title: Carbon monoxide reversibly alters iron homeostasis and respiratory epithelial cell function.
abstract: The dissociation of iron from heme is a major factor in iron metabolism and the cellular concentrations of the metal correlate with heme degradation. We tested the hypotheses that (1) exposure to a product of heme catabolism, carbon monoxide (CO), alters iron homeostasis in the lung and in cultured respiratory epithelial cells; (2) this response includes both decreased uptake and increased release of cell metal; and (3) the effects of CO on cell function track changes in metal homeostasis. In rats exposed to 50 ppm CO for 24 hours, non-heme iron concentrations decreased in the lung and increased in the liver. In respiratory epithelial cells cultured at air-liquid interface, CO exposure decreased cell non-heme iron and ferritin concentrations within 2 hours and the effect was fully reversible. CO significantly depressed iron uptake by epithelial cells, despite increased expression of divalent metal transporter-1, while iron release was elevated. The loss of non-heme iron after CO reduced cellular oxidative stress, blocked the release of the proinflammatory mediator (interleukin-8), and interfered with cell cycle protein expression. We conclude that CO reduces the iron content of the lung through both the metal uptake and release mechanisms. This loss of cellular iron after CO is in line with certain biological effects of the gas that have been implicated in the protection of cell viability.
authors.affiliation: National Health and Environmental Effects Research Laboratory, Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, North Carolina, USA. ghio.andy@epa.gov
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ghio
authors.forename: Jacqueline G
authors.initials: JG
authors.lastname: Stonehuerner
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Dailey
authors.forename: Judy H
authors.initials: JH
authors.lastname: Richards
authors.forename: Michael D
authors.initials: MD
authors.lastname: Madden
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Deng
authors.forename: N-B
authors.initials: NB
authors.lastname: Nguyen
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Callaghan
authors.forename: Funmei
authors.initials: F
authors.lastname: Yang
authors.forename: Claude A
authors.initials: CA
authors.lastname: Piantadosi
mesh_terms: D000079:Acetaldehyde / Q000378:metabolism; D000818:Animals; D000963:Antimetabolites / Q000378:metabolism / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D018893:Bronchoalveolar Lavage; D002248:Carbon Monoxide / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation; D002648:Child; D003676:Deferoxamine / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D005293:Ferritins / Q000378:metabolism; D006418:Heme / Q000737:chemistry / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D008297:Male; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects; D017262:Siderophores / Q000378:metabolism
chemical_list: D000963:Antimetabolites; D000975:Antioxidants; D016209:Interleukin-8; D017262:Siderophores; D006418:Heme; D002248:Carbon Monoxide; D005293:Ferritins; D007501:Iron; D000079:Acetaldehyde; D003676:Deferoxamine