Stuart C. Finch

Serum Muramidase and Granulocyte Turnover

Summary Studies in rabbits indicate that serum muramidase activity probably is derived mostly from the degradation of granulocytes. The data also suggest that serum muramidase levels may be a useful index of granulocyte turnover.

The Origin of Tear Lysozyme

Summary Simultaneous serum and tear lysozyme studies were performed on 39 adults with a wide range of serum lysozyme activities. Failure to establish a relationship between the enzyme activities of serum and tears is in accord with the concept that lysozyme is synthesized de novo by lacrimal cells.

The Effect of Chloramphenicol on Human Leukocyte Phagocytosis and Respiration

Summary The respiratory burst associated with phagocytosis can be significantly inhibited by high concentrations of chloramphenicol without impairment of phagocytosis perse. The impaired respiratory burst reflects decreased activation of the HMP shunt probably through the mechanism of enzyme inhibition.

Studies on the Mechanism of Chloramphenicol Impairment of Human Leukocyte Function

Summary Chloramphenicol modification of the phagocytosis-induced respiratory burst of human PMN leukocytes may be directly correlated to impairment of hexose monophosphate shunt activity. Evidence is presented that impairment of HMP shunt activity may be due to lack of activation of the shunt through partial inhibition of NADH oxidase.

Recognition of radiation-induced late bone marrow changes.

The ultimate late irreversible hematologic consequences of either single high dose or chronic low dose exposure to ionizing radiation probably are identical but the pathogenesis of these lesions is quite dissimilar. During the latent or induction period prior to the development of overt clinical disease there usually is little or no evidence of hemopoietic dysfunction. Current methods, however, for the detection of subtle, radiation-induced, chronic changes are primitive and it is likely that our yield is extremely low. Mostly, we recognize some nonspecific morphologic lesions and know of no specific radiation markers. The pathogenesis of these lesions is complex and their significance is poorly understood. It is apparent, however, that recognition of changes at biochemical, metabolic and genetic levels eventually may provide us with extremely sensitive and meaningful forms of biologic dosimetry. A sharper focus on the occult hematologic disturbances due to chronic low-dose irradiation also may be of considerable value in our understanding of the pathogenesis of various myeloproliferative disorders. The immediate, postirradiation hematologic changes in man associated with acute radiation exposure now are well known.1 The severity of the acute bone marrow damage is dose related to the extent that changes in the peripheral blood may constitute a type of biologic dosimeter.2 If bone marrow damage is severe and recovery occurs the gross hematologic values usually return to the normal range within 4-6 weeks. Of particular importance to this discussion, however, is the fact that some of the acute hematologic changes such as chromosomal aberrations, atypical mitoses, cytopenias, and alterations in leukocyte morphology may be identical to the disturbances which develop with chronic low dose irradiation. They may persist for months or years then may resolve or may blend directly into one of the irreversible disorders which characterize the late effects of either single heavy dose or chronic low dose exposure (FIGURE 1 ) . In contrast to the uniformity of biologic response to acute radiation injury, the late hematologic effects of either single acute dose or chronic low dose exposure are quite variable, and depend on the sum total of a variety of factors. If one considers an internally deposited isotope, tissue ionization will depend upon not only the total initial dose, type of particle emitted, particle energy, and physical decay, but also its tissue distribution and rate of elimination. In the case of thorium dioxide its virtual lack of elimination, increased amount of a-particle emission during the second decade of decay and long half life make its potential marrow damaging effects very high. The close proximity of the reticuloendothelial cells to the rapidly proliferating myeloid elements would seem to increase this potential. The injurious effects of this substance, however, are partially and progressively attenuated by the tendency for gradual redistribution in the direction of incremed aggregation with reticuloendothelial cells.3 This results in fewer numbers of functional hemopoietic cells being within the range of the a-particles of these aggregates and less effective tissue ionization due to increased self absorption within the thorium crystals themselves. Other important and quite unpredictable factors are the host “resistance” factors. These may be genetic or structural but also may depend to a considerable extent on a variety of poorly understood exogenous factors. The late subclinical hematologic changes associated with chronic low dose

Mechanism of Ethyl Palmitate and Cobra Venom Factor Enhancement of Heterologous Erythrocyte Survival

Summary In this study the blood survival and organ localization in rats of intravenously injected 51Cr-labeled human erythrocytes was determined in controls and following pretreatment with ethyl palmitate, a cobra venom factor, or both. Organ distribution of labeled cells was consistent with a reticuloendothelial blockade effect for the ethyl palmitate and inhibition of hemolysis for the cobra venom factor. Erythrocyte survival was enhanced only moderately following the injection of either of these substances alone. The combined administration of ethyl palmitate and the cobra venom factor, however, resulted in marked prolongation of human erythrocyte survival consistent with a synergistic effect. This suggests that in the untreated animal, both complement-dependent hemolysis and reticuloendothelial phagocytosis compete for the removal of circulating heterologous erythrocytes. Both must be blocked simultaneously for maximum heterologous erythrocyte survival.

Cross-circulation experiments in elucidating the viability and distribution of leukocytes.

The dynamics of leukocyte production in man and experimental animals are poorly understood. These studies were designed to make certain observations on the viability, distribution, and fate of transfused leukocytes by means of cross circulation in experimental animals. Osgoodl and other^^-^ have proposed the hypothesis that leukocytes in circulation represent but a fraction of the total leukocytes in the body. The actual location of the noncirculating leukocytes remains a matter of speculation, but several studies6-R suggest that, under certain conditions, leukocytes may accumulate in large numbers along vascular walls. Craddock2 has suggested that the bone marrow itself may contain a large portion of the available leukocyte ccpool.” The presence of vast reserves of mature lymphocytes in lymphatic tissue and lymph channels has been appreciated for many years. If extensive noncirculating leukocyte pools exist for all types of leukocytes, it is probable that these cells are in dynamic equilibrium with the leukocytes in circulation. One might predict that the introduction of a small number of viable leukocytes into the circulation of a severely leukopenic animal would result in rapid relocation of these cells into the depleted pools and a consequent rapid disappearance from circulation (FIGURE 1). A rapid rate of disappearance from circulation of transfused leukocytes, when viable leukocytes have been transfused into leukopenic recipients, has been observed by a number of investig a t o r ~ . ~ . 4, 8-14 On the other hand, the introduction of viable leukocytes into a normally saturated system should produce more prolonged elevations of the peripheral blood leukocyte count (FIGURE 1). A schematic representation of the predicted relative disappearance rates of viable leukocytes transfused into animals of these types is given in FIGURE 2. Confirmation of these speculations would be good evidence in favor of the large noncirculating pool hypothesis. Experiments of this type have been difficult to reproduce either in man or animals. In vitro tagging systems usually involve small numbers of leukocytes and may result in leukocyte damage. Peritoneal exudate leukocytes are abnormal in many respects, and the cells may receive additional injury during in vitro manipulation. Human transfusions and cross-transfusion studies are subject to criticisms as to leukocyte damage, too few leukocytes, and immunological incompatibility. In almost every instance cited, leukocyte circulation time has been very short and elevated leukocyte counts have not been sustained. In order to circumvent many of these criticisms, a method of temporary cross circulation in rats was employed. This technique offers certain advan-

Placental barrier to the fetal transfer of maternal chloroleukemia in rats.

Summary I. No leukemia developed in a total of 84 offspring of a group of female rats with either active or latent Shay chloroleukemia followed for periods up to 2 years. None of 22 F2 generation offspring followed for a similar period developed leukemia. II. These data indicate efficient transplacental inhibition of Shay chloroleukemia transmission in rats. Although transplacental passage of inadequate numbers of leukemic cells may account for this result there is some evidence that either the placenta or some humoral placental factor may be responsible.