title: Hyperoxia Induces Inflammation and Cytotoxicity in Human Adult Cardiac Myocytes.
abstract: Supplemental oxygen (O2) is used as adjunct therapy in anesthesia, emergency, and intensive care medicine. We hypothesized that excessive O2 levels (hyperoxia) can directly injure human adult cardiac myocytes (HACMs). HACMs obtained from the explanted hearts of transplantation patients were exposed to constant hyperoxia (95% O2), intermittent hyperoxia (alternating 10 min exposures to 5% and 95% O2), constant normoxia (21% O2), or constant mild hypoxia (5% O2) using a bioreactor. Changes in cell morphology, viability as assessed by lactate dehydrogenase (LDH) release and trypan blue (TB) staining, and secretion of vascular endothelial growth factor (VEGF), macrophage migration inhibitory factor (MIF), and various pro-inflammatory cytokines (interleukin, IL; chemokine C-X-C motif ligand, CXC; granulocyte-colony stimulating factor, G-CSF; intercellular adhesion molecule, ICAM; chemokine C-C motif ligand, CCL) were compared among treatment groups at baseline (0 h) and after 8, 24, and 72 h of treatment. Changes in HACM protein expression were determined by quantitative proteomic analysis after 48 h of exposure. Compared with constant normoxia and mild hypoxia, constant hyperoxia resulted in a higher TB-positive cell count, greater release of LDH, and elevated secretion of VEGF, MIF, IL-1β, IL-6, IL-8, CXCL-1, CXCL-10, G-CSF, ICAM-1, CCL-3, and CCL-5. Cellular inflammation and cytotoxicity gradually increased and was highest after 72 h of constant and intermittent hyperoxia. Quantitative proteomic analysis revealed that hypoxic and hyperoxic O2 exposure differently altered the expression levels of proteins involved in cell-cycle regulation, energy metabolism, and cell signaling. In conclusion, constant and intermittent hyperoxia induced inflammation and cytotoxicity in HACMs. Cell injury occurred earliest and was greatest after constant hyperoxia, but even relatively brief repeating hyperoxic episodes induced a substantial inflammatory response.
authors.affiliation: *Department of Anaesthesia, General Intensive Care and Pain Management, Medical University of Vienna, Vienna, Austria †Department of Anaesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China ‡Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center Mainz, Mainz, Germany §Clinical Institute of Laboratory Medicine, Medical University of Vienna, Vienna, Austria ||Core Facilities, Medical University of Vienna, Vienna, Austria ¶Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria #Ludwig Boltzmann Cluster for Cardiovascular Research, Vienna, Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Hafner
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Akos
authors.initials: A
authors.lastname: Tiboldi
authors.forename: Moritz
authors.initials: M
authors.lastname: Hess
authors.forename: Goran
authors.initials: G
authors.lastname: Mitulovic
authors.forename: Christoph
authors.initials: C
authors.lastname: Kaun
authors.forename: Konstantin Alexander
authors.initials: KA
authors.lastname: Krychtiuk
authors.forename: Johann
authors.initials: J
authors.lastname: Wojta
authors.forename: Roman
authors.initials: R
authors.lastname: Ullrich
authors.forename: Eva Verena
authors.initials: EV
authors.lastname: Tretter
authors.forename: Klaus
authors.initials: K
authors.lastname: Markstaller
authors.forename: Klaus Ulrich
authors.initials: KU
authors.lastname: Klein
mesh_terms: D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000097:blood; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood; D006801:Humans; D018496:Hyperoxia / Q000150:complications*; D007249:Inflammation / Q000097:blood* / Q000209:etiology*; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D007770:L-Lactate Dehydrogenase / Q000097:blood; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D054405:Chemokine CCL3; D015850:Interleukin-6; D016209:Interleukin-8; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1; D016179:Granulocyte Colony-Stimulating Factor; D007770:L-Lactate Dehydrogenase