Delayed radioprotection by nuclear transcription factor κB -mediated induction of manganese superoxide dismutase in human microvascular endothelial cells after exposure to the free radical scavenger WR1065

In the ischemic brain, reperfusion with tissue plasminogen activator (tPA) sometimes causes catastrophic hemorrhagic transformation (HT); however, the mechanism remains elusive. Here, we show that the basement membrane, and not the endothelial cells, is vulnerable to ischemic/reperfusion injury with tPA treatment. We treated a spontaneously hypertensive rat model of middle cerebral artery occlusion (MCAO) with vehicle alone, tPA alone, or a free radical scavenger, edaravone, plus tPA. Light and electron microscopic analyses of each microvascular component revealed that the basement membrane disintegrated and became detached from the astrocyte endfeet in tPA-treated animals that showed HT. On the other hand, edaravone prevented the dissociation of the neurovascular unit, dramatically decreased the HT, and improved the neurologic score and survival rate of the tPA-treated rats. These results suggest that the basement membrane that underlies the endothelial cells is a key structure for maintaining the integrity of the neurovascular unit, and a free-radical scavenger can be a viable agent for inhibiting tPA-induced HT.

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Thioredoxin Activates MKK4-NFκB Pathway in a Redox-dependent Manner to Control Manganese Superoxide Dismutase Gene Expression in Endothelial Cells

Journal of Biological Chemistry ◽

10.1074/jbc.m115.660365 ◽

2015 ◽

Vol 290 (28) ◽

pp. 17505-17519 ◽

Cited By ~ 9

Author(s):

Venkatesh Kundumani-Sridharan ◽

Jaganathan Subramani ◽

Kumuda C. Das

Keyword(s):

Gene Expression ◽

Endothelial Cells ◽

Superoxide Dismutase ◽

Manganese Superoxide Dismutase ◽

Dependent Manner ◽

Manganese Superoxide ◽

Superoxide Dismutase Gene ◽

Nfκb Pathway

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Interleukin-1-induced lung neutrophil accumulation and oxygen metabolite-mediated lung leak in rats

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1994.266.1.l2 ◽

1994 ◽

Vol 266 (1) ◽

pp. L2-L8 ◽

Cited By ~ 16

Author(s):

J. A. Leff ◽

J. W. Baer ◽

M. E. Bodman ◽

J. M. Kirkman ◽

P. F. Shanley ◽

...

Keyword(s):

Superoxide Dismutase ◽

Lung Injury ◽

Dimethyl Sulfoxide ◽

Manganese Superoxide Dismutase ◽

Interleukin 1 ◽

Lung Lavage ◽

Radical Scavenger ◽

Neutrophil Accumulation ◽

Intratracheal Administration ◽

Manganese Superoxide

We found that intratracheal administration of recombinant interleukin-1 alpha (IL-1) into rats rapidly (< 5 h) increased neutrophils in lung lavages and caused an acute edematous lung injury which was reflected by lung albumin accumulation (lung leak) and histological abnormalities (perivascular cuffing). These IL-1-dependent processes were inhibited by prior administration of recombinant IL-1 receptor antagonist and did not occur following administration of heated IL-1. Several lines of evidence suggested that neutrophil-derived oxygen metabolites contributed to lung leak. First, lung leak did not occur in rats rendered neutropenic by vinblastine treatment 4 days before IL-1 administration but did occur in neutrophil-replete rats given vinblastine 1 day before IL-1 administration and control rats given IL-1. Second, treatment with a hydroxyl radical scavenger, dimethyl sulfoxide (DMSO) or a superoxide anion scavenger, manganese superoxide dismutase, decreased lung leak, lung lavage neutrophils, and histological abnormalities in rats given IL-1 intratracheally. Third, intratracheal IL-1 administration increased lung oxidized glutathione (GSSG) levels and expired H2O2 concentrations, and these two indices of oxidative stress were decreased by dimethyl sulfoxide or manganese superoxide dismutase treatment. We conclude that intratracheal administration of IL-1 increases neutrophils in the lung and causes a neutrophil and oxygen metabolite-dependent acute edematous lung injury.

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