title: Uranyl nitrate-exposed rat alveolar macrophages cell death: influence of superoxide anion and TNF α mediators.
abstract: Uranium compounds are widely used in the nuclear fuel cycle, military and many other diverse industrial processes. Health risks associated with uranium exposure include nephrotoxicity, cancer, respiratory, and immune disorders. Macrophages present in body tissues are the main cell type involved in the internalization of uranium particles. To better understand the pathological effects associated with depleted uranium (DU) inhalation, we examined the metabolic activity, phagocytosis, genotoxicity and inflammation on DU-exposed rat alveolar macrophages (12.5-200 μM). Stability and dissolution of DU could differ depending on the dissolvent and in turn alter its biological action. We dissolved DU in sodium bicarbonate (NaHCO₃ 100 mM) and in what we consider a more physiological vehicle resembling human internal media: sodium chloride (NaCl 0.9%). We demonstrate that uranyl nitrate in NaCl solubilizes, enters the cell, and elicits its cytotoxic effect similarly to when it is diluted in NaHCO₃. We show that irrespective of the dissolvent employed, uranyl nitrate impairs cell metabolism, and at low doses induces both phagocytosis and generation of superoxide anion (O₂⁻). At high doses it provokes the secretion of TNFα and through all the range of doses tested, apoptosis. We herein suggest that at DU low doses O₂⁻ may act as the principal mediator of DNA damage while at higher doses the signaling pathway mediated by O₂⁻ may be blocked, prevailing damage to DNA by the TNFα route. The study of macrophage functions after uranyl nitrate treatment could provide insights into the pathophysiology of uranium-related diseases.
authors.affiliation: School of Science and Technology, National University of General Martín, Avda Gral Paz 5445, 1650 San Martín, Buenos Aires, Argentina.
authors.forename: N S
authors.initials: NS
authors.lastname: Orona
authors.forename: D R
authors.initials: DR
authors.lastname: Tasat
mesh_terms: D000818:Animals; D017209:Apoptosis; D001391:Azo Compounds; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D002478:Cells, Cultured; D004396:Coloring Agents; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000502:physiology*; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010587:Phagocytosis / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism*; D013778:Tetrazolium Salts; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D014502:Uranyl Nitrate / Q000633:toxicity*
chemical_list: D001391:Azo Compounds; D004396:Coloring Agents; D018836:Inflammation Mediators; D013778:Tetrazolium Salts; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D014502:Uranyl Nitrate; D013481:Superoxides; C037882:2-(5-bromo-2-pyridylazo)-5-diethylaminophenol; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; C022616:thiazolyl blue