Effects of Endotoxin and Nitrogen Mustard on Leukocyte Kinetics

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Abstract
In rabbits given a single large dose of HN2 circulating granulocytes are maintained at a normal concentration until 50-52 hours; thereafter the onset of a rapid fall in concentration coincides with maximum marrow hypocellularity. Recovery from granulocytopenia, however, does not begin until after 90 hours when considerable recovery of marrow cellularity is evident. Bacterial endotoxin in differing doses given at various times up to 24 hours after HN2 produces the same changes in circulating granulocytes as in normal animals. The rapid decline in circulating granulocytes, heralding exhaustion of the pool of postmitotic granulocytes, occurs earlier in HN2-treated animals given bacterial endotoxin; they also recover sooner than controls from HN2-induced granulocytopenia. Endotoxin given at 51 hours after HN2 when the postmitctic pool is exhausted, increases the rate of fall in the concentration of circulating granulocytes producing an earlier appearance of maximum granulocytopenia, but recovery by these animals from HN2-induced granulocytopenia does not occur sooner than in controls. Thus the time of recovery from HN2-induced granulocytopenia appears to be related to the time of depletion of marrow stores of postmitotic cells. Rabbits made tolerant to endotoxin and given HN2 show an earlier onset of the rapid fall in circulating granulocytes and an earlier recovery from granulocytopenia. Maximum marrow hypocellularity appears sooner after HN2 in tolerant animals, but marrow cellularity is always greater than in nontolerant rabbits. The increased cellularity of the marrow of tolerant animals may represent an increase in the size of the mitotic compartment of cells since the postmitotic compartment seems smaller than in normal animals. The granulocytopenia produced by endotoxin results from an increased removal of granulocytes from the circulation and significant numbers of these cells do not appear to recirculate. Granulocytosis following the injection of endotoxin results from movement of cells out of the marrow and occurs only if there is a store of postmitotic granulocytes. Release of cells from the marrow following this stimulus, however, appears to be related to cell maturity; only the more mature ones enter the circulation. Movement of mature cells out of the marrow, depleting the reservoir of these elements, may provide the stimulus for the increased cell production that appears in normal animals given endotoxin.