Excess formation of lysophosphatidic acid with age inhibits myristic acid‐induced superoxide anion generation in intact human neutrophils

Abstract

A superoxide anion generation rate upon exposure to myristate of 1.93 + 0.34 nmol/min/106 cells in neutrophils from elderly human donors was significantly less than a value of 3.02 + 0.48 nmol/min/106 neutrophils from young donors. Myristate activation resulted in equal increases of AA in both the young and the old indicating no effect of aging on the PLA2 pathway to response. By contrast, the PLD-induced generation of PA was significantly higher in the old than in the young. In addition, myristate induced a significant age-related enhancement in LPA generation, in the old but not in the young. The mass of LPA generated following activation was 3.5 nmoi/ 2.5 X 107 cellslml in the young while in the old it averaged 7.0 nmol/2.5x 107 cells /ml. The inhibitory effects of LPA may explain the age-related impaired ability to generate superoxide anion following activation by myristate.

Lysophosphatidic acid synthesis and release

“…LPA has been shown to be generated in vitro by microvesicules sheded from erythrocytes challenged with inflammatory stimuli (12). LPA has also been reported to be produced by myristic acid challenged neutrophiles from aged patients (42). In addition, serum also contains lipoproteins which may also be sources of LPA production (see next section).…”

Aging and Immune Function: Molecular Mechanisms to Interventions

“…The underlying basis for defects in neutrophil function in the elderly has been attributed either to modulation=s in cell membrane-mediated events or to defects in proximal signaling mechanisms, since stimulators such as phorbol esters are fully capable of inducing a relatively robust response in the elderly, primarily by overriding early receptor-mediated and membrane-associated activation events. Decline in priming and activation of neutrophils in response to LPS, granulocyte CSF (G-CSF), FMLP, and ligation of triggering receptor expressed on myeloid cell 1 has also been reported in elderly humans (101,112,158). Recent studies have implicated defective recruitment of signaling intermediaries into lipid rafts as a potential unifying defect in the signals generated at the membrane (9,343).…”

Myristic Acid, A Side Chain of Phorbol Myristate Acetate (PMA), Can Activate Human Polymorphonuclear Leukocytes to Produce Oxygen Radicals More Potently than PMA

“…5. Unlike C5a and N-formyl-L-methionyl-L-leucyl-L-phenylalanine, both of which can stimulate PMNs to produce O 2 ·− by inducing calcium (Ca) influx, MyA-functions, like PMA-functions, bypass Ca influx since it has been reported that MyA induces O 2 ·− production from human neutrophils in the absence of Ca 2+ and magnesium [19, 26]. Although the potency of AA to stimulate the release of ROS is much weaker than that of MyA, the possibility of involvement of AA to the effect of MyA when absorbed into the circulation should be considered.…”

“…MyA causes high LDL cholesterol and apoB levels and low HDL to LDL ratios in healthy men and women [16], a positive regression between the plasma cholesterol level and the dietary level of MyA was observed in hamsters [17], and incorporation of trimyristin in the oil resulted in marked rise in serum cholesterol of rats [18]. In term of oxidative metabolism of PMNs, it was reported that MyA has an ability to stimulate the generation of O 2 ·− from human neutrophils [19]. It was reported that MyA induces the hydrolysis of phosphatidylcholine leading to generation of arachidonic acid (AA) [19].…”

“…In term of oxidative metabolism of PMNs, it was reported that MyA has an ability to stimulate the generation of O 2 ·− from human neutrophils [19]. It was reported that MyA induces the hydrolysis of phosphatidylcholine leading to generation of arachidonic acid (AA) [19]. AA when added with membrane protein separated from bovine PMNs can activate NOX of bovine PMNs [20].…”