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Phospholipase A (PLA) comprises a supergroup of esterase enzymes present in all human cells that play a key role in mediating the production of free fatty acids and lysophospholipids from glycerophospholipids. These enzymes are essential for regulating homeostasis and disease pathogenesis in every organ system based on their activation and involvement in inflammatory mediation. Over 30 isoforms of PLA have been identified to date and differ heavily in function, cofactor requirement, and size. The isoforms fall into six main groups, including cytosolic PLA, Ca-independent PLA, secretory PLA, lysosomal PLA, adipose-specific PLA, and platelet-activating factor acetylhydrolase. Within each of these groups, research has identified numerous subtypes. This article will focus on summarizing the critical roles for each of the six studied PLA subtypes.[1]

Secretory PLA Secretory PLA plays a significant role in the pathogenesis of many conditions that involve inflammation, including rheumatoid arthritis, atherosclerosis, asthma, acute respiratory distress syndrome (ARDS), Crohn’s disease, ulcerative colitis, and tumor cell growth. The pathophysiology of ARDS and asthma involve two mechanisms related to normal respiratory physiology. Normal expression of secretory PLA results in increased leukotrienes, which serve as potent chemokines, resulting in leukocyte attraction and subsequent release of proinflammatory cytokines. This role has been established in the pathogenesis of asthma. Another mechanism that contributes more to the pathophysiology of ARDS involves secretory PLA degradation of the lung surfactants phosphatidylcholine and phosphatidylglycerol, resulting in further respiratory inflammation and alveolar collapse. The pathogenesis of atherosclerosis also correlates with increased expression of secretory PLA. The mechanism proposed involves hydrolyzation of phospholipids in LDL particles that results in macrophage uptake and subsequent intimal lipid accumulation. Studies have shown a positive correlation between blood levels of secretory PLA and coronary artery disease as a result of atherosclerosis of coronary vessels from oxidative damage. Cytosolic PLA Disturbance in the normal function of cytosolic PLA prevents the inflammatory response to take place, which results in resistance to a variety of inflammatory-mediated pathologies, including anaphylaxis, rheumatoid arthritis, fatty liver disease, and acute respiratory distress syndrome. Research has revealed cytosolic PLA as playing a noteworthy role in the pathogenesis of many forms of cancer, including estrogen-depending breast cancer, adenocarcinoma of the lung, and glioblastoma multiforme. The effect of overactivity of the enzyme on many disease processes makes it a viable research target for disease intervention. One side effect noted in knockout mice with absent enzymatic activity included a reduced function of renal concentration. Ca-Independent PLA

Disturbance in the normal function of cytosolic PLA prevents the inflammatory response to take place, which results in resistance to a variety of inflammatory-mediated pathologies, including anaphylaxis, rheumatoid arthritis, fatty liver disease, and acute respiratory distress syndrome. Research has revealed cytosolic PLA as playing a noteworthy role in the pathogenesis of many forms of cancer, including estrogen-depending breast cancer, adenocarcinoma of the lung, and glioblastoma multiforme. The effect of overactivity of the enzyme on many disease processes makes it a viable research target for disease intervention. One side effect noted in knockout mice with absent enzymatic activity included a reduced function of renal concentration. Ca-Independent PLA One of the most studied roles in Ca-independent PLA involves its participation in inducing apoptosis of beta-cells, resulting in the pathogenesis of diabetes mellitus. This situation occurs through the production of superoxide compounds by neutrophils that ultimately results in cell death. In contrast, failure of the enzyme to function under normal physiologic conditions has associations with neuroaxonal dystrophy diseases with earlier onset. Lysosomal PLA Although not as well studied as other phospholipases, evidence suggests that failure of lysosomal PLA to function plays a role in atherogenesis and formation of phospholipidosis. From an immunologic perspective, impaired enzymatic function results in the failure of pulmonary T-cell activation. This role has been the target of study in pulmonary tuberculosis infection in which mice deficient in the enzyme showed increased mycobacterial counts and decreased inflammatory response to infection. Adipose-Specific PLA Although designated as adipose-specific PLA, the enzyme expresses throughout many tissues, with the highest levels of expression occurring in adipocytes. The currently studied roles of the enzyme in the regulation of lipolysis and fatty acid oxidation make it a viable target for further research on obesity. Platelet-Activating Factor Acetylhydrolase

Although designated as adipose-specific PLA, the enzyme expresses throughout many tissues, with the highest levels of expression occurring in adipocytes. The currently studied roles of the enzyme in the regulation of lipolysis and fatty acid oxidation make it a viable target for further research on obesity. Platelet-Activating Factor Acetylhydrolase As previously mentioned, researchers have studied the role of platelet-activating factor acetylhydrolase as playing a role in atherogenesis of blood vessels. This process has shown increased expression of the enzyme in association with oxidized LDL and inflammation, promoting the formation of atherosclerotic plaques. This studied function of the enzyme makes it a potential pharmaceutical target to prevent the progression of atherosclerotic disease. Another studied pathophysiological mechanism involving platelet-activating factor acetylhydrolase includes neonatal necrotizing enterocolitis (NEC). This disease results in intestinal necrosis of premature infants. Low levels of the enzyme, along with the accumulation of platelet-activating factor in newborns, correlate with the pathogenesis of the disease. These findings suggest that the administration of exogenous forms of the enzyme may help to improve outcomes in NEC.[1][6][7][8][9]