المؤلفون: Mi So Kim, Ae-Rin Baek, Ji Min Lee, Do Jin Kim, Shunsuke Minagawa, Masahiro Yoshida, Su Sie Chin, An Soo Jang, Choon-Sik Park, Sung Woo Park, June-Hyuk Lee, Jun Araya, Kazuyoshi Kuwano

المصدر: American Journal of Respiratory Cell and Molecular Biology. 59:215-224

مصطلحات موضوعية: 0301 basic medicine, Pulmonary and Respiratory Medicine, Programmed cell death, Necroptosis, Clinical Biochemistry, Apoptosis, Kidney, Bleomycin, Pathogenesis, Mice, Necrosis, 03 medical and health sciences, chemistry.chemical_compound, Idiopathic pulmonary fibrosis, 0302 clinical medicine, Fibrosis, medicine, Animals, Humans, Molecular Biology, Lung, Caspase 3, business.industry, Graft Survival, Epithelial Cells, Cell Biology, respiratory system, medicine.disease, respiratory tract diseases, 030104 developmental biology, medicine.anatomical_structure, chemistry, Receptor-Interacting Protein Serine-Threonine Kinases, 030220 oncology & carcinogenesis, Cancer research, business

الوصف: Alveolar epithelial cell (AEC) injury leading to cell death is involved in the process of fibrosis development during idiopathic pulmonary fibrosis (IPF). Among regulated/programmed cell death, the excessive apoptosis of AECs has been widely implicated in IPF pathogenesis. Necroptosis is a type of regulated/programmed necrosis. A multiprotein complex composed of receptor-interacting protein kinase (RIPK)-1 and -3 plays a key regulatory role in initiating necroptosis. Although necroptosis participates in disease pathogeneses through the release of damage-associated molecular patterns, its association with IPF progression remains elusive. In this study, we attempted to illuminate the involvement of RIPK3-regulated necroptosis in IPF pathogenesis. IPF lung tissues were used to detect necroptosis, and the role of RIPK3 was determined using cell culturing models of AECs. Lung fibrosis models of bleomycin (BLM) treatment were also used. RIPK3 expression levels were increased in IPF lungs, and both apoptosis and necroptosis were detected mainly in AECs. Necrostatin-1 and RIPK3 knockout experiments in AECs revealed the participation of necroptosis in BLM and hydrogen peroxide-induced cell death. BLM treatment induced RIPK3 expression in AECs and increased high-mobility group box 1 and IL-1β levels in mouse lungs. The efficient attenuation of BLM-induced lung inflammation and fibrosis was determined in RIPK3 knockout mice and by necrostatin-1 with a concomitant reduction in high-mobility group box 1 and IL-1β. RIPK3-regulated necroptosis in AECs is involved in the mechanism of lung fibrosis development through the release of damage-associated molecular patterns as part of the pathogenic sequence of IPF.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::628e6e52d56d96daf1247c27d3c1a5e9Test
https://doi.org/10.1165/rcmb.2017-0034ocTest

المؤلفون: Jun Araya, Takahiro Ochiya, Takashi Ohtsuka, Shunsuke Minagawa, Hironori Kawamoto, Yu Fujita, Hiromichi Hara, Yusuke Yamamoto, Kazuyoshi Kuwano, Tsukasa Kadota, Naoaki Watanabe, Shota Fujimoto

المصدر: Journal of Extracellular Vesicles
Journal of Extracellular Vesicles, Vol 10, Iss 10, Pp n/a-n/a (2021)

مصطلحات موضوعية: Histology, senescence, Biology, Exosome, Wnt-5a Protein, Idiopathic pulmonary fibrosis, Extracellular Vesicles, Mice, Fibrosis, Transforming Growth Factor beta, Proto-Oncogene Proteins, Wnt3A Protein, Pulmonary fibrosis, medicine, Animals, Humans, exosome, Wnt Signaling Pathway, Cells, Cultured, Cellular Senescence, Research Articles, mesenchymal stem cell, QH573-671, pulmonary fibrosis, Wnt signaling pathway, Cell Differentiation, Epithelial Cells, Mesenchymal Stem Cells, Cell Biology, Extracellular vesicle, medicine.disease, Idiopathic Pulmonary Fibrosis, Mice, Inbred C57BL, Wnt Proteins, MicroRNAs, Cancer research, Cytology, Myofibroblast, lung epithelial cell, Transforming growth factor, Research Article

الوصف: Idiopathic pulmonary fibrosis (IPF) is characterized by devastating and progressive lung parenchymal fibrosis, resulting in poor patient prognosis. An aberrant recapitulation of developmental lung gene expression, including genes for transforming growth factor (TGF)‐β and WNT, has been widely implicated in the pathogenic IPF wound healing process that results from repetitive alveolar epithelial injury. Extracellular vesicles (EVs) have been shown to carry bioactive molecules and to be involved in various physiological and pathological processes. Here, we demonstrate that, by attenuating WNT signalling, human bronchial epithelial cell‐derived EVs (HBEC EVs) inhibit TGF‐β mediated induction of both myofibroblast differentiation and lung epithelial cellular senescence. This effect of HBEC EVs is more pronounced than that observed with mesenchymal stem cell‐derived EVs. Mechanistically, the HBEC EV microRNA (miRNA) cargo is primarily responsible for attenuating both myofibroblast differentiation and cellular senescence. This attenuation occurs via inhibition of canonical and non‐canonical WNT signalling pathways. Among enriched miRNA species present in HBEC EVs, miR‐16, miR‐26a, miR‐26b, miR‐141, miR‐148a, and miR‐200a are mechanistically involved in reducing WNT5A and WNT10B expression in LFs, and in reducing WNT3A, WNT5A, and WNT10B expression in HBECs. Mouse models utilizing intratracheal administration of EVs demonstrate efficient attenuation of bleomycin‐induced lung fibrosis development accompanied by reduced expression of both β‐catenin and markers of cellular senescence. These findings indicate that EVs derived from normal resident lung HBECs may possess anti‐fibrotic properties. They further suggest that, via miRNA‐mediated inhibition of TGF‐β‐WNT crosstalk, HBEC EVs administration can be a promising anti‐fibrotic modality of treatment for IPF.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e95812b0e698567d2f88fdb32561c283Test
https://pubmed.ncbi.nlm.nih.gov/34377373Test

المؤلفون: Tsukasa Kadota, Yusuke Yoshioka, Yu Fujita, Jun Araya, Shunsuke Minagawa, Hiromichi Hara, Atsushi Miyamoto, Souichiro Suzuki, Sakashi Fujimori, Tadasu Kohno, Takeshi Fujii, Kazuma Kishi, Kazuyoshi Kuwano, Takahiro Ochiya

المصدر: American Journal of Respiratory Cell & Molecular Biology; Nov2020, Vol. 63 Issue 5, p623-636, 40p

مصطلحات موضوعية: PULMONARY fibrosis, VESICLES (Cytology), EPITHELIAL cells, FIBROBLASTS, EXOSOMES, FIBROSIS

مستخلص: Aberrant epithelial-mesenchymal interactions have critical roles in regulating fibrosis development. The involvement of extracellular vesicles (EVs), including exosomes, remains to be elucidated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Here, we found that lung fibroblasts (LFs) from patients with IPF induce cellular senescence via EV-mediated transfer of pathogenic cargo to lung epithelial cells. Mechanistically, IPF LF-derived EVs increased mitochondrial reactive oxygen species and associated mitochondrial damage in lung epithelial cells, leading to activation of the DNA damage response and subsequent epithelial-cell senescence. We showed that IPF LF-derived EVs contain elevated levels of microRNA-23b-3p (miR-23b-3p) and miR-494-3p, which suppress SIRT3, resulting in the epithelial EV-induced phenotypic changes. Furthermore, the levels of miR-23b-3p and miR-494-3p found in IPF LF-derived EVs correlated positively with IPF disease severity. These findings reveal that the accelerated epithelial-cell mitochondrial damage and senescence observed during IPF pathogenesis are caused by a novel paracrine effect of IPF fibroblasts via microRNA-containing EVs. [ABSTRACT FROM AUTHOR]

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المؤلفون: Stephen L. Nishimura, Satoko Nojiri, Kazuyoshi Kuwano, Shunsuke Minagawa, Makoto Kawaishi, Jun Araya, Yoko Yumino, Makoto Odaka, Takanori Numata, Hiromichi Hara, Katsutoshi Nakayama, Toshiaki Morikawa

المصدر: American Journal of Physiology-Lung Cellular and Molecular Physiology. 300:L391-L401

مصطلحات موضوعية: Cyclin-Dependent Kinase Inhibitor p21, Pulmonary and Respiratory Medicine, Senescence, SIRT6, Proteasome Endopeptidase Complex, Physiology, Cellular differentiation, Interleukin-1beta, Bronchi, Biology, Transforming Growth Factor beta1, Fibrosis, Physiology (medical), medicine, Humans, Sirtuins, Myofibroblasts, Cellular Senescence, Interleukin, Cell Differentiation, Epithelial Cells, Articles, Cell Biology, respiratory system, beta-Galactosidase, medicine.disease, Idiopathic Pulmonary Fibrosis, respiratory tract diseases, Immunology, Cancer research, Protein Processing, Post-Translational, Cell aging, Myofibroblast, Transforming growth factor

الوصف: Reepithelialization of remodeled air spaces with bronchial epithelial cells is a prominent pathological finding in idiopathic pulmonary fibrosis (IPF) and is implicated in IPF pathogenesis. Recent studies suggest that epithelial senescence is a risk factor for development of IPF, indicating such reepithelialization may be influenced by the acceleration of cellular senescence. Among the sirtuin (SIRT) family, SIRT6, a class III histone deacetylase, has been demonstrated to antagonize senescence. We evaluated the senescence of bronchiolization in association with SIRT6 expression in IPF lung. Senescence-associated β-galactosidase staining and immunohistochemical detection of p21 were performed to evaluate cellular senescence. As a model for transforming growth factor (TGF)-β-induced senescence of abnormal reepithelialization, we used primary human bronchial epithelial cells (HBEC). The changes of SIRT6, p21, and interleukin (IL)-1β expression levels in HBEC, as well as type I collagen expression levels in fibroblasts, were evaluated. In IPF lung samples, an increase in markers of senescence and SIRT6 expression was found in the bronchial epithelial cells lining cystically remodeled air spaces. We found that TGF-β induced senescence in primary HBEC by increasing p21 expression, and, whereas TGF-β also induced SIRT6, it was not sufficient to inhibit cellular senescence. However, overexpression of SIRT6 efficiently inhibited TGF-β-induced senescence via proteasomal degradation of p21. TGF-β-induced senescent HBEC secreted increased amounts of IL-1β, which was sufficient to induce myofibroblast differentiation in fibroblasts. These findings suggest that accelerated epithelial senescence plays a role in IPF pathogenesis through perpetuating abnormal epithelial-mesenchymal interactions, which can be antagonized by SIRT6.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::667dd876eec7ed7f88704f26ad106c0cTest
https://doi.org/10.1152/ajplung.00097.2010Test