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Connexin43 hemichannels have been implicated in various pathological conditions, e.g. ischemia and inflammation, and can lead to detrimental cellular outcomes. Here, we explored whether targeting connexin43 hemichannels could alleviate TNF-induced endothelial barrier dysfunction and lethality in SIRS. Therefore, we verified whether administration of connexin43-targeting-peptides affected survival, body temperature and vascular permeability <jats:italic>in vivo<\/jats:italic>. <jats:italic>In vitro<\/jats:italic>, TNF-effects on connexin43 hemichannel function were investigated by single-channel studies and Ca<jats:sup>2+<\/jats:sup>-imaging. Blocking connexin43 hemichannels with TAT-Gap19 protected mice against TNF-induced mortality, hypothermia and vascular leakage, while enhancing connexin43 hemichannel function with TAT-CT9 provoked opposite sensitizing effects. <jats:italic>In vitro<\/jats:italic> patch-clamp studies revealed that TNF acutely activated connexin43 hemichannel opening in endothelial cells, which was promoted by CT9, and inhibited by Gap19 and intracellular Ca<jats:sup>2+<\/jats:sup>-buffering. <jats:italic>In vivo<\/jats:italic> experiments aimed at buffering intracellular Ca<jats:sup>2+<\/jats:sup>, and pharmacologically targeting Ca<jats:sup>2+<\/jats:sup>\/calmodulin-dependent protein kinase-II, a known modulator of endothelial barrier integrity, demonstrated their involvement in permeability alterations. Our results demonstrate significant benefits of inhibiting connexin43 hemichannels to counteract TNF-induced SIRS-associated vascular permeability and lethality.<\/jats:p>","DOI":"10.1038\/s41598-019-52900-4","type":"journal-article","created":{"date-parts":[[2019,11,12]],"date-time":"2019-11-12T11:03:18Z","timestamp":1573556598000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Blocking connexin43 hemichannels protects mice against tumour necrosis factor-induced inflammatory shock"],"prefix":"10.1038","volume":"9","author":[{"given":"Tinneke","family":"Delvaeye","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maarten A. 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