bims-tralur Biomed News
on Translational lung research
Issue of 2021–08–29
nine papers selected by
Willy Roque Barboza, Penn Medicine
  1. Long Noncoding RNA FENDRR Inhibits Lung Fibroblast Proliferation via a Reduction of β-Catenin.
  2. The Pathogenic Role of Smooth Muscle Cell-Derived Wnt5a in a Murine Model of Lung Fibrosis.
  3. Evaluation on epithelial-mesenchymal state and microRNAs focusing on isolated alveolar epithelial cells from bleomycin injured rat lung.
  4. Stretch increases alveolar type 1 cell number in fetal lungs through ROCK-Yap/Taz pathway.
  5. Erratum to spliceosome-associated protein 130: a novel biomarker for idiopathic pulmonary fibrosis.
  6. Alveolar macrophages rely on GM-CSF from alveolar epithelial type 2 cells before and after birth.
  7. An Update on the Role of Nrf2 in Respiratory Disease: Molecular Mechanisms and Therapeutic Approaches.
  8. Kurarinone Attenuates BLM-Induced Pulmonary Fibrosis via Inhibiting TGF-β Signaling Pathways.
  9. Proteomic Analysis Reveals Key Proteins in Extracellular Vesicles Cargo Associated with Idiopathic Pulmonary Fibrosis In Vitro.
  1. Int J Mol Sci. 2021 Aug 09. pii: 8536. [Epub ahead of print]22(16):
    Long Noncoding RNA FENDRR Inhibits Lung Fibroblast Proliferation via a Reduction of β-Catenin.
    Lakmini Kumari Senavirathna, Yurong Liang, Chaoqun Huang, Xiaoyun Yang, Gayan Bamunuarachchi, Dao Xu, Quanjin Dang, Pulavendran Sivasami, Kishore Vaddadi, Maria Cristina Munteanu, Sankha Hewawasam, Paul Cheresh, David W Kamp, Lin Liu.
      Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, and usually lethal lung disease and it has been widely accepted that fibroblast proliferation is one of the key characteristics of IPF. Long noncoding RNAs (lncRNAs) play vital roles in the pathogenesis of many diseases. In this study, we investigated the role of lncRNA FENDRR on fibroblast proliferation. Human lung fibroblasts stably overexpressing FENDRR showed a reduced cell proliferation compared to those expressing the control vector. On the other hand, FENDRR silencing increased fibroblast proliferation. FENDRR bound serine-arginine rich splicing factor 9 (SRSF9) and inhibited the phosphorylation of p70 ribosomal S6 kinase 1 (PS6K), a downstream protein of the mammalian target of rapamycin (mTOR) signaling. Silencing SRSF9 reduced fibroblast proliferation. FENDRR reduced β-catenin protein, but not mRNA levels. The reduction of β-catenin protein levels in lung fibroblasts by gene silencing or chemical inhibitor decreased fibroblast proliferation. Adenovirus-mediated FENDRR transfer to the lungs of mice reduced asbestos-induced fibrotic lesions and collagen deposition. RNA sequencing of lung tissues identified 7 cell proliferation-related genes that were up-regulated by asbestos but reversed by FENDRR. In conclusion, FENDRR inhibits fibroblast proliferation and functions as an anti-fibrotic lncRNA.
    Keywords:  FENDRR; SRSF9; mTOR signaling; β-catenin
    DOI:  https://doi.org/10.3390/ijms22168536
  2. Pharmaceuticals (Basel). 2021 Jul 31. pii: 755. [Epub ahead of print]14(8):
    The Pathogenic Role of Smooth Muscle Cell-Derived Wnt5a in a Murine Model of Lung Fibrosis.
    André Carmo-Fernandes, Michelle Puschkarow, Karin Peters, Stefanie Gnipp, Marcus Peters.
      Idiopathic pulmonary fibrosis (IPF) is a disease characterized by extensive fibrosis of the lung tissue. Wnt5a expression was observed to be upregulated in IPF and suggested to be involved in the progression of the disease. Interestingly, smooth muscle cells (SMC) are a major source of Wnt5a in IPF patients. However, no study has been conducted until now to investigate the precise role of smooth muscle-derived Wnt5a in IPF. Here, we used the bleomycin-induced lung fibrosis model in a conditional gene-deficient mouse, where the Wnt5a gene was excised from SMC. We show here that the excision of the Wnt5a gene in SMC led to significantly improved health conditions with minimized weight loss and improved lung function. This improvement was based on a significantly lower deposition of collagen in the lung with a reduced number of fibrotic foci in lung parenchyma. Furthermore, the bleomycin-induced cellular infiltration into the airways was not altered in the gene-deficient mice compared with wild-type mice. Thus, we demonstrate that the Wnt5a expression of SMC of the airways leads to aggravated fibrosis of the lung with poor clinical conditions. This aggravation was not an influence in the bleomycin-induced inflammatory processes but on the development of fibrotic foci in lung parenchyma and the deposition of collagen.
    Keywords:  Wingless-Type MMTV integration site family, member 5A; airway smooth muscle; bleomycin; fibrotic foci; pulmonary fibrosis
    DOI:  https://doi.org/10.3390/ph14080755
  3. Toxicology. 2021 Aug 20. pii: S0300-483X(21)00226-2. [Epub ahead of print]461 152903
    Evaluation on epithelial-mesenchymal state and microRNAs focusing on isolated alveolar epithelial cells from bleomycin injured rat lung.
    Masashi Kawami, Shinnosuke Takenaka, Yuri Kadekaru, Mizuki Akai, Takashi Konaka, Ryoko Yumoto, Mikihisa Takano.
      Several studies using bleomycin (BLM)-induced lung injury rat model revealed that epithelial-mesenchymal transition (EMT) contributes to pulmonary fibrosis. Conversely, microRNAs (miRNAs) are considered as useful markers of various diseases. In the present study, we aimed to characterize the EMT state through focusing on alveolar epithelial cells and identify the miRNAs that can be used as markers to predict pulmonary fibrosis using a BLM-induced lung injury rat model. Intratracheal administration of BLM increased hydroxyproline, a component of collagen, in lung tissues at day 14, but not at day 7. However, BLM induced EMT at day 7, which was accompanied with increased mRNA expression of α-smooth muscle actin, a representative EMT marker, in alveolar epithelium, thereby suggesting that EMT occurs prior to pulmonary fibrosis in alveolar epithelial cells. Using this rat model, the expression levels of several EMT-associated miRNAs were examined, and miR-222 was found to be upregulated in alveolar epithelial cells as well as bronchoalveolar lavage fluid from day 3. Our findings indicate that EMT in alveolar epithelial cells may occur before pulmonary fibrosis, and miR-222 may be used as a potential marker for early prediction of pulmonary fibrosis.
    Keywords:  Alveolar epithelium; Bleomycin; Bronchoalveolar lavage fluid; Epithelial-mesenchymal transition; Pulmonary fibrosis; microRNAs
    DOI:  https://doi.org/10.1016/j.tox.2021.152903
  4. Am J Physiol Lung Cell Mol Physiol. 2021 08 25.
    Stretch increases alveolar type 1 cell number in fetal lungs through ROCK-Yap/Taz pathway.
    Tram Mai Nguyen, Johannes van der Merwe, Linda Elowsson Rendin, Anna-Karin Larsson-Callerfelt, Jan Deprest, Gunilla Westergren-Thorsson, Jaan Toelen.
      Accurate fluid pressure in the fetal lung is critical for its development, especially at the beginning of the saccular stage when alveolar epithelial type 1 (AT1) and type 2 (AT2) cells differentiate from the epithelial progenitors. Despite our growing understanding of the role of physical forces in lung development, the molecular mechanisms that regulate the transduction of mechanical stretch to alveolar differentiation remain elusive. To simulate lung distension, we optimized both an ex vivo model with precision cut lung slices and an in vivo model of fetal tracheal occlusion. Increased mechanical tension showed to improve alveolar maturation and differentiation towards AT1. By manipulating ROCK pathway, we demonstrate that stretch-induced Yap/Taz activation promotes alveolar differentiation towards AT1 phenotype via ROCK activity. Our findings show that balanced ROCK-Yap/Taz signaling is essential to regulate AT1 differentiation in response to mechanical stretching of the fetal lung, which might be helpful in improving lung development and regeneration.
    Keywords:  alveolar cell type 1; alveolar development; congenital diaphragmatic hernia; fetal lung stretch; tracheal occlusion
    DOI:  https://doi.org/10.1152/ajplung.00484.2020
  5. Ann Transl Med. 2021 Jul;9(13): 1111
    Erratum to spliceosome-associated protein 130: a novel biomarker for idiopathic pulmonary fibrosis.
    Editorial Office
      [This corrects the article DOI: 10.21037/atm-20-4404.].
    DOI:  https://doi.org/10.21037/atm-2021-5
  6. J Exp Med. 2021 Oct 04. pii: e20210745. [Epub ahead of print]218(10):
    Alveolar macrophages rely on GM-CSF from alveolar epithelial type 2 cells before and after birth.
    Julia Gschwend, Samantha P M Sherman, Frederike Ridder, Xiaogang Feng, Hong-Erh Liang, Richard M Locksley, Burkhard Becher, Christoph Schneider.
      Programs defining tissue-resident macrophage identity depend on local environmental cues. For alveolar macrophages (AMs), these signals are provided by immune and nonimmune cells and include GM-CSF (CSF2). However, evidence to functionally link components of this intercellular cross talk remains scarce. We thus developed new transgenic mice to profile pulmonary GM-CSF expression, which we detected in both immune cells, including group 2 innate lymphoid cells and γδ T cells, as well as AT2s. AMs were unaffected by constitutive deletion of hematopoietic Csf2 and basophil depletion. Instead, AT2 lineage-specific constitutive and inducible Csf2 deletion revealed the nonredundant function of AT2-derived GM-CSF in instructing AM fate, establishing the postnatal AM compartment, and maintaining AMs in adult lungs. This AT2-AM relationship begins during embryogenesis, where nascent AT2s timely induce GM-CSF expression to support the proliferation and differentiation of fetal monocytes contemporaneously seeding the tissue, and persists into adulthood, when epithelial GM-CSF remains restricted to AT2s.
    DOI:  https://doi.org/10.1084/jem.20210745
  7. Int J Mol Sci. 2021 Aug 05. pii: 8406. [Epub ahead of print]22(16):
    An Update on the Role of Nrf2 in Respiratory Disease: Molecular Mechanisms and Therapeutic Approaches.
    Jooyeon Lee, Jimin Jang, Sung-Min Park, Se-Ran Yang.
      Nuclear factor erythroid 2-related factor (Nrf2) is a transcriptional activator of the cell protection gene that binds to the antioxidant response element (ARE). Therefore, Nrf2 protects cells and tissues from oxidative stress. Normally, Kelch-like ECH-associated protein 1 (Keap1) inhibits the activation of Nrf2 by binding to Nrf2 and contributes to Nrf2 break down by ubiquitin proteasomes. In moderate oxidative stress, Keap1 is inhibited, allowing Nrf2 to be translocated to the nucleus, which acts as an antioxidant. However, under unusually severe oxidative stress, the Keap1-Nrf2 mechanism becomes disrupted and results in cell and tissue damage. Oxide-containing atmospheric environment generally contributes to the development of respiratory diseases, possibly leading to the failure of the Keap1-Nrf2 pathway. Until now, several studies have identified changes in Keap1-Nrf2 signaling in models of respiratory diseases, such as acute respiratory distress syndrome (ARDS)/acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and asthma. These studies have confirmed that several Nrf2 activators can alleviate symptoms of respiratory diseases. Thus, this review describes how the expression of Keap1-Nrf2 functions in different respiratory diseases and explains the protective effects of reversing this expression.
    Keywords:  Nrf2; ROS; keap1; lung; oxidative stress; respiratory diseases
    DOI:  https://doi.org/10.3390/ijms22168406
  8. Int J Mol Sci. 2021 Aug 04. pii: 8388. [Epub ahead of print]22(16):
    Kurarinone Attenuates BLM-Induced Pulmonary Fibrosis via Inhibiting TGF-β Signaling Pathways.
    Soo-Jin Park, Tae-Hyoun Kim, Kiram Lee, Min-Ah Kang, Hyun-Jae Jang, Hyung-Won Ryu, Sei-Ryang Oh, Hyun-Jun Lee.
      Idiopathic pulmonary fibrosis (IPF) is a refractory interstitial lung disease for which there is no effective treatment. Although the pathogenesis of IPF is not fully understood, TGF-β and epithelial-mesenchymal transition (EMT) have been shown to be involved in the fibrotic changes of lung tissues. Kurarinone is a prenylated flavonoid isolated from Sophora Flavescens with antioxidant and anti-inflammatory properties. In this study, we investigated the effect of kurarinone on pulmonary fibrosis. Kurarinone suppressed the TGF-β-induced EMT of lung epithelial cells. To assess the therapeutic effects of kurarinone in bleomycin (BLM)-induced pulmonary fibrosis, mice were treated with kurarinone daily for 2 weeks starting 7 days after BLM instillation. Oral administration of kurarinone attenuated the fibrotic changes of lung tissues, including accumulation of collagen and improved mechanical pulmonary functions. Mechanistically, kurarinone suppressed phosphorylation of Smad2/3 and AKT induced by TGF-β1 in lung epithelial cells, as well as in lung tissues treated with BLM. Taken together, these results suggest that kurarinone has a therapeutic effect on pulmonary fibrosis via suppressing TGF-β signaling pathways and may be a novel drug candidate for pulmonary fibrosis.
    Keywords:  TGF-β; epithelial–mesenchymal transition; kurarinone; pulmonary fibrosis
    DOI:  https://doi.org/10.3390/ijms22168388
  9. Biomedicines. 2021 Aug 20. pii: 1058. [Epub ahead of print]9(8):
    Proteomic Analysis Reveals Key Proteins in Extracellular Vesicles Cargo Associated with Idiopathic Pulmonary Fibrosis In Vitro.
    Juan Manuel Velázquez-Enríquez, Jovito Cesar Santos-Álvarez, Alma Aurora Ramírez-Hernández, Edilburga Reyes-Jiménez, Armando López-Martínez, Socorro Pina-Canseco, Sergio Roberto Aguilar-Ruiz, María de Los Ángeles Romero-Tlalolini, Luis Castro-Sánchez, Jaime Arellanes-Robledo, Verónica Rocío Vásquez-Garzón, Rafael Baltiérrez-Hoyos.
      Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible, and highly fatal disease. It is characterized by the increased activation of both fibroblast and myofibroblast that results in excessive extracellular matrix (ECM) deposition. Extracellular vesicles (EVs) have been described as key mediators of intercellular communication in various pathologies. However, the role of EVs in the development of IPF remains poorly understood. This study aimed to characterize the differentially expressed proteins contained within EVs cargo derived from the fibroblast cell lines LL97A (IPF-1) and LL29 (IPF-2) isolated from lungs bearing IPF as compared to those derived from the fibroblast cell lines CCD8Lu (NL-1) and CCD19Lu (NL-2) isolated from healthy donors. Isolated EVs were subjected to label-free quantitative proteomic analysis by LC-MS/MS, and as a result, 331 proteins were identified. Differentially expressed proteins were obtained after the pairwise comparison, including all experimental groups. A total of 86 differentially expressed proteins were identified in either one or more comparison groups. Of note, proteins involved in fibrogenic processes, such as tenascin-c (TNC), insulin-like-growth-factor-binding protein 7 (IGFBP7), fibrillin-1 (FBN1), alpha-2 collagen chain (I) (COL1A2), alpha-1 collagen chain (I) (COL1A1), and lysyl oxidase homolog 1 (LOXL1), were identified in EVs cargo isolated from IPF cell lines. Additionally, KEGG pathway enrichment analysis revealed that differentially expressed proteins participate in focal adhesion, PI3K-Akt, and ECM-receptor interaction signaling pathways. In conclusion, our findings reveal that proteins contained within EVs cargo might play key roles during IPF pathogenesis.
    Keywords:  extracellular vesicles; fibroblasts; idiopathic pulmonary fibrosis; mass spectrometry; proteomic analysis
    DOI:  https://doi.org/10.3390/biomedicines9081058
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