Ultrastructural evidence for leakage of lysosomal contents after phagocytosis of monosodium urate crystals. A mechanism of gouty inflammation.

To obtain direct evidence for the mechanism involved in gouty inflammation, human leukocytes were incubated with synthetic monosodium urate microcrystals. To trace the phago(lyso)somal contents, colloidal carbon, ferritin, Thorotrast(R) or horseradish peroxidase was added to the incubation medium, or acid phosphatase activity was localized cytochemically. The interaction was analyzed in time sequence by electron microscopy. By 5 minutes' incubation, urate crystals and tracers had appeared in the single membrane-bounded vacuoles of leukocytes. After 30 minutes' incubation, the vacuoles containing the urate crystals and the tracers were found in more than 50% of the leukocyte population. The phago(lyso)somal membrane was occasionally discontinuous, and the tracers were found in the free cytoplasm near the membrane opening as well. After 60 minutes' or more incubation, the phago(lyso)somal changes and the cytoplasmic localization of the tracers were common, and many cells showed signs of degeneration. Urate crystals mixed in cell debris were often found to be ingested by other leukocytes. These results have been interpreted as follows. Monosodium urate crystals are avidly phagocytized. The urate crystal-containing phagosomes eventually become phagolysosomes. The phagolysosomal membrane is damaged and the contents leak out into the cytoplasm. The leakage of the hydrolases initiates the host cell injury. The urate crystals released by cell disruption are again phagocytized by other cells and the series of events are repeated.