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JACC Basic Transl Sci

Title:		H(2) Inhibits the Formation of Neutrophil Extracellular Traps
Author(s):		Shirakawa K; Kobayashi E; Ichihara G; Kitakata H; Katsumata Y; Sugai K; Hakamata Y; Sano M;
Address:		"Department of Cardiovascular Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan. Center for Molecular Hydrogen Medicine, Keio University, Tokyo, Japan. Department of Cardiology, School of Medicine, Keio University, Tokyo, Japan. Department of Organ Fabrication, School of Medicine, Keio University, Tokyo, Japan. Department of Basic Sciences, Faculty of Veterinary Sciences, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Tokyo, Japan"
Journal Title:		JACC Basic Transl Sci
Year:		2022
Volume:		20220112
Issue:		2
Page Number:		146 - 161
DOI:		10.1016/j.jacbts.2021.11.005
ISSN/ISBN:		2452-302X (Electronic) 2452-302X (Linking)
Abstract:		"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"
Keywords:		"BAL, bronchoalveolar lavage CVD, cardiovascular disease CitH3, citrullinated histone H3 H2 HOCl, hypochlorous acid LPS, lipopolysaccharide MI, myocardial infarction MPO, myeloperoxidase NAC, N-acetyl-L-cysteine NET, neutrophil extracellular trap PA, pulmo;"
Notes:		"PubMed-not-MEDLINEShirakawa, Kohsuke Kobayashi, Eiji Ichihara, Genki Kitakata, Hiroki Katsumata, Yoshinori Sugai, Kazuhisa Hakamata, Yoji Sano, Motoaki eng 2022/03/09 JACC Basic Transl Sci. 2022 Jan 12; 7(2):146-161. doi: 10.1016/j.jacbts.2021.11.005. eCollection 2022 Feb"