Hypoxia-induced Deoxycytidine Kinase Contributes to Epithelial Proliferation in Pulmonary Fibrosis

Weng, Tingting; Poth, Jens M.; Karmouty‐Quintana, Harry; Garcia-Morales, Luis J.; Melicoff, Ernestina; Luo, Fayong; Chen, Ning Yuan; Evans, Christopher M.; Bunge, R.R.; Bruckner, Brian A.; Loebe, Matthias; Volcik, Kelly A.; Eltzschig, Holger K.; Blackburn, Michael R.

doi:10.1164/rccm.201404-0744oc

Cited by 51 publications

(40 citation statements)

References 44 publications

(58 reference statements)

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“…Dck encodes deoxycytidine kinase which catalyzes phosphorylation of all four deoxynucleosides - essential for DNA replication. One recent study showed DCK plays a key role in cell proliferation30. Hist1h2a and Hist1h2b belong to histone cluster 1, the major histone gene locus also essential for DNA replication31.…”

Section: Resultsmentioning

confidence: 99%

Towards Functional Annotation of the Preimplantation Transcriptome: An RNAi Screen in Mammalian Embryos

Cui

Dai

Marcho

et al. 2016

Sci Rep

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With readily available transcriptome-wide data, understanding the role of each expressed gene is an essential next step. Although RNAi technologies allow for genome-wide screens in cell culture, these approaches cannot replace strategies for discovery in the embryo. Here we present, for the first time, a knockdown screen in mouse preimplantation embryos. Early mammalian development encompasses dynamic cellular, molecular and epigenetic events that are largely conserved from mouse to man. We assayed 712 genes for requirements during preimplantation. We identified 59 genes required for successful development or outgrowth and implantation. We have characterized each phenotype and revealed cellular, molecular, and lineage specific defects following knockdown of transcript. Induced network analyses demonstrate this as a valid approach to identify networks of genes that play important roles during preimplantation. Our approach provides a robust and efficient strategy towards identification of novel phenotypes during mouse preimplantation and facilitates functional annotation of the mammalian transcriptome.

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Section: Resultsmentioning

confidence: 99%

Towards Functional Annotation of the Preimplantation Transcriptome: An RNAi Screen in Mammalian Embryos

Cui

Dai

Marcho

et al. 2016

Sci Rep

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“…However, it should be noted that other pathologic phenotypes of myo-Fbs, such as augmented proliferation and resistance to apoptosis, could be also dependent on the elevated glycolysis. In addition, highly glycolytic myo-Fbs may be capable of creating a metabolically favorable microenvironment through secreting lactate and other glycolytic intermediates to cause pathologic changes in adjacent pulmonary cells, such as cellular dysplasia, which is frequently found in the alveolar epithelia surrounding the myofibroblastic foci in IPF lungs (52). Although these hypotheses remain to be tested, there is abundant evidence alluding that such events could take place during pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Glycolytic Reprogramming in Myofibroblast Differentiation and Lung Fibrosis

Xie

Tan

Banerjee

et al. 2015

Am J Respir Crit Care Med

404

381

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Rationale: Dysregulation of cellular metabolism has been shown to participate in several pathologic processes. However, the role of metabolic reprogramming is not well appreciated in the pathogenesis of organ fibrosis.Objectives: To determine if glycolytic reprogramming participates in the pathogenesis of lung fibrosis and assess the therapeutic potential of glycolytic inhibition in treating lung fibrosis.Methods: A cell metabolism assay was performed to determine glycolytic flux and mitochondrial respiration. Lactate levels were measured to assess glycolysis in fibroblasts and lungs. Glycolytic inhibition by genetic and pharmacologic approaches was used to demonstrate the critical role of glycolysis in lung fibrosis.Measurements and Main Results: Augmentation of glycolysis is an early and sustained event during myofibroblast differentiation, which is dependent on the increased expression of critical glycolytic enzymes, in particular, 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3). Augmented glycolysis contributes to the stabilization of hypoxia-inducible factor 1-a, a master regulator of glycolytic enzymes implicated in organ fibrosis, by increasing cellular levels of tricarboxylic acid cycle intermediate succinate in lung myofibroblasts. Inhibition of glycolysis by the PFKFB3 inhibitor 3PO or genomic disruption of the PFKFB3 gene blunted the differentiation of lung fibroblasts into myofibroblasts, and attenuated profibrotic phenotypes in myofibroblasts isolated from the lungs of patients with idiopathic pulmonary fibrosis. Inhibition of glycolysis by 3PO demonstrates therapeutic benefit in bleomycin-induced and transforming growth factor-b1-induced lung fibrosis in mice.Conclusions: Our data support the novel concept of glycolytic reprogramming in the pathogenesis of lung fibrosis and provide proof-of-concept that targeting this pathway may be efficacious in treating fibrotic disorders, such as idiopathic pulmonary fibrosis.

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“…The lungs of IPF patients are often characterized by the presence of fibroblastic foci surrounded by hyperplastic type II alveolar epithelial cells (AEC2s), 10 which become hypoxic and express increased levels of hypoxia-inducible factor-1 α (HIF-1 α ). 11 Further, large-scale genomic studies on lungs of IPF patients indicate that hypoxia signaling likely drives profibrotic events in IPF.…”

Section: Introductionmentioning

confidence: 99%

Galectin-1 inhibition attenuates profibrotic signaling in hypoxia-induced pulmonary fibrosis

et al. 2017

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Idiopathic pulmonary fibrosis (IPF) is characterized by lung remodeling arising from epithelial injury, aberrant fibroblast growth, and excessive deposition of extracellular matrix. Repeated epithelial injury elicits abnormal wound repair and lung remodeling, often associated with alveolar collapse and edema, leading to focal hypoxia. Here, we demonstrate that hypoxia is a physiological insult that contributes to pulmonary fibrosis (PF) and define its molecular roles in profibrotic activation of lung epithelial cells. Hypoxia increased transcription of profibrotic genes and altered the proteomic signatures of lung epithelial cells. Network analysis of the hypoxic epithelial proteome revealed a crosstalk between transforming growth factor-β1 and FAK1 (focal adhesion kinase-1) signaling, which regulated transcription of galectin-1, a profibrotic molecule. Galectin-1 physically interacted with and activated FAK1 in lung epithelial cells. We developed a novel model of exacerbated PF wherein hypoxia, as a secondary insult, caused PF in mice injured with subclinical levels of bleomycin. Hypoxia elevated expression of phosphorylated FAK1, galectin-1, and α-smooth muscle actin and reduced caspase-3 activation, suggesting aberrant injury repair. Galectin-1 inhibition caused apoptosis in the lung parenchyma and reduced FAK1 activation, preventing the development of hypoxia-induced PF. Galectin-1 inhibition also attenuated fibrosis-associated lung function decline. Further, galectin-1 transcript levels were increased in the lungs of IPF patients. In summary, we have identified a profibrotic role of galectin-1 in hypoxia signaling driving PF.

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Hypoxia-induced Deoxycytidine Kinase Contributes to Epithelial Proliferation in Pulmonary Fibrosis

Cited by 51 publications

References 44 publications

Towards Functional Annotation of the Preimplantation Transcriptome: An RNAi Screen in Mammalian Embryos

Towards Functional Annotation of the Preimplantation Transcriptome: An RNAi Screen in Mammalian Embryos

Glycolytic Reprogramming in Myofibroblast Differentiation and Lung Fibrosis

Galectin-1 inhibition attenuates profibrotic signaling in hypoxia-induced pulmonary fibrosis

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