Spatial Coordination of Cell-Adhesion Molecules and Redox Cycling of Iron in the Microvascular Inflammatory Response to Pulmonary Injury
Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA. Antioxidants and Redox Signaling
(Impact Factor: 7.41).
05/2007; 9(4):483-95. DOI: 10.1089/ars.2006.1296
Transmigration of phagocytic leukocytes (PLCs) from the peripheral blood into injured lung requires a conversion of the microvascular endothelial cells (ECs) to the proinflammatory phenotypes and spatiotemporal interplay of different types of cell adhesion molecules (CAMs) on PLC and endothelium. The present report is focused on involvement of iron-dependent redox signaling in spatial coordination of lung CAM due to either a pulmonary trauma or endotracheal iron administration in rats. Redox alterations, deposition of 3-nitrotyrosine, expression of VE-cadherin, ICAM-1, and the PLC integrins, and the status of thioredoxin, Ref-1, NF-kappaB and Nrf2 redox-sensitive elements in the alveolar microvasculature were assessed with EPR spectroscopy, immunobloting, and confocal microscopy. We demonstrated for the first time in vivo that the presence of catalytically active iron, deposition of myeloperoxidase, and induction of the oxidative stress in the lung-injury models were accompanied by (a) downregulation of VE-cadherin, (b) upregulation and polarization of ICAM-1 and the PLC integrins, and (c) nuclear translocation and interaction of thioredoxin, Ref-1, and NF-kappaB and complex structural changes in EC and PLC at the sites of their contacts. The studies suggested that a part of the proinflammatory action of iron in the lung resulted from its stimulation of the redox-sensitive factors.
Available from: Nikolai Gorbunov
- "For immunofluorescence confocal imaging the cells exposed to iron complexes were fixed at 2 h following treatments and obtained specimens were processed as described previously Gorbunov NV et al . , 2007 ) . The primary antibody against ICAM - 1 , caveolin - 1 , pho - caveolin - 1 , pho - caldesmon ("
[Show abstract] [Hide abstract]
ABSTRACT: 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.
Available from: Nikolaos Maniatis
[Show abstract] [Hide abstract]
ABSTRACT: Since pulmonary edema from increased endothelial permeability is the hallmark of acute lung injury, a frequently encountered entity in critical care medicine, the study of endothelial responses in this setting is crucial to the development of effective endothelial-targeted treatments.
From the enormous amount of research in the field of endothelial pathophysiology, we have focused on work delineating endothelial alterations elicited by noxious stimuli implicated in acute lung injury. The bulk of the material covered deals with molecular and cellular aspects of the pathogenesis, reflecting current trends in the published literature. We initially discuss pathways of endothelial dysfunction in acute lung injury and then cover the mechanisms of endothelial protection. Several experimental treatments in animal models are presented, which aid in the understanding of the disease pathogenesis and provide evidence for potentially useful therapies.
Mechanistic studies have delivered several interventions, which are effective in preventing and treating experimental acute lung injury and have thus provided objectives for translational studies. Some of these modalities may evolve into clinically useful tools in the treatment of this devastating illness.
Available from: Han-A Park
[Show abstract] [Hide abstract]
ABSTRACT: A demethylated derivative of curcumin (DC; 67.8% bisdemethylcurcumin, 20.7% demethylmonodemethoxycurcumin, 5.86% bisdemethoxycurcumin, 2.58% demethylcurcumin) was prepared by using a 95% extract of curcumin (C(95); 72.2% curcumin, 18.8% monodemethoxycurcumin, 4.5% bisdemethoxycurcumin). DC increased glutathione and reduced reactive oxygen species (ROS) in HT4 neuronal cells. In a model of glutamate-induced death of HT4, DC was more effective than C(95) in neuroprotection. The protective effects of DC were retained even when DC was withdrawn from culture media after pretreatment. DC treatment, unlike an equal dose of C(95), completely spared glutamate-induced loss of cellular GSH. Both DC and C(95) prevented glutamate-induced elevation of cellular ROS but failed to attenuate glutamate-induced elevation of intracellular calcium. In human microvascular endothelial cells (HMECs) challenged with TNF-alpha, GeneChip analysis revealed that only a subcluster of 23 TNF-alpha-inducible genes were uniquely sensitive to C(95). In sharp contrast, 1,065 TNF-alpha-inducible genes were sensitive to DC but not to C(95), suggesting that DC was more effective in antagonizing the effects of TNF-alpha on HMECs. Functional analysis identified that the genes uniquely sensitive to DC belonged in four functional categories: cytokine-receptor interaction, focal adhesion, cell adhesion, and apoptosis. Real-time PCR as well as ELISA studies demonstrated that TNF-alpha-inducible CXCL10 and CXCL11 expression was sensitive to DC but not to C(95). Flow-cytometry studies recognized ICAM-1 and VCAM-1 as TNF-alpha-inducible adhesion molecules that were uniquely sensitive to DC. Taken together, DC exhibited promising neuroprotective and antiinflammatory properties that must be characterized in vivo.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.