When granulocytes are labeled with diisopropylfluorophosphate (DFP32) and then returned to the circulation of the donor, the labeled granulocytes are distributed in a pool of cells which is approximately two times larger than that calculated from the blood volume and the concentration of granulocytes in the circulating venous blood (1, 2).This pool has been referred to as the total blood granulocyte pool (TBGP) and it consists of two subcompartments or pools. These pools have been designated the circulating granulocyte pool (CGP) and the marginal granulocyte pool (MGP). The size of the CGP can be calculated from the blood volume and the absolute granulocyte count. Equilibration between the granulocytes in the CGP and in the "noncirculating" or MGP is sufficiently rapid and complete to allow these two pools to be considered as one kinetically, and the size of the TBGP can be determined by the isotope dilution principle. Since the cells are removed from the TBGP in an exponential fashion with a mean half-time disappearance (Ti) of 6.6 hours, the granulocyte turnover rate (GTR), that is, the number of granulocytes turned over through the blood in a unit of time, can be calculated.The purpose of this paper is to present data on the GTR in normal subjects, as well as additional data on the size of the TBGP, CGP and MGP in normal subjects. The influence of steroids, physical exercise, epinephrine and bacterial endotoxin on these parameters in normal subjects has also been studied.

In a previous publication (1) it was noted that when granulocytes were labeled in vitro with radioactive diisopropylfluorophosphate (DFP32 ) and then returned to the circulation of the donor, about half of the labeled cells could not be found in the circulation at the completion of the infusion (T0). Thereafter the remaining labeled cells left the circulation in a random fashion with a mean halftime disappearance (T.) of 6.6 hours.Since cell damage and significant elution of the label could not be demonstrated tinder the conditions of the study, it was suggested that the immediate disappearance of half the infused cells was due to their rapid dilution in a larger pool than that calculated from the blood volume and the venous granulocyte count.The concept that the circulating granulocyte pool (CGP) does not constitute all of the intravascular leukocytes is not new. Vejlenis (2)

Present knowledge concerning the kinetics of granulopoiesis has been reviewed and quantitative data concerning granulokinetics in normal human subjects are presented. A. When granulocytes are labeled in vitro and returned to the circulation of the donor, the distribution of the cells in the circulation and the rate of disappearance of the cells from the circulation can be measured. 1. The total blood granulocyte pool (TBGP) consists of two compartments which are in equilibrium with each other. These pools have been designated the circulating granulocyte pool (CGP) and the marginal granulocyte pool (MGP). The size of the pools has been measured in 109 normal male subjects. The mean values, expressed as numbers of cells x 107 per Kg. of body weight were as follows: TBGP, 70; CGP, 31; and MGP, 39. The mean ratio of the CGP to the TBGP was 0.44. 2. The labeled granulocytes leave the TBGP in an exponential fashion with a mean half-time disappearance (T½) of 6.7 hours as determined in 56 normal male subjects. No evidence has been obtained for a return of granulocytes to the blood. 3. The mean value for the granulocyte turnover rate (GTR) in 56 normal male subjects was 163 x 107 granulocytes per Kg. of body weight per day. Thus, the TBGP turns over 2.3 times per day and the turnover time for the TBGP is 10.4 hours. B. When granulocytes are labeled in vivo by the intravenous administration of DFP32, the rate of disappearance of granulocytes from the circulation and the time required for myelocytes to divide, mature and appear in the blood can be measured. In addition, the generation time of myelocytes can be approximated. From the time parameters and the GTR, the bone marrow pool sizes and turnover times can be calculated. These determinations and calculations have been made for a group of 21 normal male subjects. 1. The mean half-time disappearance (T½) of in vivo labeled granulocytes from the circulation was 7.2 hours. This value agrees well with the value of 6.7 hours obtained after the in vitro labeling of granulocytes. 2. The mean time required for myelocytes to divide, mature and appear in the blood was 11.4 days. 3. The mean generation time of myelocytes was estimated to be not more than 2.9 days. 4. The total granulocyte pool in the bone marrow (neutrophilic myelocytes, neutrophilic metamyelocytes and PMN neutrophils) was calculated to be 186 x 108 cells per Kg. of body weight with a mean turnover time of 11.4 days. The myelocyte pool was estimated to be 41 x 108 cells per Kg. with a turnover time of 2.5 days; the metamyelocyte pool consisted of about 76 x 108 cells per Kg. with a turnover time of 4.7 days; the average size of the mature marrow PMN neutrophil pool was 69 x 108 cells per Kg. of body weight with a turnover time of 4.2 days. C. A kinetic model for granulopoiesis, based on the studies with the DFP32 label, is presented. In this model, myelocytes are depicted as approaching a self-perpetuating population of cells. Some cells enter this population from populations which are less mature but this latter source of cells is small under conditions of normal steady state kinetics. One of the daughter cells of a myelocyte division remains in the myelocyte population to divide again. The other daughter cell enters the metamyelocyte population. The metamyelocyte and PMN neutrophil population is incapable of division and cells move through this population in sequential fashion in the process of maturation. The cells then enter the blood where they equilibrate rapidly between the two blood compartments. The cells are removed from the total granulocyte pool in a random fashion. There is no appreciable pool of granulocytes in the extramedullary tissues of normal subjects and granulocytes do not return from the tissues to the blood. The entire movement of granulocytes from marrow to tissues is uni-directional.

No abstract

Although it seems evident that the neutrophilic leukocytosis commonly encountered in patients with purulent infections, polycythemia rubra vera, and a variety of other clinical disorders probably indicates an increased mass of neutrophils in the blood and increased neutrophil production, turnover, and utilization, it has not been possible to quantify these processes directly until recently. In normal subjects it was demonstrated that approximately one-half of the neutrophilic granulocytes in the blood are circulating freely [circulating granulocyte pool (CGP)], whereas the remainder adhere to the walls of small venules [marginal granulocyte pool (MGP)] (1). Since these two pools were shown to be in rapid equilibrium with each other they may be considered to form a single total blood granulocyte pool (TBGP) for kinetic purposes. These facts together with the finding that neutrophilic granulocytes disappear from the blood in a random manner (2) have made it possible to approximate the rate of production and destruction of neutrophils in normal man.In the present study the size of the TBGP, the distribution of cells in the two subcompartments, the CGP and the MGP, the blood granulocyte half disappearance time (tj), and the granulocyte turnover rate (GTR) were measured in patients with polycythemia vera, myelofibrosis, chronic infections, and diseases of other kinds. Studies in patients with chronic myelocytic leukemia are the