistochemistry. IL-1β and MMP-9 levels were measured by ELISA. The lentiviral transfection technique was used to overexpress miR-142-3p. Results In IPF, miR-142-3p was identified to play a negative regulatory role in lung epithelial cell senescence. Bleomycin treatment significantly reduced miR-142-3p expression in a concentration-dependent manner in vitro. miR-142-3p overexpression inhibited bleomycin-induced cellular senescence in vivo. In particular, miR-142-3p negatively regulated collagen deposition in pulmonary fibrosis by regulating p53/NF-κB expression. Conclusion MiR-142-3p plays an important role in the development of IPF by negatively regulating the p53/NF-κB network.

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Alveolar Epithelial Type 2 Cell Dysfunction in Idiopathic Pulmonary Fibrosis

Cited by 16 publications

References 75 publications

Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis

Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis

The use of exogenous surfactant in pulmonological practice

Influence of miR-142-3p on Pulmonary Fibrosis Through Regulation of p53/NF-κB

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