Oxidized Phospholipids in Healthy and Diseased Lung Endothelium

Abstract

Circulating and cell membrane phospholipids undergo oxidation caused by enzymatic and non-enzymatic mechanisms. As a result, a diverse group of bioactive oxidized phospholipids generated in these conditions have both beneficial and harmful effects on the human body. Increased production of oxidized phospholipid products with deleterious effects is linked to the pathogenesis of various cardiopulmonary disorders such as atherosclerosis, thrombosis, acute lung injury (ALI), and inflammation. It has been determined that the contrasting biological effects of lipid oxidation products are governed by their structural variations. For example, full-length products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine oxidation (OxPAPC) have prominent endothelial barrier protective and anti-inflammatory activities while most of the truncated oxidized phospholipids induce vascular leak and exacerbate inflammation. The extensive studies from our group and other groups have demonstrated a strong potential of OxPAPC in mitigating a wide range of agonist-induced lung injuries and inflammation in pulmonary endothelial cell culture and rodent models of ALI. Concurrently, elevated levels of truncated oxidized phospholipids are present in aged mice lungs that potentiate the inflammatory agents-induced lung injury. On the other hand, increased levels of full length OxPAPC products accelerate ALI recovery by facilitating production of anti-inflammatory lipid mediator, lipoxin A4, and other molecules with anti-inflammatory properties. These findings suggest that OxPAPC-assisted lipid program switch may be a promising therapeutic strategy for treatment of acute inflammatory syndromes. In this review, we will summarize the vascular-protective and deleterious aspects of oxidized phospholipids and discuss their therapeutic potential including engineering of stable analogs of oxidized phospholipids with improved anti-inflammatory and barrier-protective properties.

Oxidized phospholipids affect small intestine neuromuscular transmission and serotonergic pathways in juvenile mice

“…Phospholipids are the building blocks of all mammalian membranes, ensuring a permeable barrier and endogenous substrates in multiple enzymatic pathways usually involved in the formation of essential signaling mediators (eg, platelet‐activating factor, sphingosine‐derived phospholipids, and eicosanoids) 47 . However, several pathological conditions, including lung injury, autoimmune diseases, and sepsis, promote oxidative stress with the consequent formation of fatty acid hydroperoxides and further accumulation of full‐length and fragmented OxPLs in cell membranes and circulating lipoproteins 48 . OxPLs elicit a multiplicity of bioactivities by interacting with different pattern recognition receptors of the innate immune system cellular receptors, including TLRs and scavenger receptors 48,49 .…”

“…However, several pathological conditions, including lung injury, autoimmune diseases, and sepsis, promote oxidative stress with the consequent formation of fatty acid hydroperoxides and further accumulation of full‐length and fragmented OxPLs in cell membranes and circulating lipoproteins 48 . OxPLs elicit a multiplicity of bioactivities by interacting with different pattern recognition receptors of the innate immune system cellular receptors, including TLRs and scavenger receptors 48,49 . In contrast to these pro‐inflammatory effects, OxPLs have also been shown to mediate anti‐inflammatory responses by negatively influencing the activation of TLRs following exposure to microbial ligands 11,33,50,51 .…”

Oxidized Phospholipids in Tumor Microenvironment Stimulate Tumor Metastasis via Regulation of Autophagy

“…The full-length oxPLs exert anti-inflammatory effects and are protective for inflammatory diseases while truncated oxPLs exhibit pro-inflammatory activity and promote the development and progress of inflammatory diseases [ 54 ]. Therefore, the biological impacts upon the exposure to mixture of oxPLs in vivo could be different depending on the composition and concentration of oxPL components and the cellular context [ 54 ]. Ray et al evaluated the free radical production and malondialdehyde (MDA) concentration in the plasma of breast cancer patients.…”

The Contribution of Endothelial Dysfunction in Systemic Injury Subsequent to SARS-Cov-2 Infection

“…Many studies confirmed the protective effects of polyphenol and flavonoids' antioxidants against many pathological pathologies including neurodegenerative [107], vascular [108], and cardiovascular diseases [109]. Furthermore, numerous scientific investigations have highlighted the protective role of polyphenols against endothelial and microvascular dysfunctions [110,111].…”