{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T03:43:42Z","timestamp":1791258222009,"version":"4.1.0"},"reference-count":62,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2012,4,1]],"date-time":"2012-04-01T00:00:00Z","timestamp":1333238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Mitochondrial damage is an important component of multiple organ failure syndrome, a highly lethal complication of severe sepsis that lacks specific therapy. Mitochondrial quality control is regulated in part by the heme oxygenase-1 (HO-1; Hmox1) system through the redox-regulated NF-E2\u2013related factor-2 (Nrf2) transcription factor, but its role in mitochondrial biogenesis in Staphylococcus aureus sepsis is unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To test the hypothesis that Nrf2-dependent up-regulation of the HO-1\/carbon monoxide (CO) system would preserve mitochondrial biogenesis and rescue mice from lethal S. aureus sepsis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A controlled murine S. aureus peritonitis model with and without inhaled CO was examined for HO-1 and Nrf2 regulation of mitochondrial biogenesis and the resolution of hepatic mitochondrial damage.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>Sepsis survival was significantly enhanced using inhaled CO (250 ppm once-daily for 1 h), and linked mechanistically to Hmox1 induction and mitochondrial HO activity through Nrf2 transcriptional and Akt kinase activity. HO-1\/CO stimulated Nrf2-dependent gene expression and nuclear accumulation of nuclear respiratory factor-1, -2\u03b1 (Gabpa), and peroxisome proliferator-activated receptor gamma coactivator-1\u03b1; increased mitochondrial transcription factor-A and citrate synthase protein levels; and augmented mtDNA copy number. CO enhanced antiinflammatory IL-10 and reduced proinflammatory tumor necrosis factor-\u03b1 production. By contrast, Nrf2\u2212\/\u2212 and Akt1\u2212\/\u2212 mice lacked CO induction of Hmox1 and mitochondrial biogenesis, and CO rescued neither strain from S. aureus sepsis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We identify an inducible Nrf2\/HO-1 regulatory cycle for mitochondrial biogenesis that is prosurvival and counter-inflammatory in sepsis, and describe targeted induction of mitochondrial biogenesis as a potential multiple organ failure therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201106-1152oc","type":"journal-article","created":{"date-parts":[[2012,2,4]],"date-time":"2012-02-04T20:31:55Z","timestamp":1328387515000},"page":"851-861","source":"Crossref","is-referenced-by-count":176,"title":["Activation of Mitochondrial Biogenesis by Heme Oxygenase-1\u2013mediated NF-E2\u2013related Factor-2 Induction Rescues Mice from Lethal\n                    <i>Staphylococcus<\/i>\n                    \u00a0\n                    <i>aureus<\/i>\n                    Sepsis"],"prefix":"10.1093","volume":"185","author":[{"given":"Nancy Chou","family":"MacGarvey","sequence":"first","affiliation":[{"name":"Department of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hagir B.","family":"Suliman","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel R.","family":"Bartz","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, and"},{"name":"Department of Anesthesiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal M.","family":"Withers","sequence":"additional","affiliation":[{"name":"Department 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