記述言語：英語  

DOI： 10.1038/s41598-021-96408-2

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

<title>Abstract</title>Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that leads to severe respiratory failure (RF). It is known that host exposure to viral infection triggers an iron-lowering response to mitigate pathogenic load and tissue damage. However, the association between host iron-lowering response and COVID-19 severity is not clear. This two-center observational study of 136 adult hospitalized COVID-19 patients analyzed the association between disease severity and initial serum iron, total iron-binding capacity (TIBC), and transferrin saturation (TSAT) levels. Serum iron levels were significantly lower in patients with mild RF than in the non-RF group; however, there were no significant differences in iron levels between the non-RF and severe RF groups, depicting a U-shaped association between serum iron levels and disease severity. TIBC levels decreased significantly with increasing severity; consequently, TSAT was significantly higher in patients with severe RF than in other patients. Multivariate analysis including only patients with RF adjusted for age and sex demonstrated that higher serum iron and TSAT levels were independently associated with the development of severe RF, indicating that inadequate response to lower serum iron might be an exacerbating factor for COVID-19.

DOI： 10.1038/s41598-021-92921-6

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その他リンク： http://www.nature.com/articles/s41598-021-92921-6

担当区分：筆頭著者,　責任著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1186/s13054-021-03596-4

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その他リンク： https://link.springer.com/article/10.1186/s13054-021-03596-4/fulltext.html

記述言語：日本語   出版者・発行元：(一社)日本集中治療医学会  

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Ovid Technologies (Wolters Kluwer Health)  

Alveolar epithelial cell (AEC) death, which is classified as apoptosis or necrosis, plays a critical role in the pathogenesis of acute respiratory distress syndrome (ARDS). In addition to apoptosis, some types of necrosis are known to be molecularly regulated, and both apoptosis and necrosis can be therapeutic targets for diseases. However, the relative contribution of apoptosis and necrosis to AEC death during ARDS has not been elucidated. Here, we evaluated which type of AEC death is dominant and whether regulated necrosis is involved in lipopolysaccharide (LPS)-induced lung injury, an experimental ARDS model. In the bronchoalveolar lavage fluid from the LPS-induced lung injury mice, both the levels of cytokeratin 18-M65 antigen (a marker of total epithelial cell death) and cytokeratin 18-M30 antigen (an epithelial apoptosis marker) were increased. The M30/M65 ratio, which is an indicator of the proportion of apoptosis to total epithelial cell death, was significantly lower than that in healthy controls. In addition, the number of propidium iodide-positive, membrane-disrupted cells was significantly higher than the number of TUNEL-positive apoptotic cells in the lung sections of lung injury mice. Activated neutrophils seemed to mediate AEC death. Finally, we demonstrated that necroptosis, a regulated necrosis pathway, is involved in AEC death during LPS-induced lung injury. These results indicate that necrosis including necroptosis, rather than apoptosis, is the dominant type of AEC death in LPS-induced lung injury. Although further studies investigating human ARDS subjects are necessary, targeting necrosis including its regulated forms might represent a more efficient approach to protecting the alveolar epithelial barrier during ARDS.

DOI： 10.1097/shk.0000000000001425

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.jcrc.2019.12.020

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

BACKGROUND: The open lung approach (OLA) reportedly has lung-protective effects against acute respiratory distress syndrome (ARDS). Recently, lowering of the driving pressure (ΔP), rather than improvement in lung aeration per se, has come to be considered as the primary lung-protective mechanism of OLA. However, the driving pressure-independent protective effects of OLA have never been evaluated in experimental studies. We here evaluated whether OLA shows protective effects against experimental ARDS even when the ΔP is not lowered. METHODS: Lipopolysaccharide was intratracheally administered to rats to establish experimental ARDS. After 24 h, rats were mechanically ventilated and randomly allocated to the OLA or control group. In the OLA group, 5 cmH2O positive end-expiratory pressure (PEEP) and recruitment maneuver (RM) were applied. Neither PEEP nor RM was applied to the rats in the control group. Dynamic ΔP was kept at 15 cmH2O in both groups. After 6 h of mechanical ventilation, rats in both groups received RM to inflate reversible atelectasis of the lungs. Arterial blood gas analysis, lung computed tomography, histological evaluation, and comprehensive biochemical analysis were performed. RESULTS: OLA significantly improved lung aeration, arterial oxygenation, and gas exchange. Even after RM in both groups, the differences in these parameters between the two groups persisted, indicating that the atelectasis-induced respiratory dysfunction observed in the control group is not an easily reversible functional problem. Lung histological damage was severe in the dorsal dependent area in both groups, but was attenuated by OLA. White blood cell counts, protein concentrations, and tissue injury markers in the broncho-alveolar lavage fluid (BALF) were higher in the control than in the OLA group. Furthermore, levels of CXCL-7, a platelet-derived chemokine, were higher in the BALF from the control group, indicating that OLA protects the lungs by suppressing platelet activation. CONCLUSIONS: OLA shows protective effects against experimental ARDS, even when the ΔP is not decreased. In addition to reducing ΔP, maintaining lung aeration seems to be important for lung protection in ARDS.

DOI： 10.1186/s13054-018-2154-2

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その他リンク： http://link.springer.com/article/10.1186/s13054-018-2154-2/fulltext.html

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

Cellular bioenergetic failure caused by mitochondrial dysfunction is a key process of alveolar epithelial injury during acute respiratory distress syndrome (ARDS). Prolyl hydroxylases (PHDs) act as cellular oxygen sensors, and their inhibition activates hypoxia-inducible factor (HIF), resulting in enhanced cellular glycolytic activity, which could compensate for impaired mitochondrial function and protect alveolar epithelial cells from ARDS. Here, we evaluated the effects of pharmacological PHD inhibition with dimethyloxalylglycine (DMOG) on alveolar epithelial cell injury using in vitro and in vivo ARDS models. We established an in vitro model of alveolar epithelial injury mimicking ARDS by adding isolated neutrophils and LPS to cultured MLE12 alveolar epithelial cells. DMOG treatment protected MLE12 cells from neutrophil-LPS-induced ATP decline and cell death. Knockdown of HIF-1α or inhibition of glycolysis abolished the protective effect of DMOG, suggesting that it was exerted by HIF-1-dependent enhancement of glycolysis. Additionally, intratracheal DMOG administration to mice protected the alveolar epithelial barrier and improved arterial oxygenation, preventing ATP decline during LPS-induced lung injury. In summary, enhancement of glycolysis by PHD inhibition is a potential therapeutic approach for ARDS, protecting alveolar epithelial cells from bioenergetic failure and cell death.- Tojo, K., Tamada, N., Nagamine, Y., Yazawa, T., Ota, S., Goto, T. Enhancement of glycolysis by inhibition of oxygen-sensing prolyl hydroxylases protects alveolar epithelial cells from acute lung injury. FASEB J. 32, 2258-2268 (2018). www.fasebj.org.

DOI： 10.1096/fj.201700888r

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1096/fj.201700888R

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1096/fj.201700888R

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: We previously reported a tele-anesthesia system that connected Sado General Hospital (SGH) to Yokohama City University Hospital (YCUH) using a dedicated virtual private network (VPN) that guaranteed the quality of service. The study indicated certain unresolved problems, such as the high cost of constantly using a dedicated VPN for tele-anesthesia. In this study, we assessed whether use of a best-effort system affects the safety and cost of tele-anesthesia in a clinical setting. Methods: One hundred patients were enrolled in this study. We provided tele-anesthesia for 65 patients using a guaranteed transmission system (20 Mbit/s; guaranteed, 372,000 JPY per month: 1 JPY = US$0.01) and for 35 patients using a best-effort system (100 Mbit/s; not guaranteed, 25,000 JPY per month). We measured transmission speed and number of commands completed from YCUH to SGH during tele-anesthesia with both transmission systems. Results: In the guaranteed system, anesthesia duration was 5780 min (88.9 min/case) and surgical duration was 3513 min (54.0 min/case). In the best-effort system, anesthesia duration was 3725 min (106.4 min/case) and surgical duration was 2105 min (60.1 min/case). The average transmission speed in the best-effort system was 17.3 ± 3.8 Mbit/s. The system provided an acceptable delay time and frame rate in clinical use. All commands were completed, and no adverse events occurred with both systems. Discussion: In the field of tele-anesthesia, using a best-effort internet VPN system provided equivalent safety and efficacy at a better price as compared to using a guaranteed internet VPN system.

DOI： 10.1155/2018/9615264

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER THORACIC SOC  

Alveolar epithelial injury and increased alveolar permeability are hallmarks of acute respiratory distress syndrome. Apoptosis of lung epithelial cells via the Fas/Fas ligand (FasL) pathway plays a critical role in alveolar epithelial injury. Activation of hypoxiainducible factor (HIF)-1 by inhibition of prolyl hydroxylase domain proteins (PHDs) is a possible therapeutic approach to attenuate apoptosis and organ injury. Here, we investigated whether treatment with dimethyloxalylglycine (DMOG), an inhibitor of PHDs, could attenuate Fas/FasL-dependent apoptosis in lung epithelial cells and lung injury. DMOG increased HIF-1 alpha protein expression in vitro in MLE-12 cells, a murine alveolar epithelial cell line. Treatment of MLE-12 cells with DMOG significantly suppressed cell surface expression of Fas and attenuated FasL-induced caspase-3 activation and apoptotic cell death. Inhibition of the HIF-1 pathway by echinomycin or small interfering RNA transfection abolished these antiapoptotic effects of DMOG. Moreover, intraperitoneal injection of DMOG in mice increased HIF-1a expression and decreased Fas expression in lung tissues. DMOG treatment significantly attenuated caspase-3 activation, apoptotic cell death in lung tissue, and the increase in alveolar permeability in mice instilled intratracheally with FasL. In addition, inflammatory responses and histopathological changes were also significantly attenuated by DMOG treatment. In conclusion, inhibition of PHDs protects lung epithelial cells from Fas/FasL-dependent apoptosis through HIF-1 activation and attenuates lung injury in mice.

DOI： 10.1165/rcmb.2015-0266OC

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/EJA.0000000000000460

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その他リンク： http://orcid.org/0000-0002-1194-8636

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BioMed Central Ltd.  

DOI： 10.1186/s40560-016-0130-y

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その他リンク： http://orcid.org/0000-0002-1194-8636

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：AMER THORACIC SOC  

Nagamine Y, Tojo K, Yazawa T, Takaki S, Baba Y, Goto T, Kurahashi K, American journal of respiratory cell and molecular biology, 2016, 2016

DOI： 10.1165/rcmb.2015-0266OC

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その他リンク： http://orcid.org/0000-0002-1194-8636

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s40635-015-0056-z

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jss.2014.11.011

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1177/1357633X14562735

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbrc.2014.01.082

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1213/ANE.0b013e31829847a1

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