Information on the structure of human monocytopoiesis was derived from the chronologies of labeled monocytes entering the blood following injection of 3H-thymidine (3H-TDR) and 3H-diisopropylfluorophosphate (3H-DFP). It was found that monocytes are released into the blood directly from a proliferating precursor pool. The marrow cell egress was almost completely restricted to G1-phase monocytes. The egress rate increased with maturation time of promonocytes. The majority of the cells was released at maturation times between 50 and 60 hr. Under normal conditions promonocytes underwent a mean of two catenated cell cycles. The cell cycle time averaged 29 hr and DNA-synthesis time 10 hr. Direct investigations of the promonocytes demonstrated that the medullary promonocyte pool averages 6 x 108 cells/kg body weight in healthy adults. This pool produces a mean of 7 x 106 cells/kg-hr. Proliferation capacity of promonocytes is only partially utilized in normal monocytopoiesis. Induction of acute inflammatory reactions gave rise to an immediate enhancement of promonocyte proliferation activity, thus affording short-term adaptation of monocyte production to monocyte demand. Increase in monocyte production was associated with a shift of marrow release in favor of immature cells.
The "pharmacological dogma" that competitive antagonists cause parallel shifts to the right with sustained maximum effect of semi-logarithmic concentration-response curves of exogenous agonists may not be true if an endogenous agonist is present in the preparation. In this case, the antagonist and the exogenous agonist interfere in a complex way with an existing circuit of regulation between the response and the endogenous agonist. In consequence, it is difficult to determine the true shift in the concentration-response curves as induced by the antagonist, since a deviation of the curves in a non-parallel manner can be observed. The extent of this deviation may be used to learn more about the variables involved. The present paper discusses this phenomenon: The regulatory circuit of the (auto)receptor modulated release of neutrotransmitters is used as an example. Paired samples of data are analysed in this example. Since the extent of the non-parallel deviation also depends on the manner in which the paired samples are mathematically linked, two different ways of data evaluation have been used. A theoretical model of the relation between receptor activation and response is proposed which allows to evaluate experimental concentration-response curves by means of non-linear regression analysis. This evaluation yields quantitative information on the parameters of the regulatory circuit: the concentration of the endogenous agonist, its KD value and the true shift of the concentration-response curve caused by the applied antagonist.
Daily examinations of monocyte blood counts in healthy individuals indicated the presence of a monocyte cycle. The cycle length was between 3 and 6 days. The predominant period was 5 days. A similar oscillation frequency resulted from a computer simulation of a feedback loop which linked the blood monocyte compartment (controlled variable) to the stem cell differentiation rate (controlling variable).
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