Document Detail


Iron-induced remodeling in cultured rat pulmonary artery endothelial cells.
MedLine Citation:
PMID:  22089858     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Although iron is known to be a component of the pathogenesis and/or maintenance of acute lung injury (ALI) in experimental animals and human subjects, the majority of these studies have focused on disturbances in iron homeostasis in the airways resulting from exposure to noxious gases and particles. Considerably less is known about the effect of increased plasma levels of redox-reactive non-transferrin bound iron (NTBI) and its impact on pulmonary endothelium. Plasma levels of NTBI can increase under various pathophysiological conditions, including those associated with ALI, and multiple mechanisms are in place to affect the [Fe(2+)]/[Fe(3+)] redox steady state. It is well accepted, however, that intracellular transport of NTBI occurs after reduction of [Fe(3+)] to [Fe(2+)] (and is mediated by divalent metal transporters). Accordingly, as an experimental model to investigate mechanisms mediating vascular effects of redox reactive iron, rat pulmonary artery endothelial cells (RPAECs) were subjected to pulse treatment (10 min) with [Fe(2+)] nitriloacetate (30 μM) in the presence of pyrithione, an iron ionophore, to acutely increase intracellular labile pool of iron. Cellular iron influx and cell shape profile were monitored with time-lapse imaging techniques. Exposure of RPAECs to [Fe(2+)] resulted in: (i) an increase in intracellular iron as detected by the iron sensitive fluorophore, PhenGreen; (ii) depletion of cell glutathione; and (iii) nuclear translocation of stress-response transcriptional factors Nrf2 and NFkB (p65). The resulting iron-induced cell alterations were characterized by cell polarization and formation of membrane cuplike and microvilli-like projections abundant with ICAM-1, caveolin-1, and F-actin. The iron-induced re-arrangements in cytoskeleton, alterations in focal cell-cell interactions, and cell buckling were accompanied by decrease in electrical resistance of RPAEC monolayer. These effects were partially eliminated in the presence of N,N'-bis (2-hydroxybenzyl) ethylenediamine-N,N'-diacetic acid, an iron chelator, and Y27632, a Rho-kinase inhibitor. Thus acute increases in labile iron in cultured pulmonary endothelium result in structural remodeling (and a proinflammatory phenotype) that occurs via post-transcriptional mechanisms regulated in a redox sensitive fashion.
Authors:
Nikolai V Gorbunov; James L Atkins; Narasimman Gurusamy; Bruce R Pitt
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-11-17
Journal Detail:
Title:  Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine     Volume:  -     ISSN:  1572-8773     ISO Abbreviation:  -     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-11-17     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9208478     Medline TA:  Biometals     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
The Henry Jackson Foundation for the Advancement of Military Medicine, Inc, Washington, DC, USA, Nikolaiv.gorbunov@gmx.us.
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