William Shaw, Ph.D., Lab Director and Matt Pratt-Hyatt, Ph.D., Associate Lab Director
The Great Plains Laboratory is excited to announce a new test for PLA2 activity, and we are the only commercial lab currently offering this particular test in urine. PLA2 is elevated in a wide range of inflammatory disorders from multiple sclerosis to cancer. This test can be easily added to the organic acids test to provide powerful new clinical insights and treatments for a variety of serious illnesses.
Chronic diseases are caused by many different biological imbalances, but they almost all create and have inflammation as a cornerstone. Inflammation plays a major part in most of the disorders that we spend billions of dollars to combat, searching for relief from the pain, swelling, and other symptoms that inflammation causes. Inflammation is the immune system's natural response to infection and injury. Phospholipase A2 (PLA2) is one of the key biochemical factors produced in the inflammation response. It is commonly found in human tissues, as well as insect and snake venom. In normal amounts, PLA2 is involved in remodeling cell membranes and changing cell architecture. In infections, PLA2 can break down the phospholipids in the membranes of bacteria, fungi, and parasites leading to their death. However, inflammation, like many other biological processes often has negative effects. The same phospholipase that attacks infectious agents may also attack the cell membranes of the human host, damaging or killing those cells. In addition, the products of the PLA2 reaction, lysolecithins and free fatty acids (Figure 1) are powerful detergents that have the ability to denature proteins and destroy their biological functions. The lysolecithins produced by PLA2 initiate the pain response.
The most common free fatty acid produced by PLA2 is arachidonic acid which can increase the production of powerful mediators of inflammation called prostaglandins, leukotrienes, and thromboxanes, collectively known as eicosanoids. These mediators play an important role in the generation and maintenance of inflammation in neural cells. In addition, arachidonic acid can be converted to 4-hydroxynonenal (4-NE), which can be very toxic due to covalent modification of important biomolecules including proteins, DNA, and phospholipids containing amino groups. In addition to PLA2 causing local damage, it may be transported by the blood vessels to other parts of the body, causing widespread tissue damage.
Diseases Associated with PLA2
Increased levels of PLA2 have been observed in most systemic inflammatory diseases. Studies have linked elevated PLA2 activity with multiple sclerosis, rheumatoid arthritis, Crohn's disease, pancreatitis, ulcerative colitis, allergies, atherosclerosis and cardiovascular disease, lung, prostate, small intestine, and large intestine cancers, with increased susceptibility to metastases, Candida infection, asthma, autism, chronic pulmonary obstructive disorder (COPD), and sepsis.
What Causes Elevated PLA2?
Phospholipase A2 is produced by the pancreas and released into the small intestine following a fatty meal. Infection or trauma of the pancreas may result in the release of phospholipase into the circulation, causing widespread damage or even death. Activation by viruses of proenzymes of PLA2 within the pancreas instead of, as normally, in the intestine, may cause pancreatitis. Phosholipase may be produced by cells of the immune system in response to bacterial antigens, especially those containing certain lipopolysaccharides (LPS). Allergies, especially those to house dust and cats, have been implicated as a trigger for PLA2 synthesis and release. Venoms from snakes, spiders, and bees contain high amounts of PLA2, which is responsible for much of the toxicity of these venoms. In addition, microorganisms such as Candida albicans and certain Clostridia species produce PLA2 which increases the ability of the microorganism to infect the host. Trauma may also cause significant increases in PLA2 and result in brain injury.
PLA2 and Inflammatory Disease
Research has implicated PLA2 in the pathophysiology of neurodegenerative diseases such as multiple sclerosis (MS) and Alzheimer's disease (AD). Multiple sclerosis involves both antigen-specific mechanisms and components of the innate immune system that result in inflammatory response. Elevated PLA2 activity was found to be ongoing among MS patients, with the highest levels measured in patients with progressive disease. In the development of Alzheimer's disease, the abnormal PLA2 levels appear to be related to oxidative signaling pathways involving NADPH oxidase and production of ROS species that lead to impairment and destruction of neurons and inflammation of glial cells.
Inflammation is the hallmark of rheumatoid arthritis (RA), a joint-destructive autoimmune disease. PLA2 is found in synovial fluid of RA-affected individuals and in the cartilage of RA patients as compared to cartilage from osteoarthritic and normal individuals.
Measurement of PLA2 is emerging as an important tool for evaluating the chance of cardiovascular disease (CVD), including future stroke, myocardial infarction, heart failure, and other vascular events. PLA2 appears to be more specific than hsCRP for CVD risk and may also have a pivotal role as a mediator of cardiovascular pathology. In atherosclerosis, PLA2 not only activates macrophages and formation of foam cells, but it also hydrolyzes LDL and HDL, spawning increased numbers of pro-atherogenic small LDL particles, and impairing anti-atherogenic HDL. PLA2 activity may even precipitate bleeding from atherosclerotic plaques.
PLA2 is expressed normally in pancreatic, gall bladder, and GI epithelial cells, but is significantly increased in inflammatory gastrointestinal disorders. In ulcerative colitis and Crohn's disease, all intestinal cell types increase expression of PLA2, which increases gut permeability and may actually contribute to infectivity.
PLA2 and Cancer
Elevations of PLA2 have been found in gastrointestinal cancers including colonic adenomas and carcinomas and pancreatic ductogenic carcinomas, among others. Patients with lung tumors positive for PLA2 had a greatly increased tumor growth rate and a markedly reduced survival rate. Patients with lung cancer also had higher plasma levels of PLA2 than patients with benign nodules. A similar pattern has been observed in prostate cancer, although metastatic tumors expressed lower PLA2 than primary tumors. As PLA2 releases arachidonic acid and other fatty acids from cell membranes, they initiate downstream production of tumor-promoting eicosanoids. In cancer, the spread of tumor cells from a primary tumor to the secondary sites within the body is a complicated process involving cell proliferation and migration, degradation of basement membranes, invasion, adhesion, and angiogenesis. Continued research on PLA2 expression in cancer will certainly reveal valuable new insights.
What lowers PLA2?
There has been a great deal of research done by both academia and pharmaceutical companies to find chemical inhibitors to PLA2. However, there has also been research on more natural methods for inhibiting PLA2. Glucocorticoids such as the natural hormone cortisol and pharmaceutical agents such as dexamethasone inhibit the production of phospholipase, decreasing harm caused by the enzyme but also decreasing the benefits of the enzyme in killing harmful microorganisms. Thus, excess glucocorticoids can reduce inflammation in a patient with tuberculosis while reducing the effects of PLA2 against the bacteria resulting in spread of the illness. Lithium at pharmacological doses, carbamazepine, and the antimalarial drug chloroquine are all PLA2inhibitors. Vitamin E is also an inhibitor of PLA2. In addition, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) (belonging to the omega-3 class of fatty acids) inhibit PLA2. Analysis has shown that treatment with supplements of Cytidine 5'-Diphosphocholine (CDP-choline) can limit the ability of PLA2 to promote inflammation. CDP-choline is a precursor in the formation of phospholipids and has been used as a nutritional supplement at doses ranging from 500-4000 mg per day in the treatment of patients with a variety of disorders including Parkinson's disease, memory disorders, vascular cognitive impairment, vascular dementia, senile dementia, schizophrenia, Alzheimer's disease (especially effective in those with the epsilon-4 apolipoprotein E genotype), head trauma, and ischemic stroke. A trial in patients with Alzheimer's disease indicated that CDP-choline (1,000 mg/day) is well tolerated and improves cognitive performance, cerebral blood perfusion, and the brain bioelectrical activity pattern. No side effects were noticed at the lower doses of CDP-choline and only some mild gastrointestinal symptoms were found using higher doses. No abnormal blood chemistry or hematology values were found after the use of CDP-choline.
Testing for PLA2
Because PLA2 is a relatively small enzyme (about 14 KD), it is able to be excreted in urine. 10 mL of the first morning urine before food or drink is suggested for testing. There are no dietary restrictions. This test is convenient to include with other urine tests such as organic acids, amino acids, and peptides. Since chelating agents might interfere with the test, they should not be used for at least 48 hours prior to testing. PLA2 testing is recommended for the following disorders:
- Multiple sclerosis
- Rheumatoid arthritis
- Crohn's disease
- Ulcerative colitis
- Cardiovascular disease including atherosclerosis
- Neurodegenerative diseases
- Bipolar depression, subtype with psychosis
- Candida infection
- Long term depression
- Chronic obstructive pulmonary disease (COPD)
Inflammation plays such a key role in so many diseases, and we believe this new PLA2 test will be a valuable tool in the treatment of patients suffering from numerous disorders. The test is now available and we hope you will integrate it into your practice. For more information about PLA2 and possible treatments, please see the references below.
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