Endogenous and Exogenous Drivers of Oxidative Stress and Inflammation in Preeclampsia
(2020) In Lund University, Faculty of Medicine Doctoral Dissertation Series- Abstract
- Preeclampsia (PE), is a pregnancy related condition afflicting 3-8% of all pregnancies and a main cause of maternal and infant morbidity and mortality. It is thought to originate from a malfunctioning placental that eventually leads to damage to the maternal endothelium, which in turn gives rise to hypertension and organ dysfunction. Oxidative stress holds a central role in the development, progression and aggravation of the disease. This thesis explores two key contributors to the oxidative stress seen in PE; I) free foetal haemoglobin (HbF) and II) particulate matter generated by ambient and household air pollution (PM2.5).
A rabbit PE model was developed and evaluated. Cell-free HbF administered to pregnant rabbits during the second... (More) - Preeclampsia (PE), is a pregnancy related condition afflicting 3-8% of all pregnancies and a main cause of maternal and infant morbidity and mortality. It is thought to originate from a malfunctioning placental that eventually leads to damage to the maternal endothelium, which in turn gives rise to hypertension and organ dysfunction. Oxidative stress holds a central role in the development, progression and aggravation of the disease. This thesis explores two key contributors to the oxidative stress seen in PE; I) free foetal haemoglobin (HbF) and II) particulate matter generated by ambient and household air pollution (PM2.5).
A rabbit PE model was developed and evaluated. Cell-free HbF administered to pregnant rabbits during the second half of gestation mimics PE showing placental tissue damage and disrupted kidney function. Intravenous administration of recombinant human alpha-1-microglobulin (A1M), an endogenous scavenger protein that reversed the HbF-induced tissue damage, indicating a clear protective effect. The PE-specific renal effects were examined in a human cohort were increased plasma levels of HbF and A1M in the maternal circulation was associated with podocyte specific extracellular vesicles in the urine, pathognomic for PE. These findings were validated in the rabbit PE model showing a correlation between plasma HbF levels and kidney damage.
Air pollution is the single largest environmental threat to human health of our time. During pregnancy it is associated with an increased risk for birth- and pregnancy complications, conditions related to placental function. Particulate matter (PM) consists of, and carry, a broad range of toxic substances that can penetrate the respiratory tract and hence gain access to the blood stream and thereby the placenta.
The effects of PM of different sizes and combustion methods were explored in-vitro using an immortalised human first trimester cell line (HTR8). The trophoblast cells showed impaired cellular growth, morphological changes, endoplasmic reticulum stress, inflammation, disrupted mitochondrial function and altered protein secretion and expression.
This thesis supports and contributes to the body of evidence showing that oxidative stress and subsequent inflammation, play a pivotal role in the aetiology of PE. Free foetal HbF has been shown to be an endogenous oxidative stress trigger causing damage to the kidneys. The adverse impact of PM2.5 and indoor pollution on trophoblast cells offer a mechanistic explanation to previously well-established epidemiological associations. During pregnancy there is an elevated vulnerability to exposure-related alterations, potentially causing long-term effects for mother and child. Hence, this thesis expands prior work that has offered empirical and theoretical evidence that call for novel legislation that could make the air that we breathe safe for mothers, children and future generations. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/e0f09659-d5f6-4970-a91a-9be4da8ac2ce
- author
- Nääv, Åsa LU
- supervisor
-
- Stefan Hansson LU
- Ebba Malmqvist LU
- opponent
-
- PhD Llurba, Elisa, Department of obstetrics, University Hospital Vall d´Hebron, Barcelona, Spain
- organization
- publishing date
- 2020
- type
- Thesis
- publication status
- published
- subject
- keywords
- Oxidative stress, Air Pollutants: adverse effects, Placenta, Preeclampsia/pregnancy
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2020:53
- pages
- 68 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Tornbladsinstitutet, Biskopsgatan 9, Lund
- defense date
- 2020-05-08 13:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-7619-914-5
- language
- English
- LU publication?
- yes
- id
- e0f09659-d5f6-4970-a91a-9be4da8ac2ce
- date added to LUP
- 2020-04-17 15:27:50
- date last changed
- 2020-04-17 16:00:58
@phdthesis{e0f09659-d5f6-4970-a91a-9be4da8ac2ce,
abstract = {{Preeclampsia (PE), is a pregnancy related condition afflicting 3-8% of all pregnancies and a main cause of maternal and infant morbidity and mortality. It is thought to originate from a malfunctioning placental that eventually leads to damage to the maternal endothelium, which in turn gives rise to hypertension and organ dysfunction. Oxidative stress holds a central role in the development, progression and aggravation of the disease. This thesis explores two key contributors to the oxidative stress seen in PE; I) free foetal haemoglobin (HbF) and II) particulate matter generated by ambient and household air pollution (PM2.5).<br/>A rabbit PE model was developed and evaluated. Cell-free HbF administered to pregnant rabbits during the second half of gestation mimics PE showing placental tissue damage and disrupted kidney function. Intravenous administration of recombinant human alpha-1-microglobulin (A1M), an endogenous scavenger protein that reversed the HbF-induced tissue damage, indicating a clear protective effect. The PE-specific renal effects were examined in a human cohort were increased plasma levels of HbF and A1M in the maternal circulation was associated with podocyte specific extracellular vesicles in the urine, pathognomic for PE. These findings were validated in the rabbit PE model showing a correlation between plasma HbF levels and kidney damage.<br/>Air pollution is the single largest environmental threat to human health of our time. During pregnancy it is associated with an increased risk for birth- and pregnancy complications, conditions related to placental function. Particulate matter (PM) consists of, and carry, a broad range of toxic substances that can penetrate the respiratory tract and hence gain access to the blood stream and thereby the placenta. <br/>The effects of PM of different sizes and combustion methods were explored in-vitro using an immortalised human first trimester cell line (HTR8). The trophoblast cells showed impaired cellular growth, morphological changes, endoplasmic reticulum stress, inflammation, disrupted mitochondrial function and altered protein secretion and expression.<br/>This thesis supports and contributes to the body of evidence showing that oxidative stress and subsequent inflammation, play a pivotal role in the aetiology of PE. Free foetal HbF has been shown to be an endogenous oxidative stress trigger causing damage to the kidneys. The adverse impact of PM2.5 and indoor pollution on trophoblast cells offer a mechanistic explanation to previously well-established epidemiological associations. During pregnancy there is an elevated vulnerability to exposure-related alterations, potentially causing long-term effects for mother and child. Hence, this thesis expands prior work that has offered empirical and theoretical evidence that call for novel legislation that could make the air that we breathe safe for mothers, children and future generations.}},
author = {{Nääv, Åsa}},
isbn = {{978-91-7619-914-5}},
issn = {{1652-8220}},
keywords = {{Oxidative stress; Air Pollutants: adverse effects; Placenta; Preeclampsia/pregnancy}},
language = {{eng}},
number = {{2020:53}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{Endogenous and Exogenous Drivers of Oxidative Stress and Inflammation in Preeclampsia}},
url = {{https://lup.lub.lu.se/search/files/78486796/ThesisA_N_1_.pdf}},
year = {{2020}},
}