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Therapeutic opportunities of alpha-1-microglobulin A study in placenta, blood, skin and eye

Cederlund, Martin LU (2015) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2015:99.
Abstract
This thesis describes functional studies of the human protein alpha-1-microglobulin (A1M), with the aim of exploring its usefulness as a therapeutic agent in diseases where oxidative stress is a prominent feature. A1M is a 26 kDa plasma and tissue protein with reductase activity and radical- and heme-binding antioxidative functions.

The research focus in this thesis has been to study the in vivo protective mechanisms against oxidative stress in tissue of placenta, blood, skin and eye.

Oxidative stress in the tissues were induced by disease, surgery, culturing or addition of pro-oxidants. Damage by oxidative stress in the tissues with or without addition of A1M was analyzed by biochemical methods and electron... (More)
This thesis describes functional studies of the human protein alpha-1-microglobulin (A1M), with the aim of exploring its usefulness as a therapeutic agent in diseases where oxidative stress is a prominent feature. A1M is a 26 kDa plasma and tissue protein with reductase activity and radical- and heme-binding antioxidative functions.

The research focus in this thesis has been to study the in vivo protective mechanisms against oxidative stress in tissue of placenta, blood, skin and eye.

Oxidative stress in the tissues were induced by disease, surgery, culturing or addition of pro-oxidants. Damage by oxidative stress in the tissues with or without addition of A1M was analyzed by biochemical methods and electron microscopy.

The results show that A1M inhibits trophoblast barrier leakage, morphological damage and gene-upregulation related to oxidative stress in placenta tissue suffering from hemoglobin-induced oxidative stress, while simultaneously stimulating upregulation of genes related to extracellular matrix re-building. Skin explants, keratinocyte cultures, and purified collagen showed similar damage when exposed to heme and reactive oxygen species. Also in the skin, the damage was inhibited by A1M and signs of repair observed.

In the vitreous of eyes from patients with rhegmatogenous retinal detachment, a significant correlation between oxidative stress, A1M-concentrations and disease severity parameters was shown. A newly described retina culture method, with improved biomechanical tissue support, displayed a reduced oxidative stress and optimal mitochondrial structure.

Finally, A1M was shown to inhibit and repair oxidation of low density lipoprotein of blood by the neutrophil enzyme myeloperoxidase, an early event of atherosclerosis. The results suggest that the inhibition mechanism involves binding and degradation of the essential heme-group of myeloperoxidase by A1M.

Taken together, the results suggest that A1M has a potential as a therapeutic agent in some diseases associated with pathological oxidative stress. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Balla, Jozsef, Department of Medicine, University of Debrecen, Debrecen, Hungary
organization
publishing date
type
Thesis
publication status
published
subject
keywords
reactive oxygen species, hemoglobin, myeloperoxidase, oxidative stress, α1-microglobulin
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2015:99
pages
34 pages
publisher
Department of Clinical Sciences, Lund University
defense location
Segerfalksalen, BMC A10, Sölvegatan 17, Lund
defense date
2015-09-25 13:00
ISSN
1652-8220
ISBN
978-91-7619-178-1
language
English
LU publication?
yes
id
a0362cbc-58ab-4105-af51-cfe12fbc90cc (old id 7854542)
date added to LUP
2015-09-07 09:51:59
date last changed
2016-09-19 08:44:49
@phdthesis{a0362cbc-58ab-4105-af51-cfe12fbc90cc,
  abstract     = {This thesis describes functional studies of the human protein alpha-1-microglobulin (A1M), with the aim of exploring its usefulness as a therapeutic agent in diseases where oxidative stress is a prominent feature. A1M is a 26 kDa plasma and tissue protein with reductase activity and radical- and heme-binding antioxidative functions.<br/><br>
The research focus in this thesis has been to study the in vivo protective mechanisms against oxidative stress in tissue of placenta, blood, skin and eye.<br/><br>
Oxidative stress in the tissues were induced by disease, surgery, culturing or addition of pro-oxidants. Damage by oxidative stress in the tissues with or without addition of A1M was analyzed by biochemical methods and electron microscopy.<br/><br>
The results show that A1M inhibits trophoblast barrier leakage, morphological damage and gene-upregulation related to oxidative stress in placenta tissue suffering from hemoglobin-induced oxidative stress, while simultaneously stimulating upregulation of genes related to extracellular matrix re-building. Skin explants, keratinocyte cultures, and purified collagen showed similar damage when exposed to heme and reactive oxygen species. Also in the skin, the damage was inhibited by A1M and signs of repair observed. <br/><br>
In the vitreous of eyes from patients with rhegmatogenous retinal detachment, a significant correlation between oxidative stress, A1M-concentrations and disease severity parameters was shown. A newly described retina culture method, with improved biomechanical tissue support, displayed a reduced oxidative stress and optimal mitochondrial structure. <br/><br>
Finally, A1M was shown to inhibit and repair oxidation of low density lipoprotein of blood by the neutrophil enzyme myeloperoxidase, an early event of atherosclerosis. The results suggest that the inhibition mechanism involves binding and degradation of the essential heme-group of myeloperoxidase by A1M. <br/><br>
Taken together, the results suggest that A1M has a potential as a therapeutic agent in some diseases associated with pathological oxidative stress.},
  author       = {Cederlund, Martin},
  isbn         = {978-91-7619-178-1},
  issn         = {1652-8220},
  keyword      = {reactive oxygen species,hemoglobin,myeloperoxidase,oxidative stress,α1-microglobulin},
  language     = {eng},
  pages        = {34},
  publisher    = {Department of Clinical Sciences, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Therapeutic opportunities of alpha-1-microglobulin A study in placenta, blood, skin and eye},
  volume       = {2015:99},
  year         = {2015},
}