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Neutrophil extracellular traps (NETs) contribute to inflammatory pathogenesis in numerous conditions, including infectious and cardiovascular diseases, and have attracted attention as potential therapeutic targets. H 2 acts as an antioxidant and has been clinically and experimentally proven to ameliorate inflammation. This study was performed to investigate whether H 2 could inhibit NET formation and excessive neutrophil activation. Neutrophils isolated from the blood of healthy volunteers were stimulated with phorbol-12-myristate-13-acetate (PMA) or the calcium ionophore A23187 in H 2 -exposed or control media. Compared with control neutrophils, PMA- or A23187-stimulated human neutrophils exposed to H 2 exhibited reduced neutrophil aggregation, citrullination of histones, membrane disruption by chromatin complexes, and release of NET components. CXCR4 high neutrophils are highly prone to NETs, and H 2 suppressed Ser-139 phosphorylation in H2AX, a marker of DNA damage, thereby suppressing the induction of CXCR4 expression. H 2 suppressed both myeloperoxidase chlorination activity and production of reactive oxygen species to the same degree as N-acetylcysteine and ascorbic acid, while showing a more potent ability to inhibit NET formation than these antioxidants do in PMA-stimulated neutrophils. Although A23187 formed NETs in a reactive oxygen species-independent manner, H 2 inhibited A23187-induced NET formation, probably via direct inhibition of peptidyl arginine deiminase 4-mediated histone citrullination. Inhalation of H 2 inhibited the formation and release of NET components in the blood and bronchoalveolar lavage fluid in animal models of lipopolysaccharide-induced sepsis (mice and aged mini pigs). Thus, H 2 therapy can be a novel therapeutic strategy for NETs associated with excessive neutrophil activation., Competing Interests: This research was funded by Japanese Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research (B) grant 18H02812 (2018-2020) and grants from Doctors Man Co, Ltd (to MS); and JSPS Grant-in Aid for Young Scientists grant JP18K15197 (2018–2020), Grant in-Aid for JSPS Fellows grant JP19J00583H (2018-2020). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. Drs Kobayashi and Sano have received advisory fees and research fees from Doctors Man Co, Ltd. Dr Sano has received advisory fees and research fees from Taiyo Nippon Sanso; is the registered inventor of the following patents jointly filed by Keio University and Taiyo Nippon Sanso: hydrogen mixed gas supply device for medical purposes (patent number: 5631524), medicinal composition for improving prognosis after restart of patient’s own heartbeat, and medicinal composition for improving and/or stabilizing circulatory dynamics after onset of hemorrhagic shock; and 3 other patents (whose names are translated into English): pharmaceutical compositions for reducing weight loss after organ harvesting (joint application with Keio University and Taiyo Nippon Sanso), method for generating organ preservation solution containing hydrogen and organ preservation solution containing hydrogen (joint application with Keio University and Doctors Man, application number PCT/JP2019/045790). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Neutrophil adhesion on the atheroprone femoral artery of high-fat diet-fed low-density lipoprotein receptor-null mice was enhanced more than in wild-type mice. The inhibition of histone H3 citrullination of neutrophils reversed the enhancement of neutrophil adhesion, suggesting that hypercitrullination contributes to enhanced neutrophil adhesion. Furthermore, pemafibrate reduced the citrullination of histone H3 in these mice. Therefore, the hypercitrullination of histone H3 in neutrophils contributes to atherosclerotic vascular inflammation., Competing Interests: This work was supported by a Grant-in-Aid for Exploratory Research (16K15439 to Dr. Yoshida) and a Grant-in-Aid for Scientific Research (C) (15K09153 to Dr. Oaska; and 19K08511 to Dr. Yoshida). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)

The lean diabetic patients with heart failure with preserved ejection fraction (HFpEF) in Asia suffer from adverse clinical outcomes and poor life quality. The suitable animal models are urgently needed for mechanistic study and therapeutic innovations. Our study reports that lipodystrophic mice with seipin depletion are lean, diabetic, and recapitulate major manifestations of clinical HFpEF, thereby clarifying that lean diabetes per se may produce HFpEF characteristics. We further demonstrate that increased cardiac titin phosphorylation and reactive interstitial fibrosis associated with neutrophil extracellular traps lead to left ventricular stiffness and suggest that both pathways may be potential therapeutic targets in Asian HFpEF patients., (© 2019 The Authors.)

Psoriasis is an inflammatory skin disease associated with increased cardiovascular risk and serves as a reliable model to study inflammatory atherogenesis. Because neutrophils are implicated in atherosclerosis development, this study reports that the interaction among low-density granulocytes, a subset of neutrophils, and platelets is associated with a noncalcified coronary plaque burden assessed by coronary computed tomography angiography. Because early atherosclerotic noncalcified burden can lead to fatal myocardial infarction, the low-density granulocyte-platelet interaction may play a crucial target for clinical intervention.

Despite treatment advances for sepsis and pneumonia, significant improvements in outcome have not been realized. Antiplatelet therapy may improve outcome in pneumonia and sepsis. In this study, the authors show that ticagrelor reduced leukocytes with attached platelets as well as the inflammatory biomarker interleukin (IL)-6. Pneumonia patients receiving ticagrelor required less supplemental oxygen and lung function tests trended toward improvement. Disruption of the P2Y 12 receptor in a murine model protected against inflammatory response, lung permeability, and mortality. Results indicate a mechanistic link between platelets, leukocytes, and lung injury in settings of pneumonia and sepsis, and suggest possible therapeutic approaches to reduce complications.(Targeting Platelet-Leukocyte Aggregates in Pneumonia With Ticagrelor [XANTHIPPE]; NCT01883869).