Oxidized Phospholipids Research Articles

Elucidating the atherogenicity of Lp(a): The pro-inflammatory role of diacylglycerols and lysophosphatidic acid in monocytes

Background and Aims : The atherogenicity of Lp(a) has been attributed to the pro-inflammatory oxidized phospholipids (OxPLs) bound to its apolipoprotein(a) [apo(a)] moiety. While blocking these OxPL epitopes profoundly reduces the monocytic inflammatory response, a residual IL-8 inflammatory response remains. We hypothesized that besides OxPLs, additional features contribute to the atherogenicity of Lp(a).

The Novel Role of Metabolism-Associated Molecular Patterns in Sepsis.

Sepsis, a life-threatening organ dysfunction, is not caused by direct damage of pathogens and their toxins but by the host’s severe immune and metabolic dysfunction caused by the damage when the host confronts infection. Previous views focused on the damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), including metabolic proinflammatory factors in sepsis. Recently, new concepts have been proposed to group free fatty acids (FFAs), glucose, advanced glycation end products (AGEs), cholesterol, mitochondrial DNA (mtDNA), oxidized phospholipids (OxPLs), ceramides, and uric acid into metabolism-associated molecular patterns (MAMPs). The concept of MAMPs will bring new guidance to the research and potential treatments of sepsis. Nowadays, sepsis is regarded as closely related to metabolic disorders, and MAMPs play an important role in the pathogenesis and development of sepsis. According to this view, we have explained MAMPs and their possible roles in the pathogenesis of sepsis. Next, we have further explained the specific functions of different types of MAMPs in the metabolic process and their interactional relationship with sepsis. Finally, the therapeutic prospects of MAMPs in sepsis have been summarized.

Abstract 131: Plasminogen Oxidized Phospholipid Adducts Drive Macrophage Activation In Through TLR2

Oxidized phospholipids (OxPL) are potent proinflammatory mediators that can trigger toll-like receptor 2 (TLR2) signaling and inflammasome activation in macrophages. Plasminogen (PLG), a key enzyme in the fibrinolytic pathway, has been shown to harbor OxPL adducts. We hypothesized that PLG can drive inflammasome activity in macrophages through OxPL activation of TLR2 in a fibrin-independent mechanism. To assess PLG-induced macrophage activation, total RNA sequencing was used to quantify gene changes in response to human PLG treatments, and we observed robust induction of pro-inflammatory genes, including Il1b, Il6, Nos2, Il12 , and Nlrp3 in primary mouse macrophages. In addition, a 400-fold increase in IL-6 protein was observed in the media. To determine if this activation is specifically via TLR2, a HEK293-NF-kB reporter system was used to screen PLG-induced activation of human TLRs, and we found that human PLG significantly-induced NF-kB signaling and transactivation in reporter cells expressing TLR2, TL1/2, TLR2/6, but failed to activate TLRs1/3/4/5/6/9. PLG activation of TLR2 was found to be blocked by pre-treatment of C29, a small molecule inhibitor of TLR2. In addition, when Tlr2-/- primary macrophages were treated with human PLG a 30% reduction in Il1b, Il6 and Tnf gene (mRNA) expression was observed compared to wild-type controls. Furthermore, we found PLG-TLR2 activation to be fibrin-independent, as there was no reduction in PLG activation by the lysine analogs tranexamic acid and e-aminocaproic acid or the plasmin activity inhibitor - VPLCK in our HEK293-NF-kB reporter system. To characterize the effect of PLG on inflammation in vivo , wild-type and Plg-/- mice were injected with AAV8-PCSK9 and treated with an atherogenic diet for 16 weeks. Remarkably, the Plg-/- mice demonstrated reduced plaque mass and aortic lipid content compared to wild-type control mice, with a 40% reduction in en face Sudan IV staining and a 10% reduction in lesion area by Oil-Red-O staining of neutral lipids. Collectively these results support that PLG-OxPL likely activate inflammasomes in macrophages through TLR2 and suggest this is likely to be involved in atherogenesis in vivo .

Lipoprotein(a), a Lethal Player in Calcific Aortic Valve Disease.

Calcified aortic valve disease (CAVD) is the most common valvular cardiovascular disease with increasing incidence and mortality. The primary treatment for CAVD is surgical or transcatheter aortic valve replacement and there remains a lack of effective drug treatment. Recently, lipoprotein (a) (Lp(a)) has been considered to play a crucial role in CAVD pathophysiology. Multiple studies have shown that Lp(a) represents an independent risk factor for CAVD. Moreover, Lp(a) mediates the occurrence and development of CAVD by affecting aortic valve endothelial dysfunction, indirectly promoting foam cell formation through oxidized phospholipids (OxPL), inflammation, oxidative stress, and directly promotes valve calcification. However, there is a lack of clinical trials with Lp(a) reduction as a primary endpoint. This review aims to explore the relationship and mechanism between Lp(a) and CAVD, and focuses on the current drugs that can be used as potential therapeutic targets for CAVD.

Oxidized Phospholipids Promote NETosis and Arterial Thrombosis in LNK(SH2B3) Deficiency.

LNK/SH2B3 inhibits Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling by hematopoietic cytokine receptors. Genome-wide association studies have shown association of a common single nucleotide polymorphism in LNK (R262W, T allele) with neutrophilia, thrombocytosis, and coronary artery disease. We have shown that LNK(TT) reduces LNK function and that LNK-deficient mice display prominent platelet-neutrophil aggregates, accelerated atherosclerosis, and thrombosis. Platelet-neutrophil interactions can promote neutrophil extracellular trap (NET) formation. The goals of this study were to assess the role of NETs in atherosclerosis and thrombosis in mice with hematopoietic Lnk deficiency. We bred mice with combined deficiency of Lnk and the NETosis-essential enzyme PAD4 (peptidyl arginine deiminase 4) and transplanted their bone marrow into Ldlr-/- mice. We evaluated the role of LNK in atherothrombosis in humans and mice bearing a gain of function variant in JAK2 (JAK2V617F). Lnk-deficient mice displayed accelerated carotid artery thrombosis with prominent NETosis that was completely reversed by PAD4 deficiency. Thrombin-activated Lnk-/- platelets promoted increased NETosis when incubated with Lnk-/- neutrophils compared with wild-type platelets or wild-type neutrophils. This involved increased surface exposure and release of oxidized phospholipids (OxPL) from Lnk-/- platelets, as well as increased priming and response of Lnk-/- neutrophils to OxPL. To counteract the effects of OxPL, we introduced a transgene expressing the single-chain variable fragment of E06 (E06-scFv). E06-scFv reversed accelerated NETosis, atherosclerosis, and thrombosis in Lnk-/- mice. We also showed increased NETosis when human induced pluripotent stem cell-derived LNK(TT) neutrophils were incubated with LNK(TT) platelet/megakaryocytes, but not in isogenic LNK(CC) controls, confirming human relevance. Using data from the UK Biobank, we found that individuals with the JAK2VF mutation only showed increased risk of coronary artery disease when also carrying the LNK R262W allele. Mice with hematopoietic Lnk+/- and Jak2VF clonal hematopoiesis showed accelerated arterial thrombosis but not atherosclerosis compared with Jak2VFLnk+/+ controls. Hematopoietic Lnk deficiency promotes NETosis and arterial thrombosis in an OxPL-dependent fashion. LNK(R262W) reduces LNK function in human platelets and neutrophils, promoting NETosis, and increases coronary artery disease risk in humans carrying Jak2VF mutations. Therapies targeting OxPL may be beneficial for coronary artery disease in genetically defined human populations.

Oxidized phospholipids and lipoprotein(a): An update.

Over the past few years, there has been an undiminished interest in lipoprotein(a) [Lp(a)] and oxidized phospholipids (OxPLs), mainly carried on this lipoprotein. Elevated Lp(a) has been established as an independent causal risk factor for cardiovascular disease. OxPLs play an important role in atherosclerosis. The main questions that remain to be answered, however, is to what extent OxPLs contribute to the atherogenicity of Lp(a), what effect hypolipidaemic medications may have on their levels and the potential clinical benefit of their reduction. This narrative review aimed to summarize currently available data on OxPLs and cardiovascular risk, as well as the effect of established and emerging hypolipidaemic medications on Lp(a)-OxPLs.

Oxidized Phospholipids in Control of Endothelial Barrier Function: Mechanisms and Implication in Lung Injury.

Earlier studies investigating the pathogenesis of chronic vascular inflammation associated with atherosclerosis described pro-inflammatory and vascular barrier disruptive effects of lipid oxidation products accumulated in the sites of vascular lesion and atherosclerotic plaque. However, accumulating evidence including studies from our group suggests potent barrier protective and anti-inflammatory properties of certain oxidized phospholipids (OxPLs) in the lung vascular endothelium. Among these OxPLs, oxidized 1-palmitoyl-2-arachdonyl-sn-glycero-3-phosphocholine (OxPAPC) causes sustained enhancement of lung endothelial cell (EC) basal barrier properties and protects against vascular permeability induced by a wide variety of agonists ranging from bacterial pathogens and their cell wall components, endotoxins, thrombin, mechanical insults, and inflammatory cytokines. On the other hand, truncated OxPLs cause acute endothelial barrier disruption and potentiate inflammation. It appears that multiple signaling mechanisms triggering cytoskeletal remodeling are involved in OxPLs-mediated regulation of EC barrier. The promising vascular barrier protective and anti-inflammatory properties exhibited by OxPAPC and its particular components that have been established in the cellular and animal models of sepsis and acute lung injury has prompted consideration of OxPAPC as a prototype therapeutic molecule. In this review, we will summarize signaling and cytoskeletal mechanisms involved in OxPLs-mediated damage, rescue, and restoration of endothelial barrier in various pathophysiological settings and discuss a future potential of OxPAPC in treating lung disorders associated with endothelial barrier dysfunction.

The pore-forming activity of sticholysin I is enhanced by the presence of a phospholipid hydroperoxide in membrane

Sticholysin I (StI) is a pore-forming toxin (PFT) belonging to the actinoporin protein family characterized by high permeabilizing activity in membranes. StI readily associates with sphingomyelin (SM)-containing membranes originating pores that can lead to cell death. Binding and pore-formation are critically dependent on the physicochemical properties of membrane. 1-palmitoyl-2-oleoylphosphatidylcholine hydroperoxide (POPC–OOH) is an oxidized phospholipid (OxPL) containing an –OOH moiety in the unsaturated hydrocarbon chain which orientates towards the bilayer interface. This orientation causes an increase in the lipid molecular area, lateral expansion and decrease in bilayer thickness, elastic and bending modulus, as well as modification of lipid packing. Taking advantage of membrane structural changes promoted by POPC-OOH, we investigated its influence on the permeabilizing ability of StI. Here we report the action of StI on Giant Unilamellar Vesicles (GUVs) made of 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) and SM containing increasing amount of POPC-OOH to assess vesicle permeability changes when compared to OxPL-lacking membranes. Inclusion of POPC-OOH in membranes did not promote spontaneous vesicle leaking but resulted in increased membrane permeability due to StI action. StI activity did not modify the fluid-gel phase coexistence boundaries neither in POPC:SM or POPC-OOH:SM membranes. However, the StI insertion mechanism in membrane seems to differ between POPC:SM and POPC-OOH:SM mixtures as suggested by changes in the time course of monolayer surface tension measurements, even though a preferable binding of the toxin to OxPL-containing systems could not be here demonstrated. In summary, modifications in the membrane imposed by lipid hydroperoxidation favor StI permeabilizing activity.

Characterization of the Structural Diversity and Structure-Specific Behavior of Oxidized Phospholipids by LC-MS/MS.

Polyunsaturated fatty acids (PUFAs), esterified to phospholipids, are susceptible to oxidation. They form oxidized phospholipids (OxPLs) by oxygenases or reactive oxygen species (ROS), or both. These OxPLs are associated with various diseases, such as atherosclerosis, pulmonary injuries, neurodegenerative diseases, cancer, and diabetes. Since many types of OxPLs seem to be generated in vivo, precise determination of their structural diversity is required to understand their potential structure-specific functions. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a powerful method to quantitatively measure the structural diversity of OxPLs present in biological samples. This review outlines recent advances in analytical methods for OxPLs and their physiological relevance in health and diseases.

Lp(a)‐Associated Oxidized Phospholipids in Healthy Black and White Participants in Relation to apo(a) Size, Age, and Family Structure

BackgroundLp(a) (lipoprotein(a)) is the major lipoprotein carrier of oxidized phospholipids (OxPL) and this function mediates Lp(a) atherogenicity. However, the relationship between OxPL, Lp(a), and genetic and biological characteristics remains poorly understood. We assessed the relationship between Lp(a)‐bound OxPL, apolipoprotein(a) (apo(a)) size, age, and family structure in 2 racial groups.Methods and ResultsHealthy Black and White families were recruited from the general population (age: 6–74 years, n=267). OxPL and Lp(a) levels were assayed enzymatically; apo(a) isoform, LPA allele sizes, and allele‐specific Lp(a) levels were determined. Lp(a)‐OxPL levels did not differ significantly by racial and age groups. Lp(a)‐OxPL levels were associated with total plasma Lp(a) in all participants and in race‐specific analyses. Further, OxPL levels were significantly associated with allele‐specific Lp(a) levels carried by the smaller apo(a) size in all participants (β=0.33, P=0.0003) as well as separately for Black (β=0.50, P=0.0032) and White (β=0.26, P=0.0181) participants. A significant association of OxPL with allele‐specific Lp(a) levels for larger apo(a) sizes was seen only in Black participants (β=0.53, P=0.0076). In this group, Lp(a)‐OxPL levels were also heritable (h2=0.29, P=0.0235), resulting in a significant interracial difference in heritability between Black and White people (P=0.0352).ConclusionsLp(a)‐OxPL levels were associated with allele‐specific Lp(a) level carried on smaller apo(a) sizes and among Black participants also for larger apo(a) sizes. The heritability estimates for Lp(a)‐bound OxPL differed by race.

Oxidized phospholipids on alkyl-amide scaffold demonstrate anti-endotoxin and endothelial barrier-protective properties

Oxidized phospholipids (OxPLs) containing enzymatically or non-enzymatically oxidized fatty acids (oxylipins) are increasingly recognized as lipid mediators involved in pathogenesis of diseases. Further understanding of structure-activity relationship and molecular mechanisms activated by OxPLs is hampered by the complexity of synthesis of individual molecular species. Although dozens of individual free oxylipins are commercially available, their attachment to the phospholipid scaffold requires relatively harsh conditions during activation of carboxy-group, which may lead to decomposition of unstable oxylipins. Furthermore, additional protection-deprotection steps are required for oxylipins containing hydroxy-groups. In this work we describe synthesis of OxPLs containing oxylipins bound at the sn-2-position via an amide-bond that is characteristic of sphingophospholipids. Activation of oxylipins and attachment to the phospholipid scaffold are performed under mild conditions and characterized by high yield. Hydroxy-groups of oxylipins do not interfere with reactions and therefore no protection/deprotection steps are needed. In order to prevent oxylipin migration, a fatty acid residue at the sn-1 was bound through an alkyl bond, which is a common bond present in a large proportion of naturally occurring phospholipids. An additional advantage of combining alkyl and amide bonds in a single phospholipid molecule is that both types of bonds are phospholipase A1/A2-resistant, which may be expected to improve biological stability of OxPLs and thus simplify analysis of their effects. As proof of principle, several alkyl-amide oxidized phosphatidylcholines (OxPCs) containing either linear or prostane ring oxylipins have been synthesized. Importantly, we show here that alkyl-amide-OxPCs demonstrated biological activities similar to those of di-acyl-OxPCs. Alkyl-amide-OxPCs inhibited pro-inflammatory action of LPS and increased endothelial cellular barrier in vitro and in mouse models. The effects of alkyl-amide and di-acyl-OxPCs developed in a similar range of concentrations. We hypothesize that alkyl-amide-OxPLs may become a useful tool for deeper analysis of the structure-activity relationship of OxPLs.

Evaluation of OxPL Levels in Patients Undergoing Coronary Angiography: A Cross-Sectional Study

Background and Aim: Coronary ectasia is one of the prevalent cardiovascular diseases worldwide. It causes many deaths annually ranged between 9% to 10% which is dependent on related risk factors. The main pathogenesis has not been determined yet; however, it has been shown, that increased lipid profiles and their oxidation in patients can cause endothelial cell dysfunction and thrombosis. Therefore, here we investigated the oxidized phospholipids (OxPLs) role in the pathogenesis of coronary artery disease. Methods: This cross-sectional study was performed in Shariati Hospital, Tehran. Accordingly, patients with coronary artery angiography indications (n=360) were included and classified into one of the following three groups, based on the angiographic results: 1) normal coronary artery (not dysfunction in vessels) or mild CAD (only intimal irregularity or less than 3% narrowing without ectasia); 2) vessel dilation more than 1.5 times compared to the normal part of the vessel or compared to the normal size according to age and gender in one or more coronary vessels; and 3) patients with more than 50% stenosis in one of the coronary arteries. The peripheral blood was collected from patients in EDTA anticoagulants container tubes and the OxPL level was measured using an ELISA kit. Results: The results showed that the amount of OxPL in the third and second groups was higher than in the first group. It was also found that hyperlipidemia, diabetes, hypertension, and smoking were higher in the third and second groups; all mentioned findings were statistically significant (p-value <0.05). Conclusion: According to the findings of this study, it was shown that an increase in OxPL in patients with coronary ectasia can be considered as a risk factor for disease progression; OxPL measurement can be used to identify high-risk individuals. *Corresponding Author: Seyed Abdolhussein Tabatabaei; Email: tabatabaeiseyedah@gmailcom; ORCID iD: 0000-0001-5091-6066 Please cite this article as: Nikdoust F, Lashkari Zadeh F, Tabatabaei SA. Evaluation of OxPL Levels in Patients Undergoing Coronary Angiography: A Cross-Sectional Study. Arch Med Lab Sci. 2021;7:1-6 (e12). https://doi.org/10.22037/amls.v7.34602

The role of oxidized phospholipids in COVID-19-associated hypercoagulopathy.

There is more pronounced hypercoagulation in COVID-19 infection than in other viral lung infections. Oxidized phospholipids (OxPLs) appear in COVID-19-infected lungs due to oxidative stress, after which they promote the induction of tissue factor (TF) expression and inflammatory programmers in monocytes, as well as activate endothelial cells to recruit and bind to monocytes. Therefore, we aimed to demonstrate the role of OxPLs in inflammatory and procoagulant responses in COVID-19 infection. Patients with a positive SARS-CoV-2 polymerase chain reaction test and ten healthy donors were included in the study. Peripheral blood was drawn at inclusion for OxPAPC, IFN-γ, and CCL2 serum level measurements. Clinical data were collected from electronic patient medical files. The serum levels of OxPAPC, IFNγ, and CCL2 were measured by immune assays. Seventy-two patients were included in the study. OxPAPC and CCL2 were higher in the patients than in the controls (<0.003 and 0.011, respectively). INF-γ did not significantly differ between groups. There was no difference between the patients with lung involvement and those without CCL2, INF-γ, and OxPAPC. D-dimer, CRP, and ferritin were higher in the patients with lung involvement. Serum levels of INF-γ and CCL2 were positively correlated with each other (r:0.757, p<0.0001), but no correlation was detected between OxPAPC and INF-γ or CCL2. There was no correlation between OxPAPC and hematologic or biochemical parameters. OxPAPC, which is thought to contribute to hypercoagulability, was found to be high in the patients with Covid-19 infection. The role of OxPLs in COVID-19-associated hypercoagulopathy should be investigated further in experimental models and in larger patient groups.

Elucidating the atherogenicity of Lp(a): An unbiased lipidomics approach

Background and Aims: Mendelian randomisation as well as epidemiology studies have established an association between elevated lipoprotein(a) [Lp(a)] levels and increased cardiovascular risk. Besides the pro-atherogenic properties of the LDL- like moiety, Lp(a) further contributes to the disease pathology by carrying pro-inflammatory oxidized phospholipids (OxPLs). While blocking these OxPL epitopes profoundly reduces the monocytic inflammatory response, a residual inflammatory risk remains.

Neutralization of oxidized phospholipids attenuates age-associated bone loss in mice.

Oxidized phospholipids (OxPLs) are pro‐inflammatory molecules that affect bone remodeling under physiological conditions. Transgenic expression of a single‐chain variable fragment (scFv) of the antigen‐binding domain of E06, an IgM natural antibody that recognizes the phosphocholine (PC) moiety of OxPLs, increases trabecular and cortical bone in adult male and female mice by increasing bone formation. OxPLs increase with age, while natural antibodies decrease. Age‐related bone loss is associated with increased oxidative stress and lipid peroxidation and is characterized by a decline in osteoblast number and bone formation, raising the possibility that increased OxPLs, together with the decline of natural antibodies, contribute to age‐related bone loss. We show here that transgenic expression of E06‐scFv attenuated the age‐associated loss of spinal, femoral, and total bone mineral density in both female and male mice aged up to 22 and 24 months, respectively. E06‐scFv attenuated the age‐associated decline in trabecular bone, but not cortical bone, and this effect was associated with an increase in osteoblasts and a decrease in osteoclasts. Furthermore, RNA‐seq analysis showed that E06‐scFv increased Wnt10b expression in vertebral bone in aged mice, indicating that blocking OxPLs increases Wnt signaling. Unlike age‐related bone loss, E06‐scFv did not attenuate the bone loss caused by estrogen deficiency or unloading in adult mice. These results demonstrate that OxPLs contribute to age‐associated bone loss. Neutralization of OxPLs, therefore, is a promising therapeutic target for senile osteoporosis, as well as atherosclerosis and non‐alcoholic steatohepatitis (NASH), two other conditions shown to be attenuated by E06‐scFv in mice.

The current landscape of lipoprotein(a) in calcific aortic valvular disease.

Calcific aortic stenosis (CAVS) is the most common form of valvular heart disease in developed countries, increasing in prevalence with the aging population. Surgical or transcatheter aortic valve replacement is the only treatment available for CAVS. However, these interventions are typically reserved for severe symptomatic aortic stenosis (AS). The purpose of this review is to summarize the recent literature in uncovering the underlying pathophysiology of CAVS in the setting of lipoprotein (a) [Lp(a)] and emerging therapies targeting Lp(a) which may help halt disease progression in CAVS. Pathophysiologic, epidemiological, and genetic studies over the past two decades have provided strong evidence that Lp(a) is an important mediator of calcific aortic valvular disease (CAVD). Studies suggest that Lp(a) is a key carrier of pro-calcifying oxidized phospholipids (OxPL). The metabolism of OxPL results in a pro-inflammatory state and subsequent valvular thickening and mineralization through pro-osteogenic signaling. The identification of Lp(a) as a causal mediator of CAVD has allowed for opportunities for emerging therapeutic agents which may slow the progression of CAVD (Fig. 1JOURNAL/cocar/04.03/00001573-202109000-00007/figure1/v/2021-08-04T080204Z/r/image-jpeg). This review summarizes the current knowledge on the association of Lp(a) with CAVD and ongoing studies of potential Lp(a)-lowering therapies. Based on the rate-limiting and causal role of Lp(a) in progression of CAVS, these therapies may represent novel pharmacotherapies in AS and inform the developing role of Lp(a) in the clinical management of CAVD.

Pain Control by Targeting Oxidized Phospholipids: Functions, Mechanisms, Perspectives.

Within the lipidome oxidized phospholipids (OxPL) form a class of chemically highly reactive metabolites. OxPL are acutely produced in inflamed tissue and act as endogenous, proalgesic (pain-inducing) metabolites. They excite sensory, nociceptive neurons by activating transient receptor potential ion channels, specifically TRPA1 and TRPV1. Under inflammatory conditions, OxPL-mediated receptor potentials even potentiate the action potential firing rate of nociceptors. Targeting OxPL with D-4F, an apolipoprotein A-I mimetic peptide or antibodies like E06, specifically binding oxidized headgroups of phospholipids, can be used to control acute, inflammatory pain syndromes, at least in rodents. With a focus on proalgesic specificities of OxPL, this article discusses, how targeting defined substances of the epilipidome can contribute to mechanism-based therapies against primary and secondary chronic inflammatory or possibly also neuropathic pain.

Plasma Phospholipids: A Promising Simple Biochemical Parameter to Evaluate COVID-19 Infection Severity.

Background:Coronavirus-19 (COVID-19) pandemic is a worldwide public health problem that has been known in China since December 25, 2019. Phospholipids are structural components of the mammalian cytoskeleton and cell membranes. They suppress viral attachment to the plasma membrane and subsequent replication in lung cells. In the virus-infected lung, phospholipids are highly prone to oxidation by reactive oxygen species, leading to the production of oxidized phospholipids (OxPLs).Objective:This study was carried out to explain the correlation between the level of plasma phospholipids in patients with COVID-19 infection and the levels of cytokine storms to assess the severity of the disease.Methods:Plasma samples from 34 enrolled patients with mild, moderate, and severe COVID-19 infection were collected. Complete blood count (CBC), plasma levels of D-dimer, ferritin, C-reactive protein (CRP), cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), phospholipids, secretory phospholipase A2 (sPLA2)α2, and cytokine storms were estimated, and lung computed tomography (CT) imaging was detected.Results:The CBC picture showed the presence of leukopenia, lymphopenia, and eosinopenia in patients with COVID-19 infection. Furthermore, a significant increase was found in plasma levels of D-dimer, CRP, ferritin, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-13 as well as sPLA2α2 activity compared to normal persons. However, plasma levels of phospholipids decreased in patients with moderate and severe COVID-19 infection, as well as significantly decreased in levels of triacylglycerols and HDL-C in plasma from patients with severe infection only, compared to normal persons. Furthermore, a lung CT scan showed the presence of inflammation in a patient with mild, moderate, and severe COVID-19 infection.Conclusions:This study shows that there is a correlation between plasma phospholipid depletion and elevated cytokine storm in patients with COVID-19 infection. Depletion of plasma phospholipid levels in patients with COVID-19 infection is due to oxidative stress, induction of cytokine storm, and systemic inflammatory response after endothelial cell damage promote coagulation. According to current knowledge, patients with COVID-19 infection may need to administer surfactant replacement therapy and sPLA2 inhibitors to treat respiratory distress syndrome, which helps them to maintain the interconnected surfactant structures.

Justification for use of pentoxifylline in the complex therapy against COVID-19

During COVID-19 pandemic, the world scientific community is seeking for efficient and high-quality means to battle the virus itself and its complications. Unfortunately, so far there is no specific methods to treat COVID-19. The main therapeutic strategies include supporting and controlling approaches. So prevention is the best way to eliminate the viral contagion. In the view of this, the scientists paid their attention to pentoxofylline which has been well-known in medicinal practice for a long time. Pentoxifylline is methylxanthine-derived which has been used for the last three decades to treat remittent limp. When used in clinical doses (max. daily dose — 1200 mg), it improves rheological blood values: it reduces plasma viscosity mostly due to decrease fibrinogen level; it leads to increase of erythrocyte elasticity and decrease of thrombocyte aggregation; it provides the increase of blood filtration due to inhibition of neutrophil activation. Viral infections are usually related to the constant formation of the oxidized products and COVID-19 is not an exception as well. Post-mortem analysis of the people affected with SARS-CoV showed the massive formation of the oxidized phospholipids (OxPL) during acute lung injury (ALI). By showing its anti-oxidant and anti-inflammatory properties, pentoxifylline renews glutathione level, supports mitochondrial viability, inhibits TNF-α production, saves the functions of vascular endothelium which in its turn reduces the length of stay at the hospital and ICU, frequency of multi-organ dysfunctions, mechanical ventilation time and mortality rate. Academic works show that pentoxifylline has anti-inflammatory, anti-oxidant, immune-modulating, anti-viral properties; it also has positive effect on respiratory symptoms alleviation which supports the idea that it can used as the adjuvant therapy for COVID-19 patients. Moreover, it can be also used to treat thrombotic complications at the severe COVID-19.

The role of oxidized phospholipids in the development of disease

Oxidized phospholipids (OxPLs), complex mixtures of phospholipid oxidation products generated during normal or pathological processes, are increasingly recognized to show bioactive effects on many cellular signalling pathways. There is a growing body of evidence showing that OxPLs play an important role in many diseases, so it is essential to define the specific role of OxPLs in different diseases for the design of disease therapies. In vastly diverse pathological processes, OxPLs act as pro-inflammatory agents and contribute to the progression of many diseases; in addition, they play a role in anti-inflammatory processes, promoting the dissipation of inflammation and inhibiting the progression of some diseases. In addition to participating in the regulation of inflammatory responses, OxPLs affect the occurrence and development of diseases through other pathways, such as apoptosis promotion. In this review, the different and even opposite effects of different OxPL molecular species are discussed. Furthermore, the specific effects of OxPLs in various diseases, as well as the receptor and cellular mechanisms involved, are summarized.