Review article: Medical intelligence | Published 24 December 2014, doi:10.4414/smw.2014.14037
Cite this as: Swiss Med Wkly. 2014;144:w14037
Oxidised phospholipids as biomarkers in human disease
Maria Philippovaa, Therese Resinka, Paul Erneb, Valery Bochkovc
a
Department of Biomedicine, Laboratory for Signal Transduction, University Hospital Basel, University of Basel, Switzerland
b
Hirslanden Klinik St. Anna, Luzern, Switzerland
c
Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, Karl-Franzens-University Graz, Austria
Summary
Oxidised phospholipids (OxPLs) are generated from
(poly)unsaturated diacyl- and alk(en)ylacyl glycerophospholipids under conditions of oxidative stress. OxPLs exert
a wide variety of biological effects on diverse cell types in
vitro and in vivo and are thought to play a role in the development of several chronic diseases including atherosclerosis, a classical lipid-associated and inflammatory disorder. OxPLs are recognised as culprit molecular components
responsible for the pathophysiological actions of oxidised
low-density lipoproteins. There is growing interest in the
potential use of OxPLs as biomarkers of human pathologies. Here we offer a brief overview of current detection
methods and knowledge on relationships between levels of
circulating OxPLs and disease progression, with particular
emphasis on cardiovascular disease.
glycerophospholipids in mammalian tissues contain phosphatidylcholine as a head group, while phosphoethanolamine or phosphatidylserine represent less abundant classes,
which, however, are enriched in some tissues such as brain
[1]. Polyunsaturated fatty acids in the sn-2 position of the
glycerol moiety of PLs are the major target for oxidation.
Oxidative attack on polyunsaturated fatty acids results in
generation of multiple fragmented or non-fragmented end
products with various combinations of functional oxy
groups. These products can exert variable effects on cells
by modulating activity of intracellular signal transduction
and gene expression mechanisms, forming covalent or noncovalent complexes with proteins, inducing cellular stress
and apoptosis and further stimulating ROS production [2].
Moreover, newly formed oxidation epitopes on lipid mo-
Key words: Oxidised phospholipids; biomarkers; human
pathologies; cardiovascular disease
Structure and generation of oxidised
phospholipids
Oxidative stress is a hallmark of many pathological states.
Among various types of biomolecules lipids are particularly susceptible to oxidation due to the presence of unsaturated double bonds from which hydrogen can be easily
abstracted by oxidants. Phospholipids (PLs) are a major
class of polar lipids that are abundantly present within
cell membranes and the outer shell of lipoprotein particles.
Glycerophospholipids, which are the most abundant subclass of PLs, contain a glycerol backbone, two fatty acid
residues and a polar head group (fig. 1). The majority of
Figure 1
Abbreviations
apoB apolipoprotein B-100
CAD coronary artery disease
mAB monoclonal antibodies
MS multiple sclerosis
OxLDL oxidised low-density lipoprotein
OxPL oxidised phospholipid
PL phospholipid
ROS reactive oxygen species
ECM extracellular matrix
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Chemical structure of some biologically active oxidised
phospholipids. The image shows molecular structures of a nonoxidised phospholipid 1–palmitoyl-2–arachidonoyl-snglycero-3–phosphocholine (PAPC) and some of its oxidised
derivatives: 5–hydroxy-8–oxo-6–octenoyl-phosphocholine (HOOAPC), 1–palmitoyl-2–(5,6–epoxyisoprostane E2)-snglycero-3–phosphocholine (PEIPC),
1–palmitoyl-2–(5–oxovaleroyl)-sn-glycero-3–phosphocholine
(POVPC) and 1–palmitoyl-2–glutaroyl-snglycero-3–phosphocholine (PGPC). Bold lines, glycerol
“backbones”; shadow, polar head groups.
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Review article: Medical intelligence
lecules are targets for adaptive and innate immune responses which significantly contribute to pathological conditions characterised by chronic inflammation [3].
Methods for detection of circulating
oxidised phospholipids
Quantification of oxidised phospholipids (OxPLs) in biological samples is difficult due both to their low concentrations as compared to non-oxidised precursors and the very
wide range of structurally different oxidation products. The
most sensitive and powerful method for OxPL analysis is
mass spectrometry [4, 5]. Development of soft ionisation
procedures such as electrospray ionisation mass spectrometry (ESI-MS) or atmospheric pressure chemical ionisation mass spectrometry (APCI-MS) enabled sensitive and
efficient metabolic profiling of lipids present in a variety
of biological samples (tissues and fluids) including atherosclerotic plaque, brain, plasma and cerebrospinal fluid.
However, large-scale mass spectrometry analysis of clinical samples remains a challenge due to the complexity and
high costs of the technique. The bulk of existing clinical
data on OxPL levels in human disease has been obtained
using immunological methods.
Two monoclonal antibodies (mAb) against OxPLs (DLH3
and E06) have been used in clinical studies. DLH3 was
generated by immunising mice with a homogenate of human atheroma [6]. A limitation of DLH3–based ELISA
is that low density lipoprotein (LDL) fractions have to
be isolated from plasma, which makes large-scale screening impractical. In contrast, mAB E06 raised from B-cell
clones of apoE-deficient mice [7, 8] is exploited for a
sandwich ELISA in which LDL particles are captured directly from plasma by another mAb (MB47) recognising
apolipoprotein B-100 (apoB-100) and oxidation-generated
epitopes are detected with biotinylated E06 followed by
chemiluminescence-based detection; this sandwich ELISA
has been used for the majority of clinical investigations on
circulating OxPLs. Both DLH3 and E06 antibodies recognise the oxidised, but not native, phosphatidylcholine moiety on PLs, although the exact structures of their respective target epitopes are not characterised. Apart from OxPL
present on oxidised LDL (OxLDL), E06 can bind to apoptotic cells which express oxidised phosphatidylcholinecontaining epitopes on their surface due to oxidative stress
[9] and to phosphocholine present in the capsular polysaccharide of many bacteria (e.g., Streptococcus pneumonia)
[10]. There are also other commercially available OxLDLrecognising monoclonal antibodies. One example is ML25
which binds to malondialdehyde-modified LDL (MDALDL) and is often used in combination with anti-apoB-100
antibody to measure MDA-LDL in serum [11]. However,
the epitopes of these antibodies contain covalent adducts
of apoB-100 with small molecules generated by non-enzymatic peroxidation of all sorts of esterified and nonesterified fatty acids (e.g., MDA or 4–hydroxynonenal).
Therefore these mAbs are not specific for OxPLs and will
not be discussed in this review.
Swiss Med Wkly. 2014;144:w14037
Oxidised phospholipids as biomarkers
in cardiovascular disease
Proatherogenic effects of OxPLs
Oxidative stress and oxidation of lipids are held to be decisive events in progression of atherosclerosis and its clinical complications. Initial studies on involvement of oxidised lipids in atherogenesis demonstrated that avid OxLDL
uptake mediated mostly by macrophage scavenger receptors SR-A and CD36 promoted lipid accumulation in macrophages and formation of foam cells in atherosclerotic
plaques [12, 13]. Today it is recognised that OxLDL and
its major active factor OxPLs can elicit multiple proatherogenic effects by acting on several different cell types in
blood and the vascular wall [14] (fig. 2). The role of OxPLs
in atherosclerosis is supported by studies demonstrating the
presence of OxPLs in atherosclerotic vessels of hypercholesterolaemic animal models [15] and in human lesions.
Various OxPL species have been documented at different
stages of atherosclerosis in different areas of plaques including oxidatively fragmented phospholipid species containing saturated and unsaturated truncated residues,
phospholipid-esterified isoprostanes, phospholipid hydroperoxides and others [2]. Amounts of OxPLs increase proportionally with plaque burden and are specifically associated with unstable and ruptured advanced plaques [16].
OxPLs significantly contribute to inflammation in diseased
vessels both by inducing expression of proinflammatory
cytokines and adhesion molecules on vascular endothelial
cells and promoting monocyte adhesion, and by acting directly on leukocytes [17]. Other activities of OxPLs relevant
to initiation, progression and development of complications of atherosclerosis include stimulation of ROS production, attenuation of endothelial-dependent vasorelaxation, induction of phenotypic modulation and migration of
smooth muscle cells, enhancement of thrombogenic activity of endothelial cells, activation of platelets, induction of
smooth muscle cell apoptosis and stimulation of vessel calcification. Activation of intraplaque angiogenesis and increased production of metalloproteinases by OxPLs contributes to destabilisation of coronary plaques, predisposing them to rupture and causing thrombosis and acute
Figure 2
The role of OxPLs in the pathophysiology of atherosclerosis.
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coronary syndromes. OxPLs can modulate functions of
dendritic cells and T- lymphocytes and thus may influence
the outcome of adaptive immune reactions. Under certain
conditions OxPLs may also stimulate tissue-protective processes via upregulation of stress response genes, attenuation of inflammation and maintenance of the endothelial
barrier function [2].
Clinical studies on biomarker value of circulating
OxPLs
Since pathological effects of OxLDL and OxPLs have been
investigated most extensively in the context of atherosclerosis, the majority of studies aimed at the evaluation of circulating OxPL levels as biomarkers have also been performed in the field of cardiovascular disease. A series of
studies utilising E06–based ELISA have demonstrated a
clear correlation between OxPL content per particle of
apoB (OxPL/apoB ratio) and the presence of coronary and
peripheral artery disease. A strong and graded association
with the extent of coronary artery disease (CAD) defined
as stenosis of more than 50 percent of the luminal diameter
was demonstrated in a study involving 504 subjects, the
correlation being strongest for patients aged 60 years or
younger [18]. The highest quartile of OxPL/apoB was associated with an odds ratio for CAD of 3.12 (P <0.001) compared with subjects in the lowest quartile. Interestingly, in
the entire cohort OxPL/apoB predicted CAD independently
of all other clinical markers except for Lp(a), a subclass of
lipoproteins characterised by the presence of a unique apolipoprotein apo(a). OxPL/apoB showed strong correlation
with Lp(a) levels suggesting that the majority of oxidative
epitopes detected by E06 are located on Lp(a) particles, the
main function of which is supposed to be sequestration of
toxic proinflammatory OxPLs. Recent mass spectroscopy
analysis revealed that OxPL are both present in the lipid
phase of Lp(a) and are covalently bound to apo(a) [19].
Interestingly, this relationship between OxPL and Lp(a)
was dependent on the size of apo(a) isoforms. Apo(a) proteins vary in size due to a variable number of the so-called
kringle IV type 2 repeats in the apo(a) gene. Correlation of
OxPL levels was weakest with the largest apo(a) isoforms
and strongest with the small isoforms containing lowest
number of kringle IV type 2 repeats [20]. Among patients
aged 60 years or younger the predictive value of OxPL/
apoB was independent even of Lp(a), perhaps reflecting
additional proinflammatory Lp(a)-independent risks of
OxPL elevation. Studies performed using DLH3 antibody
confirmed association of higher OxPL levels with coronary
[21] and carotid [22] atherosclerosis.
The prospective Bruneck study performed with a 5 year interval demonstrated high predictive value of OxPL/apoB
measured by E06 antibody also for the presence, extent
and development of carotid and femoral atherosclerosis
[23]. In the 10 year [24] and 15 year [25] follow-up analyses OxPL/apoB and Lp(a) predicted future cardiovascular events (cardiovascular death, myocardial infarction,
stroke and transient ischaemic attack) beyond the information provided by the Framingham Risk Score, and allowed
reclassification of a significant proportion of patients into
higher or lower risk categories after traditional risk assessment. The EPIC-Norfolk study involving 763 cases
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Swiss Med Wkly. 2014;144:w14037
and 1,397 controls demonstrated that the highest tertiles of
OxPL/apoB and Lp(a) were associated with a higher risk
of CAD-related events and provided better cumulative predictive value when added to traditional cardiovascular risk
factors [26]. However, in patients with previous myocardial
infarction no correlation was found between E06–detected
OxPL/apoB and recurrent cardiovascular events (cardiovascular death, nonfatal reinfarction or stroke, percutaneous coronary intervention, coronary artery bypass
grafting and hospitalisation due to angina pectoris) [27].
Importantly, the Dallas Heart Study demonstrated significant race/ethnicity-related differences in oxidative markers,
with the level of OxPL/apoB and its correlation with Lp(a)
being highest in black subjects as compared with whites
and Hispanics [28]. These data suggest that proinflammatory OxPLs present on Lp(a) represent a genetic predisposition to increased oxidative stress. Positive association of
OxPL/apoB with peripheral artery disease has been confirmed in a recent study which included two parallel nested case-control studies within the Health Professionals
Follow-up Study and the Nurses’ Health Study [29].
Temporary increases in plasma OxPL detected by E06 or
DLH3 antibodies have been observed in acute coronary
syndromes such as myocardial infarction [22, 30–33].
Studies performed using DLH3 antibody demonstrated
strong accumulation of OxPLs in ruptured lipid cores of
culprit coronary and carotid atherosclerotic plaques [22,
31, 32]. Plasma levels of DLH3–OxPL increased in acute
cerebral infarction [34], stayed persistently elevated during
the early phase after the stroke in association with enlargement of the ischaemic area in patients with cortical lesions [35], and reflected reduction of oxidative brain damage in patients with cortical infarcts treated by free radical
scavenger edaravone [36]. Interestingly, a mass spectrometry approach identified a distinct plasma pool of OxPL
that is covalently bound to plasminogen. OxPL/plasminogen levels did not correlate with Lp(a) and were acutely
increased over the first month in patients following acute
myocardial infarction [37].
Percutaneous coronary intervention (PCI) is a standard diagnostic and therapeutic method for management of CAD.
A major complication of PCI is vascular restenosis, a
gradual re-narrowing of the treated segment that occurs
between 3 to 12 months after the intervention. Several studies attempted to establish the potential value of OxPLs as a
predictor of restenosis. Results on changes in OxPL levels
obtained using E06 and DLH3 antibodies are not strictly
consistent: while both approaches demonstrated elevation
of OxPL after the percutaneous intervention and stenting
[38–40], E06 reactivity in plasma was not associated with
the restenosis risk either in balloon- or stent-treated groups
[40], while OxPL levels detected by DLH3 were a strong
independent predictor of in-stent restenosis at six month
follow-up in acute myocardial infarction patients [41]. Interestingly, oxidation epitopes recognised by E06 could be
coimmunoprecipitated with Lp(a) from plasma samples at
every time point after PCI except for those collected immediately after the intervention, suggesting that OxPLs are
released briefly and then reassociate with Lp(a) [38]. A
complex study utilising immunoassays and mass spectrometry confirmed the presence of multiple oxidised lipid
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species including phosphatidylcholine-containing OxPL in
lipid extracts from obstructive plaques and in OxPL released into the circulation during percutaneous coronary
and peripheral arterial interventions [42]. Accumulation
of fragmented phosphatidylcholine during the reperfusion
period was also detected by high performance liquid chromatography after cardiopulmonary bypass [43]. Fast
changes in OxPL concentrations after acute events or revascularisation procedures might reflect oxidative stress
caused by tissue injury, increased production of ROS during ischaemia/reperfusion or release of lipid components
from ruptured atherosclerotic plaques into the circulation.
Several studies have addressed the value of OxPL measurements in monitoring efficiency of medicamentous treatments and life style changes aimed at management of cardiovascular disease. Unexpectedly, most data obtained using E06 antibody revealed elevations in OxPL levels in
response to cholesterol-lowering agents. In the MIRACL
(Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering) Trial atorvastatin treatment decreased total
OxPL on all apoB particles in patients with acute coronary syndromes but increased OxPL/apoB, Lp(a) levels and
Lp(a)-associated OxPL [44, 45]. The VISION (Value of
oxIdant lipid lowering effect by Statin InterventON in hypercholesterolaemia) study compared oxidation biomarker
values in two groups of hypercholesterolaemic patients
treated either with pitavastatin or atorvastatin. No difference between the groups was observed with respect to OxPL/
apoB; however, within each group OxPL/apoB significantly increased upon treatment as compared to baseline
[46]. Similar results were obtained in the REVERSAL
(Reversal of Atherosclerosis with Aggressive Lipid Lowering) Trial for atorvastatin and pravastatin [47] and in two
other studies [48, 49]. Patients on a low-fat, high-carbohydrate diet exhibited elevated levels of OxPLs and an accompanying shift in plasma lipoprotein profile (decrease in
LDL particle size and increase of Lp(a)) [50]. As a further example of inverse correlations between OxPL levels
and disease progression, increases in OxPL/apoB and Lp(a)
were found to strongly correlate with improved vascular
function and to predict a lack of progression of coronary
artery calcification [51]. Some attempt at explaining these
inverse correlative data was made in an experimental study
which analysed dietary-induced atherosclerosis progression and regression in cynomolgus monkeys and New Zealand White rabbits. Hypercholesterolaemia was associated
with a decrease in plasma OxPL/apoB, whereas during reversal to normocholesterolaemia OxPL/apoB increased and
was accompanied with the disappearance of OxPLs from
atherosclerotic plaque lesions [52]. Taken together, these
data might suggest that statins and lipid lowering diets promote formation of Lp(a) lipoproteins resulting in mobilisation of OxPL from the vessel wall, transfer to Lp(a)
particles and improved clearance of OxPLs from the vascular system. However, in contrast to these studies, OxPL
levels detected by DLH3 mAB decreased in patients with
hypocholesterolaemia after treatment with fluvastatin and
pravastatin [53], thus showing a tendency similar to MDALDL levels which were reduced by pitavastatin and atorvastatin [46].
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Endothelial dysfunction is an early event in the pathogenesis of atherosclerosis which is characterised by decreased
vasodilator function, increased coagulation activity and enhanced proinflammatory properties of vascular endothelial cells. Inflammation and oxidative stress which results in
reduced availability of the major vasodilator factor NO are
potent triggers of endothelial dysfunction. Improvement of
endothelial function after lipid lowering therapy in patients
with coronary atherosclerosis assessed by quantitative angiography strongly correlated with OxPL levels. The number of E06 epitopes per LDL particle was related to the
severity of endothelial dysfunction and was the single most
powerful independent risk factor in the post-therapy study
suggesting that OxPL may contribute to abnormal coronary
vasomotion in atherosclerosis [54].
Oxidised lipids in diabetes and
metabolic syndrome
The metabolic syndrome, a constellation of symptoms including obesity, dyslipidaemia, hypertension and insulin
resistance, is a risk factor for both CAD and diabetes [55].
Some components of metabolic syndrome are traditional
risk factors for these pathologies, but they only partially account for the increased incidence of CAD and diabetes in
persons with metabolic syndrome. Among emerging common non-traditional risk factors are low-grade inflammation and oxidative stress. In population studies elevated
levels of proinflammatory biomarkers CRP and IL-6 were
found to predict the development of type 2 diabetes [56].
Increased oxidative stress in adipose tissue contributes to
the metabolic syndrome and is associated with type 2 diabetes [57]. The role for oxidised lipids in metabolic syndrome was suggested by the findings that obesity-associated dyslipidaemia and hyperglycaemia in humans are
associated with increased LDL oxidation and that dyslipidaemia and insulin resistance in obese LDL receptor-deficient mice were associated with increased oxidative stress
and impaired antioxidant defence [58]. LDL from patients
with non–insulin-dependent diabetes mellitus were more
susceptible to oxidative modification due to a reduced vitamin E/lipid peroxide ratio in blood, a factor that may represent a possible link between the increased incidence of
vascular disease and diabetes mellitus [59]. High-density
lipoproteins isolated from type 2 diabetic patients exhibited
a decreased capacity for clearance of OxPLs, which may
increase the risk for cardiovascular disease [60]. Further,
levels of OxLDL and advanced glycation end
products–modified LDL in circulating immune complexes
were strongly associated with carotid intima thickening in
patients with type I diabetes [61].
DLH3 mAb-based ELISA demonstrated higher OxPL in
patients with unstable angina pectoris that also had diabetes
mellitus as compared to non-diabetic subjects [31] and in
subjects with diabetic nephropathy [62]. Altogether, these
data suggest that OxPLs may reflect and/or contribute to
progression of metabolic disorders and the linkage to a constellation of their complications and related pathologies.
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Oxidized phospholipids in renal
dysfunction
Disturbances in lipid metabolism are a characteristic feature of chronic renal disease. Renal insufficiency is accompanied by shifts in plasma lipid profiles, and high triglyceride and cholesterol plasma levels are independent risk
factors for renal disease progression. Experimental data
suggest that oxidative stress may be among possible mechanisms linking hyperlipidaemia with the renal damage [63].
Increased cellular accumulation of lipids and oxidised fatty
acids were detected in the glomerulosclerotic lesions [64].
Patients with uraemia, which is a major contributor to oxidative stress, exhibit increased susceptibility of LDL for oxidation [65]. The haemodialysis procedure per se may also
promote LDL oxidation due to activation of neutrophils or
bacterial contamination [66].
Several studies analysed levels of OxPLs in blood of patients with renal disease and reported variable results.
DLH3 mAb-based ELISA demonstrated more than eightfold increase in LDL oxidation in patients receiving haemodialysis [6]. Low levels of lysophosphatidylcholine determined by an enzymatic assay were reported to be associated with increased risk of cardiovascular disease in
Korean haemodialysis patients [67]. In end-stage renal failure patients undergoing haemodialysis OxPL/apoB levels
measured by E06 mAb dropped immediately following the
procedure, while other markers of LDL oxidation such
as autoantibody titers to copper-oxidised LDL and
malondialdehyde-LDL significantly increased. E06–based
detection also did not reveal any association between
OxPL/apoB levels and cardiovascular disease in chronic
haemodialysis patients [68]. Further large-scale prospective studies are required to estimate predictive value of
OxPL levels as a biomarker of clinical outcome in renal
disease.
Oxidised phospholipids in neurological
disorders
Brain and nervous tissue are very susceptible to oxidation
due to their high lipid content and intense consumption
of oxygen. Oxidative stress and lipid peroxidation have
been related to progression of many neurological disorders
such as schizophrenia, bipolar disorder and neurodegenerative diseases. Involvement of OxPLs in onset and progression of Alzheimer’s and Parkinson diseases has been
proposed [69, 70]. Multiple sclerosis (MS) is a disabling
neurodegenerative disease characterised by the presence of
demyelinated plaques and axonal degeneration. Autoimmune attack on the myelin sheath in the brain and the spinal
cord is supposed to be the major cause for the disease;
however, the identity of the antigens remains elusive. Since
lipids comprise >70% of the myelin sheath, lipids have
been considered capable of inducing autoimmune reactions in MS [71]. Oxidized 1–palmitoyl-2–(5'-oxo)valerylsn-glycero-3–phosphatidylcholine, detected by E06 antibody, was found to be present in high amounts in brain
tissue of MS patients but almost absent in control samples
[72].
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Another neuropathological condition involving OxPLs is
that of neurobehavioral problems in children treated for
acute lymphoblastic leukaemia. Chemotherapy with methotrexate causes an injury of the central nervous system
leading to neurocognitive deficiencies, anxiety and depression. Children with high-risk acute lymphoblastic leukaemia receiving the most intensive methotrexate treatment
displayed the highest levels of oxidised phosphatidylcholine in the cerebrospinal fluid suggesting that
this OxPL species may be a marker of therapy-induced
central nervous system injury [73]. OxPL levels also predicted behavioural changes such as executive dysfunction
[74], aggression at the end of therapy and postconsolidation
adaptability [75]. These studies would justify development
of OxPL-based biomarker methods for predicting the degree of neuropathological symptoms caused by chemotherapy, and also suggest that use of antioxidants may limit toxic effects of the treatment.
Other pathologies characterised by
accumulation of oxidised
phospholipids
Lung injury
PLs are a major component of pulmonary surfactant and
easily undergo oxidation under pathological conditions
characterised by oxidative stress, such as viral or bacterial
infections. Accumulation of OxPLs has been reported in
animal models of lung injury as well as in humans infected
with SARS, Anthrax or H5N1 [76]. Experimental evidence
suggests that OxPLs have dual pro- and anti-inflammatory
functions in the lung. On the one hand OxPLs stimulate
production of proinflammatory cytokines and TLR4 signalling in alveolar macrophages [76] thus contributing to
lung tissue injury, and they increase endothelial permeability by inducing cellular cytoskeleton reorganisation [77,
78]. On the other hand, under certain conditions OxPLs
may inhibit LPS-induced inflammation in animal models
[79, 80] and also protect endothelial barrier function, the
differential effects being dependent on concentration and
structural characteristics of OxPL species [77, 78]. Quantitative assessment of levels of tissue and systemic OxPLs
in pulmonary injury has not been performed.
Leprosy
Accumulation of fatty acids and PLs is a characteristic feature of the lepromatous (disseminated, L-lep) form of human leprosy. Lipid accumulation is related to changes in
the expression profile of genes involved in lipid metabolism in the host, such that the newly synthesised lipids in
leprous lesions derive from human tissue and not from the
mycobacteria. Functionally, OxPLs produced mainly by
macrophages promoted survival of the pathogen by interfering with innate and specific immune responses such as
CD1b-mediated presentation of antigens to T-cells, TLR2/1
activity and IL-12 secretion [81]. Interestingly, the accumulation of OxPLs in leprosy lesions was very similar to
atherosclerosis, suggesting common innate immunity-controlled mechanisms in progression of infectious and metabolic diseases.
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Cancer
Bilary strictures may develop due to a number of pathologies, among them cholangiocarcinoma and pancreatic cancer. Correct diagnosis of the bilary stricture aetiology remains a challenge since existing diagnostic methods such
as bile duct brushing do not allow differentiation between
malignant and benign origin of the strictures. Lipidomic
profiling using liquid chromatography-ESI-MS technique
demonstrated elevation of two OxPL species,
1–palmitoyl-2–(9–oxononanoyl)-sn-glycero-3–phosphatidylcholine
and
1–palmitoyl-2–succinoyl-sn-glycero-3–phosphatidylcholine, in bile samples of patients
with cholangiocarcinoma, distinguishing these cases from
strictures of other origins with 100% sensitivity and 83.3%
specificity. This approach may enhance the accuracy of endoscopic tests during diagnosis of indeterminate biliary
strictures [82].
Conclusion
Emerging data suggest that OxPLs significantly contribute
to progression of many pathological conditions and might
serve as biomarkers to predict the risk of the diseases, monitor disease progression and check therapeutic intervention
efficacy. Broadening the range of monoclonal antibodies to
enable detection of various types of OxPLs as well as better
characterisation of their target oxidation-specific epitopes
would help to overcome the limitations of current OxPL
detection methods. Mass spectrometry analysis of the spectrum and structure of OxPL species differentially expressed
in health and disease has great potential for rapid progress
in the field and will allow identification of both novel biomarkers and molecular mechanisms underlying pathological effects of OxPLs.
Funding / potential competing interests: OxPL-related
research of MP is supported by the Stiftung für Herz- und
Kreislaufkrankheiten. None of the authors have any conflict of
interest to declare.
Correspondence: Maria Philippova, PhD, Laboratory for Signal
Transduction, Department of Biomedicine, Basel University
Hospital, CH-4031 Basel, Switzerland,
maria.filippova[at]unibas.ch
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Figures (large format)
Figure 1
Chemical structure of some biologically active oxidised phospholipids. The image shows molecular structures of a non-oxidised phospholipid
1–palmitoyl-2–arachidonoyl-sn-glycero-3–phosphocholine (PAPC) and some of its oxidised derivatives: 5–hydroxy-8–oxo-6–octenoylphosphocholine (HOOA-PC), 1–palmitoyl-2–(5,6–epoxyisoprostane E2)-sn-glycero-3–phosphocholine (PEIPC),
1–palmitoyl-2–(5–oxovaleroyl)-sn-glycero-3–phosphocholine (POVPC) and 1–palmitoyl-2–glutaroyl-sn-glycero-3–phosphocholine (PGPC). Bold
lines, glycerol “backbones”; shadow, polar head groups.
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Figure 2
The role of OxPLs in the pathophysiology of atherosclerosis.
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