PLA2 - One of the Most Important Markers, and Cheapest to test.

PLA2 you say !? What is that ? Why should i get that lab test done !? Common questions among the chronically ill community, or those folks searching for the mysteries of why they feel less than vital. Phospholipase A2 has received more attention recently as Bruce Patterson has helped bring attention to chronic platelet activation and elevated levels of Rantes (CCL5) from long haul, and cfs. PLA2, which has 3 forms, has a role to play in platelet activation - and so it has come back from the shadows. In every person with long haul or Chronic Fatigue I have met with (60) who got tested - most have elevated PLA2. And those same folks have elevated levels of VEGF and SCD 40L - associated with platelet activation. In a later article, I will go into the depths of platelet activation and why its a core feature of chronic fatigue and post viral malaise. In this later article, I will reference the 60 cases of chronic fatigue i have received genetics from, and the database of 4,000 chronic fatigue folks' genetics I had access to develop a model to assess the most important genetic factors in chronic fatigue and in post viral malaise.

What is PLA2?

Phospholipase A2 (PLA2) catalyzes the hydrolysis of the sn-2 position of membrane glycerophospholipids to liberate arachidonic acid (AA), a precursor of eicosanoids including prostaglandins (PGs) and leukotrienes (LTs). The same reaction also produces lysophosholipids, which represent another class of lipid mediators. So far, at least 19 enzymes that possess PLA2 activity have been identified in mammals. [4]

What conditions is it associated with, and who should get tested ?

Some of the conditions and diseases in which PLA2 is associated (not suggesting causal) are : Autism, Multiple sclerosis, Cancer, Schizophrenia, Bipolar depression, Cardiovascular disease, Alzheimer's disease, Parkinson's disease, Pancreatitis, Stroke, Brain injury, and Memory impairment [30]. Not directly linked yet - but researches have been circling around a link between elevated PLA2, and vagal nerve dysfunction. Gulp!? Isn't that everybody !? But wait there is more, its associated with Covid, Candida, Mast Cell Activation, NFALD, elevated iNOS (what!?), COPD, vascular wall inflammation, increases foam cell formation and athreosclorosis,

How to get tested ?

Great Plains Laboratories used to offer t his as an option in their urine based Organic Acids test - but no longer offer it; apparently they are working to see if it can be added back in as an option. It was an inexpensive add on (<$100). A blood based PLA2 test by Vibrant America exists (PLAC marker) in their cardiac panel which is less than $100, and you can also order the PLAC marker for about the same cost as a CMP or CBC as a stand alone.

Below I have highlighted some of the more interesting research regarding PLA2. Including some of the benefits that have been documented from taking citicholine to help lower elevated PLA2, recover from brain injury, recover from stroke, and drive cognitive improvement in alzheimers patients. And that is just the start!

Three (3) Types of PLA2

Phospholipase A2 (PLA2) plays crucial roles in diverse cellular responses, including phospholipid digestion and metabolism, host defense and signal transduction. PLA2 provides precursors for generation of eicosanoids, such as prostaglandins (PGs) and leukotrienes (LTs). As overproduction of these lipid mediators causes inflammation and tissue disorders, it is extremely important to understand the mechanisms regulating the expression and functions of PLA2. PLA2s are classified into three large groups, namely, secretory (sPLA2), cytosolic (cPLA2), and Ca2+-independent PLA2s, on the basis of their enzymatic properties and structures and focus on the general understanding of the possible regulatory functions of each PLA2 isozyme. [4]

Phospholipase has inflammatory and anti inflammatory roles:

Phospholipase A2 (PLA2) catalyses the release of arachidonic acid for generation of lipid mediators of inflammation and is crucial in diverse inflammatory processes. We find that the group V sPLA2 isoform plays a novel anti-inflammatory role that opposes the pro-inflammatory activity of group IIA sPLA2. Mechanistically, group V sPLA2 counter-regulation includes promotion of immune complex clearance by regulating cysteinyl leukotriene synthesis. These observations identify a novel anti-inflammatory function for a PLA2 and identify group V sPLA2 as a potential biotherapeutic for treatment of immune-complex-mediated inflammation. [1]

Calcium dependence (Ca2+) - interesting!

The cytosolic PLA2 (cPLA2) family consists of 3 enzymes, among which cPLA2alpha plays an essential role in the initiation of AA metabolism. Intracellular activation of cPLA2alpha is tightly regulated by Ca2+ and phosphorylation. The Ca2+-independent PLA2 (iPLA2) family contains 2 enzymes and may play a major role in membrane phospholipid remodeling. The platelet-activating factor (PAF) acetylhydrolase (PAF-AH) family represents a unique group of PLA2 that contains 4 enzymes exhibiting unusual substrate specificity toward PAF and/or oxidized phospholipids. [2]

Involved In Non-Alcoholic Fatty Liver Disease, and Activated Platelets

Non-alcoholic fatty liver disease (NAFLD) is a multifaceted clinicopathological syndrome characterized by excessive hepatic lipid accumulation that causes steatosis, excluding alcoholic factors. Platelet-activating factor (PAF), a biologically active lipid transmitter, induces platelet activation upon binding to the PAF receptor. Recent studies have found that PAF is associated with gamma-glutamyl transferase, which is an indicator of liver disease. Moreover, PAF can stimulate hepatic lipid synthesis and cause hypertriglyceridaemia. Furthermore, the knockdown of the PAF receptor gene in the animal models of NAFLD helped reduce the inflammatory response, improve glucose homeostasis and delay the development of NAFLD. These findings suggest that PAF is associated with NAFLD development. According to reports, patients with NAFLD or animal models have marked platelet activation abnormalities, mainly manifested as enhanced platelet adhesion and aggregation and altered blood rheology. Pharmacological interventions were accompanied by remission of abnormal platelet activation and significant improvement in liver function and lipids in the animal model of NAFLD. These confirm that platelet activation may accompany a critical importance in NAFLD development and progression. However, how PAFs are involved in the NAFLD signaling pathway needs further investigation. [3]

PLA2 implicated in Mast Cell Activation

Recent studies using transgenic and knockout mice for individual sPLA2 isofoms have revealed their involvement in various pathophysiological events, specifically their roles in mast cells (MCs) in the context of allergology. In particular, we highlight group III sPLA2 (PLA2G3) as an "anaphylactic sPLA2" that promotes MC maturation and thereby anaphylaxis through a previously unrecognized lipid-orchestrated circuit.[5]

Elevated COX-2, sPLA2, implicated in small bowel and colorectal adenocarcinomas

Cyclooxygenase-2 (COX-2), human synovial inflammatory secreted phospholipase A2 (sPLA2) and cytoplasmic phospholipase A2 (cPLA2) are involved in eicosanoid production and also seem to participate in colorectal tumorigenesis. As there are no data regarding these enzymes in human small bowel tumors, we wanted to determine whether they were involved in human small bowel tumorigenesis, and whether their expression was different in small bowel compared to colorectal adenocarcinomas, as suggested by animal studies. Seventy-six percent of the small bowel and 88% of the colorectal adenocarcinomas had a moderate or strong COX-2 expression. Sixty-eight percent of the small bowel and 67% of the colorectal adenocarcinomas had a moderate or strong sPLA2 expression. Forty-eight percent of the small bowel and 35% of the colorectal adenocarcinomas had a moderate or strong cPLA2 expression. In conclusion, the increased expression of COX-2, sPLA2, and sometimes cPLA2 in both small bowel and colorectal adenocarcinomas is in accordance with the likely eicosanoid involvement in tumor development. [8]

Relationship between serum levels of Lp-PLA2 and COVID-19 severity

The potential of serum levels of Lp-PLA2 as a marker of inflammation quantifying cardio-metabolic risk, renal impairment and oxidative stress has been explored in earlier studies. It has also been used in chronic obstructive pulmonary disease, hepatic disease, metabolic conditions and exercise tolerance. Additionally, it shows promising evidence for the assessment of risk for certain cardiovascular conditions in otherwise seemingly healthy individuals. Elevated PLA2 implicated on COVID-19. [9]

ALA reduces ox-LDL and Lp-PLA2 mass and improves Lp-PLA2 distribution

In a double-blind, randomized, placebo-controlled clinical trial, seventy diabetic patients were randomly allocated to ALA (1200 mg ALA as two 600 mg capsules/day) and placebo (two maltodextrin capsules/day) groups. The serum levels of total Lp-PLA2 mass, HDL-Lp-PLA2, oxidized low-density lipoproteins (ox-LDL), apolipoprotein A1 (apo A1), lipid profiles, fasting blood sugar (FBS), and insulin were measured, and apolipoprotein B- (apoB-) associated Lp-PLA2 and homeostasis model of assessment index (HOMA-IR) were calculated at the baseline and after 8 weeks of intervention. ALA significantly decreased the ox-LDL, total Lp-PLA2 mass, apoB-associated Lp-PLA2, and percent of apoB-associated Lp-PLA2 and triglyceride and increased the percent of HDL-Lp-PLA2 compared with the placebo group but had no significant effect on HDL-Lp-PLA2 mass, apo A1, lipid profiles, and glycemic indices. [11]

PLA2 is a novel biomarker for vascular wall inflammation

The majority of the acute coronary events are caused by coronary artery segments with minimal luminal disease, but with potentially significant vascular wall inflammation and oxidative stress leading to plaque vulnerability. It has become apparent that an initial injury at the endothelial surface, is the primary site of the mechanisms involved and a role for vascular inflammation and the interaction with oxidative stress continues to emerge. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a novel biomarker for vascular wall inflammation that circulates in the blood bound to both low density (LDL) and high density (HDL) lipoprotein and promotes vascular inflammation. Circulating levels of Lp-PLA2 mass and activity are an independent risk factor for cardiovascular events. Recent studies, demonstrating that Lp-PLA2 is also associated with coronary endothelial dysfunction. [12]

COPD Risk - PLA2 is a promising biomarker for COPD

Immune infiltrate and enrichment analysis suggest PLA2G7 may regulate immune pathway via macrophages. Next, Lp-PLA2 level was upregulated in COPD patients, increased along with The Global Average of COPD (GOLD) stage. In additional, Lp-PLA2 level was significant correlate with FEV1/FVC, BMI, FFMI, CAT score, mMRC score and 6MWD of COPD patients. Finally, the predictive efficiency of Lp-PLA2 level (AUC:0.796) and derived nomogram model (AUC:0.884) in exercise tolerance was notably superior to that of the sit-to-stand test and traditional clinical features. Conclusion: Lp-PLA2 is a promising biomarker for COPD patients and is suitable for assessing exercise tolerance in clinical practice.[13]

CA-PLA2 Elevated in pancreatitis

In a prospective clinical trial, 85 patients with acute pancreatitis, including 50 with acute interstitial-edematous pancreatitis and 35 with necrotizing pancreatitis, were recruited. Serum pancreatic immuno reactive phospholipase A2 (IR-PLA2), serum phospholipase A catalytic activity (CA-PLA), and serum phospholipase A2 catalytic activity (CA-PLA2) were determined daily between day 1 and day 10 after the onset of the disease. The serum course of IR-PLA2 values for patients with acute interstitial-edematous pancreatitis was comparable to that for patients with necrotizing pancreatitis. In contrast, the determination of CA-PLA and of CA-PLA2 specific activity in the serum revealed a high differentiation between patients with interstitial edematous and those with necrotizing pancreatitis. The overall accuracy for differentiating patients with necrotizing pancreatitis from those with the interstitial-edematous type was 79% for CA-PLA and 77% for CA-PLA2 (cut-off level: CA-PLA, 15 U/L, day 1-5; CA-PLA2, 3.5 U/L, day 1-5). Patients with pancreatitis-associated pulmonary complications showed significantly higher CA-PLA and CA-PLA2 values in the serum. This study demonstrates the role of serum catalytic phospholipase A2 in human acute pancreatitis where the development of pancreatic necrosis and pulmonary failure is concerned.[14]

Several studies suggest that phospholipase A2 (PLA2) plays an important role in the pathology of acute pancreatitis. PLA2 is activated within the pancreas in experimental and human acute pancreatitis. Elevated catalytic activity of PLA2 in serum is associated especially with the severe forms of the disease. The pancreas seems not to be the only source of the enzyme entering the circulation in acute pancreatitis. The source of the non-pancreatic PLA2 may be various inflammatory cells, but this hypothesis remains to be proven. The results of the treatment of experimental acute pancreatitis with PLA2 inhibitors have been promising, but adequate human trials have not been conducted. [15]

The activity and the content of phospholipase A2 (PLA2), a potential 'toxin' in pancreatitis, were determined separately by respective methods in pancreatic tissue resected from 22 patients treated for acute necrotizing pancreatitis. Correspondent enzyme assays were analyzed in the serum of 6 last patients. In cases with total necrosis in the tissue resected, the pancreatic PLA2 activity, but not the content, was almost totally lost. Serum PLA2 activity slightly decreased within the extension of pancreatic necrosis. The timing of sampling, number of positive Ranson signs or the course of the disease had no influence on the tissue PLA2 results. Serum PLA2 activity showed a correlation with tissue PLA2 activity.[16]

High PLA2 induced NO production through iNOS(inducible NO synthase) in rats

Reportedly, nitric oxide (NO) derived from alveolar macrophages (AMs) and increased serum phospholipase A2 (PLA2) activity are associated with the pathogenesis of lung injury in acute pancreatitis. The serum with high PLA2 activity induced NO production by rat AMs. PLA2 (50 ng/ml) induced significant amounts of NO production, inducible NO synthase mRNA expression, and cytotoxicity toward the human umbilical vein endothelial cells in normal rat AMs, and these activities were significantly inhibited by quinacrine. PLA2 induces AMs to release NO, which contributes to lung injury in acute pancreatitis. This lung injury was prevented by the administration of the PLA2 inhibitor quinacrine.[17]

In Schizophrenia - PLA2 activity associated with structural brain alterations

Regional structural brain changes are among the most robust biological findings in schizophrenia, yet the underlying pathophysiological changes remain poorly understood. Recent evidence suggests that abnormal neuronal/dendritic plasticity is related to alterations in membrane lipids. We examined whether serum activity of membrane lipid remodeling/repairing cytosolic phospholipase A(2) (PLA(2)) were related to regional brain structure in magnetic resonance images (MRI). Findings demonstrate a potential association between membrane lipid biochemistry and focal brain structural abnormalities in schizophrenia. Differential patterns in first-episode vs. chronic patients might be related to PLA(2)-increase at disease-onset reflecting localized regenerative activity, whereas correlations in recurrent-episode patients might point to less specific neurodegenerative aspects of disease progression. [18]

PLA2 activated by Candida albicans

Candida albicans is an increasingly important pulmonary fungal pathogen. We investigated the ability of C. albicans to activate cPLA2α in unprimed alveolar macrophages and after priming with granulocyte macrophage colony-stimulating factor (GM-CSF), which regulates alveolar macrophage maturation. AA was released within minutes by GM-CSF–primed but not unprimed alveolar macrophages in response to C. albicans, and was blocked by soluble glucan phosphate (S-GP). The expression of the β-glucan receptor dectin-1 was increased in GM-CSF–primed macrophages, and AA release from GM-CSF–primed dectin-1−/− alveolar macrophages was reduced to basal levels. The results demonstrate that dectin-1 mediates the acute activation of cPLA2α in GM-CSF–primed alveolar macrophages, but not in the more delayed phase of AA release and GM-CSF–dependent prostanoid production.[20]

PLA2 Inhibitors - quinacrine and chloroquine, arachidonyl trifluoromethyl ketone, bromoenol lactone, cytidine 5-diphosphoamines, and vitamin E

The phospholipase A(2) family includes secretory phospholipase A(2), cytosolic phospholipase A(2), plasmalogen-selective phospholipase A(2), and calcium-independent phospholipase A(2). It is generally thought that the release of arachidonic acid by cytosolic phospholipase A(2) is the rate-limiting step in the generation of eicosanoids and platelet activating factor. These lipid mediators play critical roles in the initiation and modulation of inflammation and oxidative stress. Neurological disorders, such as ischemia, spinal cord injury, Alzheimer's disease, multiple sclerosis, prion diseases, and epilepsy are characterized by inflammatory reactions, oxidative stress, altered phospholipid metabolism, accumulation of lipid peroxides, and increased phospholipase A(2) activity. Increased activities of phospholipases A(2) and generation of lipid mediators may be involved in oxidative stress and neuroinflammation associated with the above neurological disorders. Several phospholipase A(2) inhibitors have been recently discovered and used for the treatment of ischemia and other neurological diseases in cell culture and animal models. At this time very little is known about in vivo neurochemical effects, mechanism of action, or toxicity of phospholipase A(2) inhibitors in human or animal models of neurological disorders. In kainic acid-mediated neurotoxicity, the activities of phospholipase A(2) isoforms and their immunoreactivities are markedly increased and phospholipase A(2) inhibitors, quinacrine and chloroquine, arachidonyl trifluoromethyl ketone, bromoenol lactone, cytidine 5-diphosphoamines, and vitamin E, not only inhibit phospholipase A(2) activity and immunoreactivity but also prevent neurodegeneration, suggesting that phospholipase A(2) is involved in the neurodegenerative process. This also suggests that phospholipase A(2) inhibitors can be used as neuroprotectants and anti-inflammatory agents against neurodegenerative processes in neurodegenerative diseases.[21]

Citicoline (1,000 mg/day) improves cognitive performance in Alzheimer's patients

Cytidine 5'-diphosphocholine (citicoline) is a an endogenous intermediate in the biosynthesis of structural membrane phospholipids and brain acetylcholine. Citicoline has been extensively used for the treatment of neurodegenerative disorders associated with head trauma, stroke, brain aging, cerebrovascular pathology and Alzheimer's disease. In this study we have investigated the efficacy and safety of the treatment with citicoline versus placebo in patients with Alzheimer disease. Thirty patients (age = 73.0 +/- 8.5 years; range = 57-87 years) with mild to moderate senile dementia (GDS: stages 3-6) of the Alzheimer type were included in a double-blind, randomized and placebo-controlled clinical trial. After a 2-week period of drug washout, patients were treated with i) placebo (n = 17; age = 73 +/- 5 years) or ii) 1,000 mg/day of citicoline (n = 13; age = 76 +/- 9 years) for 12 weeks (84 days). Examinations were done at baseline (T0) and after the 12 weeks of treatment (T12). As compared to placebo, citicoline improved cognitive performance in Alzheimer's disease patients with APOE E4 (ADAS: difference between groups = -3.2 +/- 1.8 scores, p < 0.05; ADAS-cog: difference between groups = -2.3 +/- 1.5, ns); and this improvement on cognition was more pronounced (ADAS, p < 0.01; ADAS-cog: difference between groups = -2.8 +/- 1.3, p < 0.06) in patients with mild dementia (GDS < 5). Citicoline also increased cerebral blood flow velocities in comparison with placebo (p < 0.05) when transcranial Doppler recordings from both hemispheres were considered together, as well as diastolic velocity in the left middle cerebral artery (p < 0.05). Patients treated with citicoline showed an increase in the percentage of brain bioelectrical activity of alpha (occipital electrodes) and theta type (left side electrodes), accompanied by a decrease in relative delta activity particularly marked in the left temporal lobe. Significant differences with respect to placebo (p < 0.05) were observed for theta activity in several fronto-parieto-temporal electrodes of the left hemisphere. Treatment with citicoline tended to reduce serum IL-1 beta levels, mainly after 4 weeks of administration, with no modified blood histamine content. In addition, neither adverse side effects nor alterations in biological and hematological parameters were induced by citicoline. The present data indicate that citicoline (1,000 mg/day) is well tolerated and improves cognitive performance, cerebral blood perfusion and the brain bioelectrical activity pattern in AD patients. According to our results, it seems that citicoline might be a useful treatment in Alzheimer's disease, and that the efficacy of this compound is greater in patients with mild mental deterioration and/or bearing the epsilon 4 allele of the APOE. [22]

Benefits of CDP Choline [30]

1) Used for the treatment of neurodegenerative disorders associated with head trauma, stroke, brain aging, cerebrovascular apthology and Alzheimer's disease.

2) Double blind placebo controlled study in Alzheimer's disease patients indicates that CDP Choline (1,000mg/day) is well tolerated and improves cognitive performance, cerebral perfusion, and the brain bio electric patterns.

Even more effective in those with the e4 APOE genotype.

PLA2 increase foam cell formation and atherosclorosis

PLA2 enzymes are involved in multiple steps in atherosclorosis that include lipoprotein remodeling, generation of pro-inflammatory bio active lipids, and activation of inflammatory pathways. Transgeneic mice overexpress PLA2 have all shown an increase in foam cell formation and atherosclorosis. Correspondingly, reduced athreosclorosis has been observed through the use of an inhibitor of PLA2 activity.[23]

PLA2 elevated in cancer patients (colorectal, lung, pancreatic, and bladder cancers)

Only in recent years have phospholipase A2 enzymes (PLA2s) emerged as cancer targets - the detection of elevated PLA2 activities in plasma from patients with colorectal, lung, pancreatic, and bladder cancers showed elevated PLA2 levels vs healthy controls. PLA2 activities were increased in late stage vs. early stage cases in CRC. PLA2 activities were not influenced by sex, smoking, alcohol consumption, or body-mass index (BMI). Plasma PLA2 activities had approximately 70% specificity and sensitivity to detect cancer. [24]

High PLA2 Found In Alzheimer's Patients vs Healthy Controls

It was found that due to its higher sensitivity cerebrospinal fluid PLA2 could discriminate Alzheimer's disease from health controls. It also showed blood-cerebrospinal fluid barrier impairments in neurological control cases. Additionally, CFS PLA2 activity showed that around half of Alzheimers disease patients were characterized by blood-cerebrospinal fluid barrier impairment. Higher PLA2 was found in Alzheimer's patients vs healthy controls across statistically significant samples sizes. [25]

Some of the benefits of CDP Choline on brain function[30]:

• Activates the biosynthesis of phospholipids in neuronal membranes

• Increases brain metabolism

• Increases norepinephrine and dopamine levels in the central nervous system

• Neuroprotective effects during hypoxia and ischemia

• Improves learning and cognitive performance in animals

• Protects ATPase activity of mitochondrial and membrane Na+/K+ ATPase

• Inhibits Phospholipase A2

• Reverses cerebral edema in various experimental models

• Use for healthy people to increase focus

• Take before evening, may be stimulating for some

• CDP Choline markedly improved reduction in stroke impairment across 197 patients [27]

• Clearly elevated PLA2 level for MS patients, and markedly different levels of PLA2 of mild vs severe MS patients. [30]

• Clearly elevated PLA2 activity for Autism patients, with data almost completely non overlapping compared to controls. [30]

According to Titsworth, et al, blocking sPLA2 action may represent a novel and efficient strategy to block multiple injury pathways associated with the CNS secondary injury with emphasis placed on the possible roles of sPLA2 in mediating CNS injuries, particularly the traumatic and ischemic injuries in the brain and spinal cord.[26]

• PLA2 is involved in host defense, phospholipid digestion and metabolism in health

• In pathology, increased PLA2 activity and excessive production of free fatty acids and their metabolites may lead to inflammation, loss of membrane integrity, oxidative stress, and subsequent tissue injury.

• Emerging evidence suggests that PLA2 plays a role in secondary injury processes after traumatic or ischemic injuries in the brain and spinal cord.

• Importantly, PLA2 may act as a convergence molecule that mediates multiple key mechanisms involved in the secondary injury since it can be induced by multiple toxic factors such as inflammatory cytokines, free radicals, and excitatory amino acids, and its activation and metabolites can exacerbate the secondary injury.[26]

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