المؤلفون: Tsukasa Kadota, Yu Fujita, Yusuke Yoshioka, Jun Araya, Kazuyoshi Kuwano, Takahiro Ochiya

المصدر: International Journal of Molecular Sciences, Vol 17, Iss 11, p 1801 (2016)

مصطلحات موضوعية: COPD, extracellular vesicles, exosome, microRNA, microvesicle, pathogenesis, biomarker, therapy, exacerbation, endothelial microparticle, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: Chronic obstructive pulmonary disease (COPD) is characterized by the progression of irreversible airflow limitation and is a leading cause of morbidity and mortality worldwide. Although several crucial mechanisms of COPD pathogenesis have been studied, the precise mechanism remains unknown. Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, are released from almost all cell types and are recognized as novel cell–cell communication tools. They have been shown to carry and transfer a wide variety of molecules, such as microRNAs, messenger RNAs, and proteins, which are involved in physiological functions and the pathology of various diseases. Recently, EVs have attracted considerable attention in pulmonary research. In this review, we summarize the recent findings of EV-mediated COPD pathogenesis. We also discuss the potential clinical usefulness of EVs as biomarkers and therapeutic agents for the treatment of COPD.

وصف الملف: electronic resource

العلاقة: http://www.mdpi.com/1422-0067/17/11/1801Test; https://doaj.org/toc/1422-0067Test

الوصول الحر: https://doaj.org/article/85b2bd8cd6b844b9b67e117b2bc61800Test

المؤلفون: Keitaro Okuda, Takeo Ishikawa, Hirofumi Utsumi, Yu Fujita, Shunsuke Minagawa, Jun Araya, Hanae Miyagawa, Mitsuo Hashimoto, Takanori Numata, Hiromichi Hara, Kazuyoshi Kuwano, Daisuke Takekoshi

المصدر: Journal of Asthma and Allergy

مصطلحات موضوعية: Pulmonary and Respiratory Medicine, medicine.medical_specialty, benralizumab, Combination therapy, business.industry, switching, mepolizumab, Retrospective cohort study, Omalizumab, Single Center, Benralizumab, Dupilumab, chemistry.chemical_compound, chemistry, Internal medicine, dupilumab, Exhaled nitric oxide, medicine, Journal of Asthma and Allergy, Immunology and Allergy, omalizumab, business, Mepolizumab, medicine.drug, Original Research

الوصف: Takanori Numata, Jun Araya, Hanae Miyagawa, Keitaro Okuda, Yu Fujita, Hirofumi Utsumi, Daisuke Takekoshi, Mitsuo Hashimoto, Shunsuke Minagawa, Takeo Ishikawa, Hiromichi Hara, Kazuyoshi Kuwano Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, JapanCorrespondence: Takanori Numata Tel +81-3-3433-1111 (ex 3271)Fax +81-3-3433-1020Email t-numata@jikei.ac.jpBackground: In Japan, biologic therapy was initiated for patients with severe asthma in 2009. In recent years, four biologics with different mechanisms of action have become available in the clinical setting. However, the efficacy of switching between biologics remains uncertain.Methods: To elucidate the efficacy of switching between biologics, 97 patients were enrolled who had received any biologic therapy for severe asthma at Jikei University Hospital, Tokyo, Japan, from July 2009 to December 2020. We retrospectively examined the patient characteristics, biomarkers, pulmonary function test results, selected biologics, and efficacy.Results: Thirty-one males and 66 females received any biologics. The mean age was 53.3 years at the initiation of biologic therapy. Initially, 33, 41, 15 and eight patients received omalizumab, mepolizumab, benralizumab, and dupilumab, respectively. Among three representative indicators for biologics administration, the peripheral blood eosinophil count, serum IgE levels and fractional exhaled nitric oxide, 64% of the patients had two indicators, and 28% had three indicators. Thirty-four patients (35%) switched from the initial biologic to another, and the reasons for switching included persistent asthmatic symptoms (n=22), schedule of hospital visits (n=5), and other reasons. Thus, the treatment was effective in 11 patients after switching. In addition, two patients received combination therapy with different biologics. Eighteen patients (19%) interrupted treatment for various reasons. Regardless of whether the biologic was the initial therapy, the overall efficacy of the four biologics was 60% based on the global evaluation of treatment effectiveness.Conclusion: Switching between biologics can be a promising option for severe asthma patients in whom treatment with an initial biologic is ineffective.Keywords: benralizumab, dupilumab, mepolizumab, omalizumab, switching

وصف الملف: text/html

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::329ef0bb5a47e28c9aea7b322f99c35eTest
http://europepmc.org/articles/PMC8184231Test

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

المصدر: American Journal of Respiratory Cell and Molecular Biology. 63:623-636

مصطلحات موضوعية: 0301 basic medicine, Pulmonary and Respiratory Medicine, Senescence, DNA damage, Chemistry, Clinical Biochemistry, Cell Biology, respiratory system, medicine.disease, Exosome, humanities, respiratory tract diseases, 03 medical and health sciences, Idiopathic pulmonary fibrosis, Paracrine signalling, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, 030228 respiratory system, Fibrosis, Pulmonary fibrosis, medicine, Cancer research, Fibroblast, Molecular Biology

الوصف: 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.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::f8ae09fb1aceb5590fa9f4b54180a5cdTest
https://doi.org/10.1165/rcmb.2020-0002ocTest

المؤلفون: Tsukasa Kadota, Kenji Kobayashi, Yusuke Kurita, Saburo Ito, Katsutoshi Nakayama, Hiromichi Hara, Makoto Odaka, Takanori Numata, Hiroshi Wakui, Yumi Kaneko, Kazuya Tsubouchi, Shohei Mori, Akihiro Ichikawa, Makoto Yamashita, Yusuke Hosaka, Shunsuke Minagawa, Hirotaka Imai, Hisatoshi Asano, Kazuyoshi Kuwano, Nayuta Saito, Nahoko Sato, Masahiro Yoshida, Toshiaki Morikawa, Taro Sakamoto, Hirohumi Utsumi, Jun Araya, Takeo Iwamoto

المصدر: Nature Communications, Vol 10, Iss 1, Pp 1-14 (2019)
Nature Communications

مصطلحات موضوعية: 0301 basic medicine, General Physics and Astronomy, 02 engineering and technology, GPX4, medicine.disease_cause, Pathogenesis, Lipid peroxidation, chemistry.chemical_compound, Pulmonary Disease, Chronic Obstructive, lcsh:Science, Phospholipids, COPD, Multidisciplinary, biology, Chronic obstructive pulmonary disease, Smoking, respiratory system, 021001 nanoscience & nanotechnology, Deferoxamine, 0210 nano-technology, medicine.drug, Cell death, Programmed cell death, Iron, Science, Nuclear Receptor Coactivators, Mice, Transgenic, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, medicine, Animals, Ferroptosis, Humans, business.industry, Epithelial Cells, General Chemistry, medicine.disease, respiratory tract diseases, Ferritin, Mice, Inbred C57BL, 030104 developmental biology, chemistry, biology.protein, Cancer research, lcsh:Q, Lipid Peroxidation, business, Reactive Oxygen Species, Oxidative stress

الوصف: Ferroptosis is a necrotic form of regulated cell death (RCD) mediated by phospholipid peroxidation in association with free iron-mediated Fenton reactions. Disrupted iron homeostasis resulting in excessive oxidative stress has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, we demonstrate the involvement of ferroptosis in COPD pathogenesis. Our in vivo and in vitro models show labile iron accumulation and enhanced lipid peroxidation with concomitant non-apoptotic cell death during cigarette smoke (CS) exposure, which are negatively regulated by GPx4 activity. Treatment with deferoxamine and ferrostatin-1, in addition to GPx4 knockdown, illuminate the role of ferroptosis in CS-treated lung epithelial cells. NCOA4-mediated ferritin selective autophagy (ferritinophagy) is initiated during ferritin degradation in response to CS treatment. CS exposure models, using both GPx4-deficient and overexpressing mice, clarify the pivotal role of GPx4-regulated cell death during COPD. These findings support a role for cigarette smoke-induced ferroptosis in the pathogenesis of COPD.
Altered iron homeostasis resulting in excessive oxidative stress has been implicated in smoke-induced lung diseases. Here the authors show that ferroptosis of lung epithelial cells, potentially resulting from excessive ferritinophagy, is involved in the pathogenesis of COPD.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::841b34bc8bc50cc9523737c8cc820ffeTest
https://doaj.org/article/7f973dabdbee4e05bfa82fda5c334da7Test

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: Hanae Miyagawa, Mitsuo Hashimoto, Jun Araya, Takanori Numata, Takeo Ishikawa, Hirofumi Utsumi, Shunsuke Minagawa, Kazuyoshi Kuwano, Hiromichi Hara, Saiko Nishioka, Keitaro Okuda

المصدر: BMC Pulmonary Medicine
BMC Pulmonary Medicine, Vol 20, Iss 1, Pp 1-10 (2020)

مصطلحات موضوعية: Male, Eosinophilic asthma, Severity of Illness Index, Pulmonary function testing, Leukocyte Count, chemistry.chemical_compound, 0302 clinical medicine, Adrenal Cortex Hormones, Forced Expiratory Volume, Anti-Asthmatic Agents, 030212 general & internal medicine, Respiratory disease, Benralizumab, Middle Aged, Global evaluation of treatment effectiveness, medicine.anatomical_structure, Disease Progression, Corticosteroid, Drug Therapy, Combination, Female, Life study, Research Article, medicine.drug, Adult, Pulmonary and Respiratory Medicine, medicine.medical_specialty, medicine.drug_class, Antibodies, Monoclonal, Humanized, Young Adult, 03 medical and health sciences, Internal medicine, medicine, Humans, Aged, Retrospective Studies, lcsh:RC705-779, Eosinophilic chronic rhinosinusitis, business.industry, lcsh:Diseases of the respiratory system, Eosinophil, medicine.disease, Asthma, Eosinophils, Logistic Models, 030228 respiratory system, chemistry, Multivariate Analysis, Asthma, Aspirin-Induced, Interleukin-5, business, Mepolizumab

الوصف: Background Benralizumab, an anti-interleukin-5 (IL-5) receptor α monoclonal antibody, significantly reduces the number of annual exacerbations and oral corticosteroid (OCS) maintenance doses for patients with severe eosinophilic asthma (SEA). However, few studies on the efficacy of this biologic in real life are available. The aim was to elucidate the efficacy of benralizumab by evaluating changes in clinical parameters after benralizumab treatment in patients with SEA. Methods From July 2018 to December 2019, 24 Japanese patients with SEA received benralizumab at Jikei University Hospital. We retrospectively evaluated the patients’ characteristics, parameters, numbers of exacerbations and maintenance OCS doses. Results Among the 24 patients, eleven patients had received mepolizumab treatment and were directly switched to benralizumab. The peripheral blood eosinophil and basophil counts significantly decreased after benralizumab treatment regardless of previous mepolizumab treatment. Pulmonary function, Asthma Control Test scores, the numbers of annual exacerbations and maintenance OCS doses in patients without previous mepolizumab treatment tended to improve without significant differences. Fourteen patients (58%) were responders according to the Global Evaluation of Treatment Effectiveness (GETE) score. The proportion of GETE responders among patients with aspirin-exacerbated respiratory disease (AERD) tended to be lower than that among patients without AERD (p = 0.085). After benralizumab treatment, the change in the forced expiratory volume in 1 s from baseline was 200 ml or greater in eight patients (33%), including three patients who were switched from mepolizumab. Conclusion Benralizumab treatment improved and controlled asthma symptoms based on the GETE score.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c9efeec0cb87b1ebdad261febd939241Test
https://doi.org/10.1186/s12890-020-01248-xTest

المؤلفون: Hiromichi Hara, Keitaro Okuda, Jun Araya, Hirofumi Utsumi, Daisuke Takekoshi, Saburo Ito, Hiroshi Wakui, Shunsuke Minagawa, Takanori Numata, Kazuyoshi Kuwano

المصدر: PLoS ONE
PLoS ONE, Vol 16, Iss 12, p e0261866 (2021)

مصطلحات موضوعية: Lung Diseases, Male, Physiology, Esophageal Diseases, Pathology and Laboratory Medicine, Diagnostic Radiology, Gastroesophageal Reflux Disease, Medicine and Health Sciences, Tomography, Multidisciplinary, Mycobacterium abscessus, Organic Compounds, Radiology and Imaging, Nontuberculous Mycobacteria, Middle Aged, Bacterial Pathogens, Body Fluids, Actinobacteria, Chemistry, Medical Microbiology, Physical Sciences, Medicine, Female, Steroids, Pathogens, Anatomy, Dilatation, Pathologic, Research Article, Imaging Techniques, Science, Mycobacterium Infections, Nontuberculous, Neuroimaging, Gastroenterology and Hepatology, Research and Analysis Methods, Microbiology, Esophagus, Signs and Symptoms, Diagnostic Medicine, Humans, Microbial Pathogens, Aged, Retrospective Studies, Bacteria, Organic Chemistry, Organisms, Sputum, Chemical Compounds, Biology and Life Sciences, Mycobacteria, Computed Axial Tomography, Gastrointestinal Tract, Mucus, Lesions, Clinical Medicine, Digestive System, Neuroscience

الوصف: Objectives Recently, incidence of Mycobacterium abscessus (Mab) pulmonary disease (Mab-PD) is increasing worldwide. We aimed to identify factors associated with severity of Mycobacterium abscessus (Mab) pulmonary disease (Mab-PD). Methods All patients diagnosed as Mab-PD based on the official ATS/IDSA statement between 2017 January 1 and 2021 July 31 were included (n = 13). We reviewed medical records, bacteriological and laboratory data of the patients. Severity of lung lesions and esophageal diameters in chest CT were quantitatively evaluated. Gaffky score in the sputum was used as airway mycobacterial burden. We explored the factors associated with high CT score and high Gaffky score. Results Maximum diameter of esophagus (MDE) in severe disease (CT score≧10) was greater than that in milder disease (CT score Conclusions Esophageal dilatation was correlated with severity of Mab-PD and airway mycobacterial burden. Gastroesophageal reflux might be associated with Mab disease progression.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0d114f9925c3590f34bdef17b0acfefdTest
https://doi.org/10.1371/journal.pone.0261866Test

المؤلفون: Shigehiro Yagishita, Shota Fujimoto, Akihiro Ichikawa, Tsukasa Kadota, Jun Araya, Shunsuke Minagawa, Yusuke Yamamoto, Yu Fujita, Akihiko Ito, Hiromichi Hara, Hironori Kawamoto, Mitsuo Hashimoto, Yusuke Hosaka, Noriko Motoi, Naoaki Watanabe, Nayuta Saito, Takahiro Ochiya, Kazuyoshi Kuwano, Masahiro Yoshida

المصدر: Cancer Science

مصطلحات موضوعية: 0301 basic medicine, Cancer Research, Programmed cell death, Lung Neoplasms, Gene Expression, LAMP2A, 03 medical and health sciences, 0302 clinical medicine, Chaperone-mediated autophagy, Downregulation and upregulation, Cell, Molecular, and Stem Cell Biology, chaperone‐mediated autophagy, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Lysosomal-Associated Membrane Protein 2, medicine, Biomarkers, Tumor, Animals, Humans, health care economics and organizations, Cell Proliferation, Cell growth, Chemistry, Intrinsic apoptosis, Autophagy, apoptosis, Cancer, chemoresistance, General Medicine, Original Articles, medicine.disease, Prognosis, Immunohistochemistry, humanities, respiratory tract diseases, lung cancer, 030104 developmental biology, Oncology, Apoptosis, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Gene Knockdown Techniques, Proteolysis, Cancer research, Original Article, Lysosomes, Signal Transduction

الوصف: Chaperone‐mediated autophagy (CMA) is a lysosomal degradation pathway of selective soluble proteins. Lysosome‐associated membrane protein type 2a (LAMP2A) is the key receptor protein of CMA; downregulation of LAMP2A leads to CMA blockade. Although CMA activation has been involved in cancer growth, CMA status and functions in non–small cell lung cancer (NSCLC) by focusing on the roles in regulating chemosensitivity remain to be clarified. In this study, we found that LAMP2A expression is elevated in NSCLC cell lines and patient's tumors, conferring poor survival and platinum resistance in NSCLC patients. LAMP2A knockdown in NSCLC cells suppressed cell proliferation and colony formation and increased the sensitivity to chemotherapeutic drugs in vitro. Furthermore, we found that intrinsic apoptosis signaling is the mechanism of cell death involved with CMA blockade. Remarkably, LAMP2A knockdown repressed tumorigenicity and sensitized the tumors to cisplatin treatment in NSCLC‐bearing mice. Our discoveries suggest that LAMP2A is involved in the regulation of cancer malignant phenotypes and represents a promising new target against chemoresistant NSCLC.
Lysosome‐associated membrane protein type 2a (LAMP2A) is the key receptor protein of chaperone‐mediated autophagy (CMA). Downregulation of LAMP2A leads to CMA blockade. Our discoveries suggest that LAMP2A is involved in the regulation of cancer malignant phenotypes through CMA modulation and represents a promising new target against chemoresistant non–small cell lung cancer (NSCLC).

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::616b207a3b1cc1b20236e8ac2e65e8baTest
https://pubmed.ncbi.nlm.nih.gov/32860290Test

المؤلفون: Masahiro Yoshida, Hiromichi Hara, Jun Araya, Shunsuke Minagawa, Hirotaka Imai, Kazuyoshi Kuwano

المصدر: American journal of respiratory cell and molecular biology. 62(5)

مصطلحات موضوعية: 0301 basic medicine, Pulmonary and Respiratory Medicine, Lung Diseases, Cell type, Programmed cell death, Necroptosis, Clinical Biochemistry, Context (language use), Biology, 03 medical and health sciences, Necrosis, 0302 clinical medicine, Autophagy, Alarmins, Animals, Ferroptosis, Humans, Protein kinase A, Molecular Biology, chemistry.chemical_classification, Reactive oxygen species, Effector, Cell Biology, Cell biology, 030104 developmental biology, 030228 respiratory system, chemistry

الوصف: To date, increasing evidence suggests the possible involvement of various types of cell death in lung diseases. The recognized regulated cell death includes necrotic cell death that is immunogenic, releasing damage-associated molecular patterns and driving tissue inflammation. Necroptosis is a well-understood form of regulated necrosis that is executed by RIPK3 (receptor-interacting protein kinase 3) and the pseudokinase MLKL (mixed lineage kinase domain-like protein). Ferroptosis is a newly described caspase-independent form of regulated necrosis that is characterized by the increase of detrimental lipid reactive oxygen species produced via iron-dependent lipid peroxidation. The role of these two cell death pathways differs depending on the disease, cell type, and microenvironment. Moreover, some experimental cell death models have demonstrated shared ferroptotic and necroptotic cell death and the synergistic effect of simultaneous inhibition. This review examines the role of regulated necrotic cell death, particularly necroptosis and ferroptosis, in lung disease pathogenesis in the context of recent insights into the roles of the key effector molecules of these two cell death pathways.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::df0c16be92039eb7eb5e421a92d28e00Test
https://pubmed.ncbi.nlm.nih.gov/32017592Test

المؤلفون: Tsukasa Kadota, Nahoko Sato, Kenji Kobayashi, Hiroshi Wakui, Toshiaki Morikawa, Yoichi Nakanishi, Makoto Yamashita, Takeo Ishikawa, Hirofumi Utsumi, Kazuyoshi Kuwano, Yu Fujita, Makoto Odaka, Yumi Kaneko, Saburo Ito, Mitsuo Hashimoto, Katsutoshi Nakayama, Kazuya Tsubouchi, Haruhiko Yanagisawa, Jun Araya, Hisatoshi Asano, Shunsuke Minagawa, Hiromichi Hara, Yusuke Kurita, Masahiro Yoshida, Yutaka Yoshii, Nayuta Saito, Takanori Numata, Akihiro Ichikawa

المصدر: Autophagy. 13:1420-1434

مصطلحات موضوعية: 0301 basic medicine, Proteasome Endopeptidase Complex, Translational Research Paper, Ubiquitin-Protein Ligases, Azithromycin, Biology, Bleomycin, Models, Biological, Transforming Growth Factor beta1, 03 medical and health sciences, Idiopathic pulmonary fibrosis, chemistry.chemical_compound, Fibrosis, medicine, Animals, Humans, Myofibroblasts, Lung, Molecular Biology, urogenital system, Autophagy, Ubiquitination, NOX4, Cell Differentiation, Cell Biology, medicine.disease, Idiopathic Pulmonary Fibrosis, Mitochondria, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Proteostasis, chemistry, NADPH Oxidase 4, Proteolysis, Immunology, Unfolded Protein Response, Cancer research, Reactive Oxygen Species, Myofibroblast, Transforming growth factor

الوصف: Accumulation of profibrotic myofibroblasts is involved in the process of fibrosis development during idiopathic pulmonary fibrosis (IPF) pathogenesis. TGFB (transforming growth factor β) is one of the major profibrotic cytokines for myofibroblast differentiation and NOX4 (NADPH oxidase 4) has an essential role in TGFB-mediated cell signaling. Azithromycin (AZM), a second-generation antibacterial macrolide, has a pleiotropic effect on cellular processes including proteostasis. Hence, we hypothesized that AZM may regulate NOX4 levels by modulating proteostasis machineries, resulting in inhibition of TGFB-associated lung fibrosis development. Human lung fibroblasts (LF) were used to evaluate TGFB-induced myofibroblast differentiation. With respect to NOX4 regulation via proteostasis, assays for macroautophagy/autophagy, the unfolded protein response (UPR), and proteasome activity were performed. The potential anti-fibrotic property of AZM was examined by using bleomycin (BLM)-induced lung fibrosis mouse models. TGFB-induced NOX4 and myofibroblast differentiation were clearly inhibited by AZM treatment in LF. AZM-mediated NOX4 reduction was restored by treatment with MG132, a proteasome inhibitor. AZM inhibited autophagy and enhanced the UPR. Autophagy inhibition by AZM was linked to ubiquitination of NOX4 via increased protein levels of STUB1 (STIP1 homology and U-box containing protein 1), an E3 ubiquitin ligase. An increased UPR by AZM was associated with enhanced proteasome activity. AZM suppressed lung fibrosis development induced by BLM with concomitantly reduced NOX4 protein levels and enhanced proteasome activation. These results suggest that AZM suppresses NOX4 by promoting proteasomal degradation, resulting in inhibition of TGFB-induced myofibroblast differentiation and lung fibrosis development. AZM may be a candidate for the treatment of the fibrotic lung disease IPF.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d3ce4d718f81443200fa75afe89021a2Test
https://doi.org/10.1080/15548627.2017.1328348Test