Transcription factor Fra-2 and its emerging role in matrix deposition, proliferation and inflammation in chronic lung diseases

Birnhuber, Anna; Biasin, Valentina; Schnoegl, Diana; Marsh, Leigh M.; Kwapiszewska, Grażyna

doi:10.1016/j.cellsig.2019.109408

Cited by 51 publications

(37 citation statements)

References 95 publications

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“…S3, A-D; https://doi.org/10.5281/zenodo.3532795), have increased coverage of distal pulmonary vessels by ␣SMAϩ cells with deposition of intra-/perivascular collagen (Supplemental Fig. S4, A-D; https://doi.org/10.5281/zenodo.3532795), and have impaired lung function with restrictive phenotype (2)(3)(4).…”

Section: ␣Smaϩ Cells Are a Separate Subpopulation Of Fibroblasts Withmentioning

confidence: 99%

“…Remodeling is first observable only in the vascular compartment and accompanied by PH at the age of 7-8 wk (1a). Over the course of the next few weeks, parenchymal changes are visible, starting first with perivascular and interstitial inflammation at 12-16 wk and progressing to fibrosis-characteristic restrictive lung function impairment (3,4). Genetic labeling of Acta2-expressing cells was performed in Fra-2 Tg mice carrying the Acta2-CreERT2; tdTomato flox alleles before parenchymal changes and cell fate were investigated at 20 wk (Supplemental Fig.…”

Section: ␣Smaϩ Cells Are a Separate Subpopulation Of Fibroblasts Withmentioning

confidence: 99%

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PDGFRα and αSMA mark two distinct mesenchymal cell populations involved in parenchymal and vascular remodeling in pulmonary fibrosis

Biasin

Crnković

Sahu-Osen

et al. 2020

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pulmonary fibrosis is characterized by pronounced collagen deposition and myofibroblast expansion, whose origin and plasticity remain elusive. We utilized a fate-mapping approach to investigate α-smooth muscle actin (αSMA)+ and platelet-derived growth factor receptor α (PDGFRα)+ cells in two lung fibrosis models, complemented by cell type-specific next-generation sequencing and investigations on human lungs. Our data revealed that αSMA+ and PDGFRα+ cells mark two distinct mesenchymal lineages with minimal transdifferentiation potential during lung fibrotic remodeling. Parenchymal and perivascular fibrotic regions were populated predominantly with PDGFRα+ cells expressing collagen, while αSMA+ cells in the parenchyma and vessel wall showed variable expression of collagen and the contractile protein desmin. The distinct gene expression profile found in normal conditions was retained during pathologic remodeling. Cumulatively, our findings identify αSMA+ and PDGFRα+ cells as two separate lineages with distinct gene expression profiles in adult lungs. This cellular heterogeneity suggests that anti-fibrotic therapy should target diverse cell populations.

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Section: ␣Smaϩ Cells Are a Separate Subpopulation Of Fibroblasts Withmentioning

confidence: 99%

Section: ␣Smaϩ Cells Are a Separate Subpopulation Of Fibroblasts Withmentioning

confidence: 99%

PDGFRα and αSMA mark two distinct mesenchymal cell populations involved in parenchymal and vascular remodeling in pulmonary fibrosis

Biasin

Crnković

Sahu-Osen

et al. 2020

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…The Fos-related antigen-1 (Fra-1) transcription factor is thought to play a key role in promoting chronic cigarette smoke- (CS-) induced lung macrophagic inflammation in vivo and experiments have shown that the absence of Fra-1 in mice bone marrow can reduce the expression of inflammatory factors and the aggregation of macrophages in the lung [ 34 ]. Additionally, Fos-related antigen-2 (Fra-2) expression has also been described in COPD for the upregulation of monocyte-derived macrophages upon CS stimulation [ 35 ]. Activating transcription factor 3 (ATF3) may be involved in transcriptional promotion of CS-induced MUC5AC expression, which is a key pathologic feature of COPD in airway epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Determining Pharmacological Mechanisms of Chinese Incompatible Herbs Fuzi and Banxia in Chronic Obstructive Pulmonary Disease: A Systems Pharmacology‐Based Study

Cai

Chen

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Aconiti Lateralis Radix Praeparata (Fuzi) and Pinelliae Rhizoma (Banxia) are among the 18 incompatible medications that are forbidden from use in one formulation. However, there is increasing evidence implying that this prohibition is not entirely correct. According to the theory of Chinese traditional medicine, they can be used for the treatment of chronic obstructive pulmonary disease (COPD). Thus, we analyzed the possible approaches for the treatment of COPD using network pharmacology. The active compounds of Fuzi and Banxia (FB) were collected, and their targets were identified. COPD-related targets were obtained by analyzing the differentially expressed genes between COPD patients and healthy individuals, which were expressed using a Venn diagram of COPD and FB. Protein-protein interaction data and network regarding COPD and drugs used were obtained. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted. The gene-pathway network was constructed to screen the key target genes. In total, 34 active compounds and 47 targets of FB were identified; moreover, 7,153 differentially expressed genes were identified between COPD patients and healthy individuals. The functional annotations of target genes were found to be related to mechanisms such as transcription, cytosol, and protein binding; furthermore, 68 pathways including neuroactive ligand-receptor interaction, Kaposi sarcoma-associated herpesvirus infection, apoptosis, and measles were significantly enriched. FOS CASP3, VEGFA, ESR1, and PTGS2 were the core genes in the gene-pathway network of FB for the treatment of COPD. Our results indicated that the effect of FB against COPD may involve the regulation of immunological function through several specific biological processes and their corresponding pathways. This study demonstrates the application of network pharmacology in evaluating mechanisms of action and molecular targets of herb-opponents FB.

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“…As shown in researches, PKC activated RhoA/Rock to promote contraction of PASMCs by inhibiting MLCP, which disappeared when PKC inhibitors were used [9]. It has also been con rmed that hypoxia induced up-regulation of PKCα expression resulting to the proliferation of PASMCs [10]. Moreover, other studies have suggested that PKC expression changes do not directly affect cell proliferation but may alter a series of downstream proliferation-related pathways.…”

Section: Introductionmentioning

confidence: 86%

Up-regulation of nPKC Contributes to Proliferation of Pulmonary Artery Smooth Muscle Cells in Hypoxia-induced Pulmonary Hypertension

Shi

Jiang

Qin

et al. 2020

Preprint

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Background It has been indicated that protein kinase C (PKC) plays a vital role in the pathogenesis of hypoxia-induced pulmonary hypertension (PH). The functions or the pathogenic roles of PKCs vary from different types, and their related downstream pathways may also be distinct. Therefore, the specific role of different types of PKC deserves to be elucidated. Discussions regarding conventional PKC (cPKC) have dominated research in recent years, however, the relationship between novel PKC (nPKC) and the development of PH remain unclear. In addition, it is less known whether nPKC has a direct effect on the proliferation of pulmonary artery smooth muscle cells (PASMCs). This study is designed to investigate the role of nPKC in mediating PASMCs proliferation in PH and the underlying mechanisms. Methods Mouse PASMCs was isolated using magnetic separation technology. The PASMCs were divided into 24 h group, 48 h group and 72 h group according to different hypoxia treatment time, then detected cell proliferation rate and nPKC expression level in each group. We treated PASMCs with agonists or inhibitors of PKCδ and PKCε and exposed them to hypoxia or normoxia for 72 h, then measured the proliferation of PASMCs. We also constructed a lentiviral vector containing siRNA fragments for inhibiting PKCδ and PKCε to transfected PASMCs, then examined their proliferation. Results PASMCs isolated successfully by magnetic separation method and were in good condition. Hypoxia promoted the proliferation of PASMCs, and the treatment for 72 h had the most significant effect. Hypoxia upregulated the expression of PKCδ and PKCε in mouse PASMCs, leading to PASMCs proliferation. Moreover, Our study demonstrated that hypoxia induced upregulation of PKCδ and PKCε expression resulting to the proliferation of PASMCs via up-regulating the phosphorylation of AKT and ERK. Conclusions Our study provides clear evidence that increased nPKC expression contributes to PASMCs proliferation and uncovers the correlation between AKT and ERK pathways and nPKC-mediated proliferation of PASMCs. These findings may provide novel targets for molecular therapy of pulmonary hypertension.

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Transcription factor Fra-2 and its emerging role in matrix deposition, proliferation and inflammation in chronic lung diseases

Cited by 51 publications

References 95 publications

PDGFRα and αSMA mark two distinct mesenchymal cell populations involved in parenchymal and vascular remodeling in pulmonary fibrosis

PDGFRα and αSMA mark two distinct mesenchymal cell populations involved in parenchymal and vascular remodeling in pulmonary fibrosis

Determining Pharmacological Mechanisms of Chinese Incompatible Herbs Fuzi and Banxia in Chronic Obstructive Pulmonary Disease: A Systems Pharmacology‐Based Study

Up-regulation of nPKC Contributes to Proliferation of Pulmonary Artery Smooth Muscle Cells in Hypoxia-induced Pulmonary Hypertension

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