Secretion of lactic acid by peritoneal macrophages during extracellular phagocytosis. The possible role of local hyperacidity in inflammatory demyelination.
Culture of thioglycollate-elicited rat peritoneal macrophages in the presence of derivatized, non-ingestible, bovine CNS material results in a release of the lysosomal marker enzyme beta-glucuronidase that is both dose- and time-dependent. Concomitant with enzyme secretion, lactic acid is secreted in a manner that is also dose- and time-dependent. The secretion of lactic acid represents an increased dependence on anaerobic glycolysis by the aerobic phagocyte cultures and is paralleled by an increase in cytoplasmic lactate dehydrogenase. When unbuffered media are used, the secretion of lactic acid is accompanied by a drop in the pH of the culture medium. Culture of the cells in the presence of the pyruvate dehydrogenase stimulator, dichloroacetate, inhibits the formation of lactic acid and the resulting drop in pH. Suspensions of multilamellar myelin undergo turbidity changes and aggregation in acidic media. Initial rates of turbidity changes follow a titration curve with an apparent pKa of 6.0. Because of the sensitivity of the myelin lamellae to an acidic microenvironment, it is suggested that a local hyperlactemia, with the resulting decrease in interstitial pH, may be a major pathological process in cell-mediated inflammatory demyelination. Antihyperlactemics, such as dichloroacetate, may therefore provide a new therapeutic approach to minimizing myelin degeneration in multiple sclerosis and in other CNS disorders characterized by inflammatory demyelination.
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D003999:Dichloroacetic Acid / Q000494:pharmacology; D005966:Glucuronidase / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007773:Lactates / Q000378:metabolism*; D019344:Lactic Acid; D008264:Macrophages / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism*; D010529:Peritoneal Cavity / Q000166:cytology; D010587:Phagocytosis; D051381:Rats; D011919:Rats, Inbred Strains
D007773:Lactates; D019344:Lactic Acid; D003999:Dichloroacetic Acid; D007770:L-Lactate Dehydrogenase; D005966:Glucuronidase