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Platelet-activating factor (PAF) is a potent phospholipid mediator that was first described by its ability to cause platelet aggregation and dilation of blood vessels. It is now also known as a potent mediator of inflammation, allergic responses, and shock. It causes a dramatic inflammation of the air passage, resulting in asthmalike symptoms. Production of PAF is induced by toxins from bacterial fragments, leading to vasodilation, decreased blood pressure, reduced cardiac output, and shock. Platelets, endothelial cells, macrophages, monocytes, and neutrophils continuously produce PAF in low quantities. PAF acetylhydrolase (PAF-AH), also known as Lipoprotein-associated phospholipase A2 (Lp-PLA2), inactivates the PAF and PAF-like phospholipids, controlling their actions.[1] Its activity increases when specific stimuli activate inflammatory cells. Lp-PLA2 is a biomarker for cardiovascular risk assessment and is associated with unstable atherosclerotic plaques. PAF also correlates with various medical conditions like asthma, stroke, myocardial infarction, certain tumors and cancers, and various other inflammatory conditions.[2]

PAF is not the sole mediator of diseases, but it has a crucial role in specific syndromes and diseases. Most of these conditions result from increased PAF or PAF-like activity, which can be due to increased production of PAF or decreased degradation of PAF or PAF-like lipids. PAF acetylhydrolase is the key enzyme responsible for PAF degradation. PAF acetylhydrolase (PAF-AH) has 2 intracellular isoforms (PAF-AH 1 and PAF-AH II) and one extracellular form called lipoprotein-associated phospholipase (Lp-PLA2). PAH-AH I plays a vital role in brain development, sperm production, amyloid-beta precursor trafficking to lysosomes, cancer pathogenesis, protein trafficking and sorting, and aspirin metabolism.[39] PAH-AH II protects cells from oxidative stress and maintains cell integrity by degrading oxidized phospholipid fragments.[40][41][42][43] It can transacetylase PAF to other lipid mediators, modifying its cellular function.[44] Lipoprotein-associated phospholipase (Lp-PLA2) or plasma platelet-activating factor acetylhydrolase (PAF-AH) is mainly associated with LDL (>80%) and HDL (<20%). However, only <1% of LDL particles contain Lp-PLA2. A small subset of LDL particles, as measured by Lp-PLA2, is protective against oxidative inactivation. Oxidants are potent and irreversible inhibitors of Lp-PLA2 activity.[45] The Lp-PLA2 has 2 main biological activities. It hydrolyzes and inactivates PAF and hydrolyzes PAF-like oxidized lipids found in oxidized LDL. The latter role is crucial in the pathogenesis of atherosclerosis because it results in the production of 2 pro-inflammatory mediators: lysophosphatidylcholine (lysoPC) and oxidized nonesterified fatty acid (OxNEFA). Low Lp-PLA2 activity is also associated with asthma, attributed to higher PAF levels in those patients.

The Lp-PLA2 has 2 main biological activities. It hydrolyzes and inactivates PAF and hydrolyzes PAF-like oxidized lipids found in oxidized LDL. The latter role is crucial in the pathogenesis of atherosclerosis because it results in the production of 2 pro-inflammatory mediators: lysophosphatidylcholine (lysoPC) and oxidized nonesterified fatty acid (OxNEFA). Low Lp-PLA2 activity is also associated with asthma, attributed to higher PAF levels in those patients. Epidemiological studies indicate that Lp-PLA2 activity plays a protective role against atherosclerotic lesions. These studies of the Japanese population reveal that 4% carry the Lp-PLA2 variant with the loss-of-function V279F mutation. People with the V279F variant of Lp-PLA2 have a higher risk of stroke, MI (in men only), cardiomyopathy (both dilated and hypertrophic), coronary artery disease, cerebral hemorrhage, atherosclerosis, polycystic ovary syndrome, and asthma. Also, adenovirus-mediated Lp-PLA2 gene transfer has shown that plasma Lp-PLA2 expression is associated with reduced oxidized LDL accumulation in the arteries. However, a meta-analysis of 32 prospective studies has shown that Lp-PLA2 activity has a strong positive association with the risk of coronary heart disease (CHD) and stroke. The magnitude of the relationship of Lp-PLA2 is similar to that of non-HDL cholesterol or systolic blood pressure.[46] The discrepancy between epidemiological and clinical studies is related to the pathophysiology of atherosclerosis, which involves the production of pro-inflammatory mediators. The protective role of Lp-PLA2 is due to PAF hydrolysis. However, its role in atherosclerosis stems from the hydrolysis of PAF-like oxidized lipids in LDL.

However, a meta-analysis of 32 prospective studies has shown that Lp-PLA2 activity has a strong positive association with the risk of coronary heart disease (CHD) and stroke. The magnitude of the relationship of Lp-PLA2 is similar to that of non-HDL cholesterol or systolic blood pressure.[46] The discrepancy between epidemiological and clinical studies is related to the pathophysiology of atherosclerosis, which involves the production of pro-inflammatory mediators. The protective role of Lp-PLA2 is due to PAF hydrolysis. However, its role in atherosclerosis stems from the hydrolysis of PAF-like oxidized lipids in LDL. When Lp-PLA2 hydrolyzes PAF-like oxidized lipids in LDL, it generates 2 pro-inflammatory mediators. These are lysophosphatidylcholine (lysoPC) and oxidized nonesterified fatty acids (OxNEFA), which promote plaque development. These pro-inflammatory mediators can recruit and activate leukocytes, impair the clearance of dead cells, and induce apoptosis. LysoPC and oxFFA bind to G2A, a G protein-coupled receptor that is highly expressed by macrophages in atherosclerotic lesions.[47][13] LysoPC is a direct chemoattractant for monocytes and induces the expression of VCAM-1 and ICAM-1, promoting monocyte adhesion. It causes macrophages and smooth muscle cells to proliferate and leads to endothelial dysfunction in various arteries. OxNEFA can cause platelet aggregation and vasoconstriction.[48] Lp-PLA2 promotes the instability of atherosclerotic plaques because vulnerable and ruptured plaques with a necrotic core and apoptotic macrophages exhibit the highest Lp-PLA2 expression. Stable and less advanced plaques do not express Lp-PLA2. Lp-PLA2 is a reliable plasma biomarker for cardiovascular disease, and its activity is an independent predictor of coronary heart disease in the general population.[48] Animal studies have shown that darapladib, a drug that inhibits Lp-PLA2, reduces lypoPC content in coronary artery lesions. It also reduced the expression of pro-inflammatory cytokines needed for macrophage and T-cell recruitment and functioning.[49][50] Several large-scale phase-III clinical trials showed that darapladib reduced the rate of major coronary events and total coronary events in patients with atherosclerosis. However, it did not reduce the risk of cardiovascular death, stroke, or myocardial infarction.[51]

Lp-PLA2 is a reliable plasma biomarker for cardiovascular disease, and its activity is an independent predictor of coronary heart disease in the general population.[48] Animal studies have shown that darapladib, a drug that inhibits Lp-PLA2, reduces lypoPC content in coronary artery lesions. It also reduced the expression of pro-inflammatory cytokines needed for macrophage and T-cell recruitment and functioning.[49][50] Several large-scale phase-III clinical trials showed that darapladib reduced the rate of major coronary events and total coronary events in patients with atherosclerosis. However, it did not reduce the risk of cardiovascular death, stroke, or myocardial infarction.[51] Increased PAF activity in the lungs is associated with the pathogenesis of asthma. It mediates bronchoconstriction, bronchial hyperreactivity, mucous secretion, and inflammatory cell infiltration. Aerosolized inhaled PAF causes hyperresponsiveness with methacholine challenge in healthy and asthmatic patients. It increases blood flow through poorly ventilated areas in the lungs. Clinical trials in Japan with the PAF receptor antagonist apafant showed dose-dependent improvement in symptoms over 8 weeks in patients with mild to moderate asthma.[52] Plasma PAF-AH deficiency is associated with asthma severity. A V279F polymorphism is a loss-of-function mutation of plasma PAF-AH in the Japanese population, and it is associated with an increased risk of developing asthma and atopy compared to the wild type. Other genetic mutations associated with polymorphisms in the plasma PAF-AH gene have been found in German and British individuals.[20]