strontium-radioisotopes and Agranulocytosis

We have recently demonstrated that diethylstilbestrol (DES) significantly suppresses macrophage (M phi) activation by Propionibacterium acnes. Because the initial activation of M phi by P. acnes appears to involve the close interaction of the killed bacteria with inflammatory neutrophils (PMN) and resident M phi in the peritoneal cavity, we investigated whether the DES inhibition of M phi activation was associated with inhibition of the PMN response. Our data demonstrate that treatment of mice with DES did not interfere with the acute inflammatory peritoneal PMN influx 5 h after P. acnes injection. DES treatment also did not affect development of the early (day 4) tumor cytotoxic activity of P. acnes activated M phi; this M phi activity has been shown to be mediated by the acute PMN influx. DES treatment, however, did reduce M phi activation as evidenced by alterations in other markers typically associated with M phi activation by P. acnes, including the characteristic reductions in alkaline phosphodiesterase (APD) ectoenzyme activity and the total RNA synthesis, as well as the characteristic persistence of the peritoneal PMN response seen on days 4 and 7 after P. acnes injection. In addition, M phi activity 7 days after P. acnes injection was inhibited in DES treated mice, as evidenced by reduced antitumor activity, and alteration of the markers mentioned above. As a second approach to elucidate the involvement of the acute and persistent PMN response in the M phi activation process, we depleted mice of circulating PMN by treatment of mice with 89Sr before administration of P. acnes.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Agranulocytosis; Animals; Cytotoxicity, Immunologic; Diethylstilbestrol; Female; Macrophage Activation; Mice; Mice, Inbred Strains; Neutrophils; Peritoneal Cavity; Propionibacterium acnes; Strontium Radioisotopes

89Sr was used to ablate the marrows of 12- to 16-week-old CAF1 mice. The CFU-S of their blood, marrows, and spleens were assayed at intervals from days 10 through 56. The effects of splenectomy performed on day 14 or 42 on the numbers of CFU-S in the blood and marrow were also studied. On day 10 after treatment with 89Sr both the cellularity and CFU-S of the marrow were markedly decreased. Later, especially during the third week after treatment, marrow cellularity increased and by day 56 had returned to 74 percent of normal; the concentration of marrow CFU-S also increased but by day 56 had attained a level of only one-third normal. Thus, replenishment of the marrow's CFU-S lagged behind the repletion of its cellularity. Spleen and blood CFU-S were elevated throughout the 56 days. The number of splenic CFU-S was highest at day 10, decreased somewhat by day 21, and remained remarkably stable thereafter. After splenectomy there was a significant decline in the content of both blood and marrow CFU-S, whereas the reverse occurred in the "cold" 88Sr-treated control group. The results of these studies suggest that in the 89Sr-irradiated animal the spleen is transformed from a trapper to the prime supplier of CFU-S and that in normal mice the spleen may suppress marrow CFU-S proliferation. An inverse relationship between the size of the pool of mature granulocytes and the number of CFU-S was found, suggesting that the granulocyte compartment may, at least in part, play a role in the regulation of CFU-S proliferation.

Topics: Agranulocytosis; Animals; Bone Marrow; Cell Movement; Female; Hematopoiesis; Hematopoietic Stem Cells; Mice; Mice, Inbred Strains; Spleen; Splenectomy; Strontium Radioisotopes