title: Deferoxamine mimics the pattern of hypoxia-related injury at the microvasculature.
abstract: Oxygen is essential for the maintenance of life, and when oxygen levels decline to critical levels, a program of complex mechanisms exists to i) sense hypoxia, ii) respond to minimize acute tissue injury, and iii) result in adaptations that offer protection against further hypoxia challenges. Alternative adaptation-related protection may also be inducible through the increased activity of hypoxia-inducible factors activated by hypoxia mimics such as iron chelation with deferoxamine (DFA). We have characterized a set of hypoxia-related responses at the microvasculature and postulated that microvascular injury in response to hypoxia could be reproduced by the reduction of bioavailable iron through chelation by DFA. We were able to induce a similar degree of leukocyte adherence and emigration and vascular leak with DFA infusion as compared with hypoxia exposure in an intact physiological rodent model. However, in contrast to hypoxia-exposed groups, we were unable to detect reactive oxygen species or alter the injury pattern with reactive oxygen species scavenger in the groups treated with DFA. Thus, we demonstrate that DFA mimics the pattern and intensity of hypoxia-related injury on the microvasculature; however, differences in the time course and mechanism of injury were identified. In addition, DFA saturated with iron did not completely reverse the effects of DFA, suggesting a mechanism(s) beyond a reduction in the bioavailability of iron. These findings may have importance in the targeting of iron for the development of hypoxia mimics that may offer protection against subsequent hypoxia exposure in clinical setting such as myocardial infarction and stroke.
authors.affiliation: Department of Pulmonary and Critical Care Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors.forename: Sonja
authors.initials: S
authors.lastname: Bartolome
authors.forename: Navneet K
authors.initials: NK
authors.lastname: Dhillon
authors.forename: Shilpa
authors.initials: S
authors.lastname: Buch
authors.forename: Alfred J
authors.initials: AJ
authors.lastname: Casillan
authors.forename: John G
authors.initials: JG
authors.lastname: Wood
authors.forename: Amy R
authors.initials: AR
authors.lastname: O'Brien-Ladner
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003676:Deferoxamine / Q000633:toxicity*; D000860:Hypoxia / Q000503:physiopathology*; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D055806:Microvessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D003676:Deferoxamine