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Ferrum Forges Fibrin Formation
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ironjustice
May 5, 2013, 2:58:41 PM5/5/13
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A novel method for assessing the role of iron and its functional
chelation in fibrin fibril formation: the use of scanning electron
microscopy
Posted online on April 19, 2013.
Etheresia Pretorius1, Natasha Vermeulen1, Janette Bester1, Boguslaw
Lipinski2, and Douglas B. Kell3
1Department of Physiology, Faculty of Health Sciences, University of
Pretoria, Arcadia, South Africa,
2Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA, and
3School of Chemistry and Manchester Institute of Biotechnology,
University of Manchester, Manchester, UK
Address for correspondence: Etheresia Pretorius, Department of
Physiology, Faculty of Health Sciences, University of Pretoria,
Private Bag x323, Arcadia 0007, South Africa. Tel: +27 12 420 2864.
Fax: +27 12 420 4482. E-mail: resia.p...@up.ac.za
Abstract
Aims: Inflammatory diseases associated with iron overload are
characterized by a changed coagulation profile, where there is a
persistent presence of fibrin-like material of dense-matted deposits
(DMDs). It is believed that one source of such material is a result of
the activation of blood coagulation without the generation of
thrombin, causing clots to become resistant to fibrinolytic
dissolution. The aim of the current manuscript therefore is to apply a
novel scanning electron microscopy method for assessing the role of
functional chelation in the prevention or reversal of iron-induced
fibrin formation.
Methods and results: Purified fibrinogen and platelet-rich plasma were
exposed to chelating agents followed by iron, to determine the
chelating effects. We show that there is another, pathological pathway
of fibrin formation initiated by free iron (initially as Fe (III)),
leading to the formation of highly reactive oxygen species such as the
hydroxyl radical that can oxidize and insolubilize proteins, a process
that might be inhibited by iron-chelating compounds. The final product
of such a pathway is a fibrin-like material, termed DMDs that are
remarkably resistant to proteolytic degradation.
Conclusions: Scanning electron microscopy shows that iron-chelating
agents are effective inhibitors of DMD formation. The most active
inhibitors of DMD formation proved to be Desferal, Clioquinol and
Curcumin, whereas Epigallocatechin gallate and Deferiprone were less
effective. The functional model we describe may point the clinical
utility of various substances in iron-mediated degenerative diseases.
(doi:10.3109/15376516.2012.762082)
---------------------
Published online 30 July 2007
The Journal of Experimental Medicine
Fibrin deposition accelerates neurovascular damage and
neuroinflammation in mouse models of Alzheimer's disease
Justin Paul, Sidney Strickland, and Jerry P. Melchor
Laboratory of Neurobiology and Genetics, The Rockefeller University,
New York, NY 10065
CORRESPONDENCE Sidney Strickland: strickl...@rockefeller.edu
Cerebrovascular dysfunction contributes to the pathology and
progression of Alzheimer's disease (AD), but the mechanisms are not
completely understood. Using transgenic mouse models of AD (TgCRND8,
PDAPP, and Tg2576), we evaluated blood-brain barrier damage and the
role of fibrin and fibrinolysis in the progression of amyloid-ß
pathology. These mouse models showed age-dependent fibrin deposition
coincident with areas of blood-brain barrier permeability as
demonstrated by Evans blue extravasation. Three lines of evidence
suggest that fibrin contributes to the pathology. First, AD mice with
only one functional plasminogen gene, and therefore with reduced
fibrinolysis, have increased neurovascular damage relative to AD
mice.
Conversely, AD mice with only one functional fibrinogen gene have
decreased blood-brain barrier damage. Second, treatment of AD mice
with the plasmin inhibitor tranexamic acid aggravated pathology,
whereas removal of fibrinogen from the circulation of AD mice with
ancrod treatment attenuated measures of neuroinflammation and
vascular
pathology. Third, pretreatment with ancrod reduced the increased
pathology from plasmin inhibition. These results suggest that fibrin
is a mediator of inflammation and may impede the reparative process
for neurovascular damage in AD. Fibrin and the mechanisms involved in
its accumulation and clearance may present novel therapeutic targets
in slowing the progression of AD.
http://www.jem.org/cgi/content/abstract/jem.20070304v1?papetoc
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Jesus Was A Vegetarian!
http://tinyurl.com/2r2nkh
Man Is A Herbivore!
http://tinyurl.com/4rq595
DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk
chelation in fibrin fibril formation: the use of scanning electron
microscopy
Posted online on April 19, 2013.
Etheresia Pretorius1, Natasha Vermeulen1, Janette Bester1, Boguslaw
Lipinski2, and Douglas B. Kell3
1Department of Physiology, Faculty of Health Sciences, University of
Pretoria, Arcadia, South Africa,
2Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA, and
3School of Chemistry and Manchester Institute of Biotechnology,
University of Manchester, Manchester, UK
Address for correspondence: Etheresia Pretorius, Department of
Physiology, Faculty of Health Sciences, University of Pretoria,
Private Bag x323, Arcadia 0007, South Africa. Tel: +27 12 420 2864.
Fax: +27 12 420 4482. E-mail: resia.p...@up.ac.za
Abstract
Aims: Inflammatory diseases associated with iron overload are
characterized by a changed coagulation profile, where there is a
persistent presence of fibrin-like material of dense-matted deposits
(DMDs). It is believed that one source of such material is a result of
the activation of blood coagulation without the generation of
thrombin, causing clots to become resistant to fibrinolytic
dissolution. The aim of the current manuscript therefore is to apply a
novel scanning electron microscopy method for assessing the role of
functional chelation in the prevention or reversal of iron-induced
fibrin formation.
Methods and results: Purified fibrinogen and platelet-rich plasma were
exposed to chelating agents followed by iron, to determine the
chelating effects. We show that there is another, pathological pathway
of fibrin formation initiated by free iron (initially as Fe (III)),
leading to the formation of highly reactive oxygen species such as the
hydroxyl radical that can oxidize and insolubilize proteins, a process
that might be inhibited by iron-chelating compounds. The final product
of such a pathway is a fibrin-like material, termed DMDs that are
remarkably resistant to proteolytic degradation.
Conclusions: Scanning electron microscopy shows that iron-chelating
agents are effective inhibitors of DMD formation. The most active
inhibitors of DMD formation proved to be Desferal, Clioquinol and
Curcumin, whereas Epigallocatechin gallate and Deferiprone were less
effective. The functional model we describe may point the clinical
utility of various substances in iron-mediated degenerative diseases.
(doi:10.3109/15376516.2012.762082)
---------------------
Published online 30 July 2007
The Journal of Experimental Medicine
Fibrin deposition accelerates neurovascular damage and
neuroinflammation in mouse models of Alzheimer's disease
Justin Paul, Sidney Strickland, and Jerry P. Melchor
Laboratory of Neurobiology and Genetics, The Rockefeller University,
New York, NY 10065
CORRESPONDENCE Sidney Strickland: strickl...@rockefeller.edu
Cerebrovascular dysfunction contributes to the pathology and
progression of Alzheimer's disease (AD), but the mechanisms are not
completely understood. Using transgenic mouse models of AD (TgCRND8,
PDAPP, and Tg2576), we evaluated blood-brain barrier damage and the
role of fibrin and fibrinolysis in the progression of amyloid-ß
pathology. These mouse models showed age-dependent fibrin deposition
coincident with areas of blood-brain barrier permeability as
demonstrated by Evans blue extravasation. Three lines of evidence
suggest that fibrin contributes to the pathology. First, AD mice with
only one functional plasminogen gene, and therefore with reduced
fibrinolysis, have increased neurovascular damage relative to AD
mice.
Conversely, AD mice with only one functional fibrinogen gene have
decreased blood-brain barrier damage. Second, treatment of AD mice
with the plasmin inhibitor tranexamic acid aggravated pathology,
whereas removal of fibrinogen from the circulation of AD mice with
ancrod treatment attenuated measures of neuroinflammation and
vascular
pathology. Third, pretreatment with ancrod reduced the increased
pathology from plasmin inhibition. These results suggest that fibrin
is a mediator of inflammation and may impede the reparative process
for neurovascular damage in AD. Fibrin and the mechanisms involved in
its accumulation and clearance may present novel therapeutic targets
in slowing the progression of AD.
http://www.jem.org/cgi/content/abstract/jem.20070304v1?papetoc
Who loves ya.
Tom
Jesus Was A Vegetarian!
http://tinyurl.com/2r2nkh
Man Is A Herbivore!
http://tinyurl.com/4rq595
DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk
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