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Biomedical subjects

A Volkman

Publications and source records attributed to A Volkman.

At least 19 recordsLinked to original sources

Assessment of survey radiography as a method for diagnosis of congenital cardiac disease in dogs.

In order to assess the diagnostic accuracy of survey radiography for canine congenital cardiac anomalies, thoracic radiographs of 57 dogs with congenital cardiac anomalies, 31 normal dogs and 27 dogs with acquired cardiac disease were mixed, and reviewed by two independent observers, who were blinded to any patient information. The congenital anomalies were aortic stenosis (n=25), pulmonic stenosis (n=10), patent ductus arteriosus (n=9), ventricular septal defect (n=8), tricuspid dysplasia (n=3) and mitral dysplasia (n=2). Both observers were moderately accurate at identifying dogs with cardiac disease. Their ability to distinguish dogs with congenital versus acquired cardiac disease was poorer and this assessment was probably influenced by the recognition of patients that were skeletally immature, which biased observers towards a diagnosis of congenital cardiac anomaly. The diagnosis rate for specific congenital anomalies was also poor (the differential list included a correct diagnosis in only 40 and 37 per cent of cases). Radiographic signs of specific cardiac chamber enlargement or pulmonary vascular abnormalities were recognised by both observers in only 20 per cent of instances in which they might be expected. They were, however, recognised more frequently in dogs with anomalies that imposed a volume load on the heart than in dogs with anomalies that induced a pressure load on the organ. It is concluded that survey radiography is an inaccurate method for diagnosis of canine congenital cardiac anomalies because of the difficulty of recognising radiographic signs, which are not present in many cases.

Animals↗

Macrophage colony-stimulating factor-induced bone marrow macrophages do not synthesize or release prostaglandin E2.

Previously, we found that murine bone marrow-derived macrophages (MO) induced in vitro by MO-specific colony-stimulating factor (M-CSF) have little capacity to release prostaglandin E2 (PGE2) and other eicosanoids. This work focused on the functional and transcriptional expression of the key enzymes for the PGE2 synthesis in the MO. Nonadherent bone marrow cells were cultured with RPMI1640 plus 10% fetal bovine serum (FBS) further supplemented with either M-CSF or granulocyte-macrophage (GM)-CSF and interleukin-3 (IL-3). Cellular PGG/H synthase (cyclooxygenase) levels were quantified by cytometric analysis with antibodies specific for the two isozymes of PGG/H synthase (PGG/H synthases 1 and 2). The enzyme activity was monitored by adding exogenous arachidonic acid (AA) substrate to the bone marrow MO cultures and to the cell-free particulate fractions. The levels of PGE2 converted were quantitated by radioimmunoassay (RIA). mRNA levels of the enzymes were detected by Northern blot analysis hybridized with mouse PGG/H synthase cDNA probes, 2.7 kb (PGG/H synthase 1) and 4.2 kb (PGG/H synthase 2). In addition, cellular phospholipase A2 (PLA2) activities were detected with sn-2-14C-arachidonyl phosphatidylcholine as a substrate. Cells proliferating in the presence of GM-CSF and IL-3 for more than 4 days showed significant release of PGE2 (> 7 ng/10(6) cells) when stimulated by AA. These cells also expressed significant amounts of PGG/H synthase 1 protein, its mRNA (2.7 kb) and cellular PLA2. M-CSF-induced MO, in sharp contrast, expressed little PGG/H synthase protein, mRNA, cellular enzyme activity, or PGE2 release, despite comparable levels of cellular PLA2 activity. These data suggest that the capacity of differentiating marrow-derived MO to form PGE2 is growth factor-dependent.

Animals↗

MRL mice produce anti-Su autoantibody, a specificity associated with systemic lupus erythematosus.

Certain autoimmune mouse strains exhibit features similar to human SLE. To discover genetic and immunologic events governing expression of a new SLE-associated antibody, the presence of anti-Su and its relationship to other SLE-related antibodies (anti-Sm, -ribonucleoprotein, -Ro (SS-A), -La (SS-B)) were determined in MRL and other autoimmune and nonautoimmune mice. By double immunodiffusion, sera from 34/183 (19%) 4- to 10-mo-old MRL/Mp-lpr/lpr (MRL/lpr) and 28/108 (26%) 8- to 20-mo-old MRL/Mp(-)+/+ (MRL/+) mice were positive for anti-Su antibodies. Anti-Sm antibodies were found in 60/183 (33%) and 39/108 (36%) of these animals, respectively. The two specificities were found together in individual mice more frequently than would be predicted by chance. In contrast, C57BL/6-lpr/lpr (B6/lpr) mice rarely showed either specificity. Analysis of F1 hybrids between B6/lpr and MRL/lpr and of F1 x MRL/lpr backcross mice suggested that a small number of autosomal recessive genes controlled the anti-Su and anti-Sm responses. With the exception of a single NZB serum sample, NZB, BXSB, and nonautoimmune mice were negative for all antibodies tested, and no mice were positive for anti-RNP, anti-Ro, or anti-La. MRL/lpr and MRL/+ autoimmune mice thus provide unique models for human SLE, because they express several of the SLE-specific marker autoantibodies. These models should be useful in disclosing molecular and immunologic events governing autoantibody expression in this condition.

Animals↗

Regulation of phospholipase A2 activation and arachidonic acid metabolism in an interleukin-3-dependent macrophage-like cell line.

An interleukin 3 (IL-3)-dependent macrophage-like cell line, 11-1-B3, was newly established from CBA/J mouse bone marrow cell cultures. Assay of eicosanoids in the culture supernatants of the intact and [3H]arachidonic acid (AA)-prelabeled cells showed that, after stimulation with the Ca2+ ionophore A23187, the 11-1-B3 cells synthesized and released relatively large amounts of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) but not LTC4. In addition, 11-1-B3 cells showed Ca(2+)-dependent and alkaline pH-optimal phospholipase A2 (PLA2) activity that preferentially hydrolyzed cleavage of sn-2-arachidonyl- but not sn-2-oleoylphosphatidylcholine. The cellular enzyme was distributed with 90% of the activity in the cytosol and 10% in the membrane fraction. Treatment of cells with A23187 for 5-10 min resulted in five- to sevenfold increases in the membrane-associated PLA2 but activity in the cytosol was unchanged. This increase in membrane-associated enzyme activity was transient, returning to the pretreatment distribution after 30 min. In sharp contrast, phorbol myristate acetate (PMA) stimulation failed to induce either eicosanoid release or PLA2 activation, although PMA induced translocation of protein kinase C (PKC) to the membrane fraction within 10 min. The data suggest that increases in cellular Ca2+ directly activate membrane-associated PLA2 and consequently initiate AA metabolism; PKC activation by PMA requires additional steps to activate PLA2, a mechanism that is apparently deficient in the IL-3-dependent M phi-like cells.

Animals↗

Extraction and differentiation of the Su autoantigen from calf thymus nuclei.

Antibodies to Su antigen have been reported previously as a distinct antigen-antibody system associated with connective tissue diseases; most specifically systemic lupus erythematosus and undifferentiated connective tissue disease. The Su antigen was first identified by double immunodiffusion using calf thymus nuclear extract (CTNE) as a source for Su antigen. In this report, enhanced extraction of Su antigen was achieved using deoxyribonuclease I (DNase) for preparation of CTNE. Only the Sm antigen was found in comparable quantities in the DNase CTNE. Western immunoblotting and immunoprecipitation employing DNase CTNE and extracts of [35S]methionine-labeled HeLa cells respectively were used for further characterization and differentiation of the Su antigen. Sera from patients positive for Su antibodies by double immunodiffusion were found to react most specifically with antigen components in a molecular weight range of approximately 50-55 kDa. These methods should assist in further understanding the biochemical properties of the Su antigen.

Ammonium Sulfate↗

Restoration of prostaglandin releasing macrophage populations in lethally irradiated mice with spleen cells from bone marrow-depleted donors.

Previous studies in mice severely depleted of bone marrow cells by 89Sr showed persistent monocytopenia and impaired expression of prostaglandin E2-releasing splenic macrophages (PGSM) despite the occurrence in the spleen of more than 10-fold increases in pluripotential stem cells and M phi colony-forming cells. To determine whether the observed deficits were due to a lack of precursors of blood monocytes and PGSM in the spleens of 89Sr-treated mice, radiation chimeras were established by i.v. infusion of 2 x 10(6) spleen cells from 89Sr donor CBA/J or semisyngeneic B6CB F1 hybrid mice into lethally gamma-irradiated CBA/J recipients. Blood monocyte levels were greater than normal by day 14 and PGSM induced by Corynebacterium parvum were demonstrated by day 28. These restored M phi populations expressed the donor haplotype detected in vitro with haplotype-specific monoclonal anti-H-2K plus complement. 89Sr treatment of the chimeras resulted in profound depletion of monocytes and PGSM. The data indicate that the spleen of the 89Sr-treated mouse, which is an ineffective source of circulating monocytes and PGSM, contains cells which can generate both of these populations following infusion into lethally irradiated recipients. Since the bone marrow of such recipients was capable of being repopulated, the aggregate observations suggest that functional bone marrow is obligatory for the generation of blood monocytes and PGSM populations.

Animals↗

Further morphological and biochemical observations on early low dose streptozocin diabetes in mice.

Conflicting published data regarding the role of macrophages and other cell types during the early stages of diabetes mellitus led us to further study this problem. To this end we diabetized mice, using low doses of streptozocin (STZ), 40 mg/kg body wt/day/5 days, and processed their pancreatic tissue for immunocytochemistry and ultrastructural observations; immunohistochemistry was performed on days 5 and 18 after the first STZ injection, and islets were observed ultrastructurally on days 5, 9, 10, and 18. Animals were tested for fasting serum glucose, and isolated islets were assayed for insulin secretion capacity. Immunohistology demonstrated that expression of major histocompatability complex class 2 antigens is strongly induced by multiple, low dose STZ treatments prior to impaired insulin release, and that different types of cells within the islet are capable of expressing Ia molecules. Ultrastructurally we found (a) a small number of macrophages (most probably resident monocytes/macrophages) containing B-cell debris, that were located close to either damaged or intact B cells; (b) a large number of recruited macrophages in a vascular or perivascular position; and (c) macrophages recognizable in the exocrine portion, close to the islets, occasionally containing exocrine cell debris. This led us to believe that recruited macrophages play an important role in the early islet-infiltrating stage.

Animals↗

Regulation of insulin and interleukin-1 release after Propionibacterium acnes-induced macrophage activation in mice.

The administration of a potent activator of macrophages (M phi), Propionibacterium acnes, in nondiabetic mice was associated with the release of significant amounts of interleukin-1 (IL-1) in the peritoneal cavity and plasma within 4 hours after treatment. Shortly before IL-1 peaks were observed, the levels of pancreatic insulin, [3H]leucine-proinsulin, and insulin/total protein ratio were elevated, and followed by a transient but marked hyperinsulinemia at 4 hours after treatment. A single dose of recombinant murine IL-1 in mice was also associated with a 2- to 9-fold increase in the levels of insulin in the pancreas and plasma at 4 hours after treatment. During the period of observation after the administration of P. acnes, plasma glucose levels in treated mice were significantly less than in parallel controls. Mild hypoglycemia was observed at 7 to 10 days posttreatment. Although circulating IL-1-like activity could not be detected in plasma 1 to 10 days after P. acnes treatment, this activity was measured in activated peritoneal and liver M phi. IL-1-like activity (specific activity: 276 units/mg protein) was detected in plasma, after it was chromatographed on a Sephadex G-150 column to remove proteins with higher molecular weight. Peritoneal and liver M phi from P. acnes mice were also able to elaborate significant amounts of IL-1-like activity in their supernatants with or without Escherichia coli lipopolysaccharide. At the same time, total protein synthesis and insulin content in the pancreas in P. acnes mice were significantly lower than the parallel control (p less than 0.01). These results suggest that P. acnes-induced M phi activation in mice was associated with the modulation of insulin release and glucose homeostasis which may be attributed to the accumulation and release of IL-1 by activated M phi.

Animals↗

Effects of bone marrow ablation on compartmental prostaglandin synthesis by mononuclear phagocytes.

Mononuclear phagocyte functions were studied in mice selectively deprived of bone marrow and rendered profoundly monocytopenic by the administration of the bone seeking isotope, 89Sr. Characteristics of such mice include severe impairment of monocyte-M phi elicitation, ablation of C. parvum induction of PGSM but the persistence of resident peritoneal and pulmonary alveolar M phi populations; splenic M phi increase in number concomitantly with splenic hemopoiesis. Studies on compartmental regulation in this model suggest that the capacity of splenic M phi to synthesize and release PGE2 is dependent upon a function of the bone marrow and is not wholly determined by the local environment. The relationship of blood monocytes to PGSM is uncertain. In contrast to splenic M phi, the capacity of resident peritoneal M phi for eicosanoid synthesis appears to be independent of bone marrow function. Monocyte influx, moreover, does not appear necessary for the maintenance of the resident peritoneal and alveolar M phi populations. We do not yet know whether bone marrow ablation destroys a migratory precursor of PGSM or the source of a crucial regulatory agent. In conclusion, the observations discussed show that prostaglandin metabolism within the spleen is subject to extracompartmental influence. It is clearly important to determine the regulatory characteristics of individual M phi compartments and generalizations about functional properties of mononuclear phagocytes should be made with circumspection.

Animals↗

Down-regulation of insulin receptors in Propionibacterium acnes-activated macrophages in the mouse.

Intraperitoneal administration of Propionibacterium acnes in CD-1 mice was associated with the reduction in number of insulin receptors in peritoneal macrophages (M phi), and with elevated levels of insulin in plasma and the peritoneal cavity. When insulin levels returned to normal, insulin receptors in P. acnes-M phi were still reduced. Insulin appears to contribute significantly to the down-regulation of the M phi-insulin receptors during the early stage of activation. Other biologically active substances released during M phi activation might assume greater influence on insulin resistance in activated M phi at a later stage. The induction of transient hyperinsulinemia in P. acnes-treated mice might be attributed to the effect of concurrently elevated interleukin-1 (IL-1) released in the early course of M phi activation.

Animals↗

Eicosanoid production by peritoneal and splenic macrophages in mice depleted of bone marrow by 89Sr.

Previous studies showed that the prostaglandin-forming macrophages (M phi) induced in the spleens of CBA/J mice by intraperitoneal administration of Corynebacterium parvum (CP) could not be demonstrated following the depletion of bone marrow and blood monocytes with 89Sr. The present study compares prostaglandin E2 (PGE2), leukotriene C4 (LTC4), and LTB4 release by splenic and resident peritoneal M phi in 89Sr-treated mice and 88Sr controls following in vivo CP and in vitro incubation with zymosan, calcium ionophore A23187, or phorbol ester (PMA). Intraperitoneal administration of CP resulted in the appearance of PGE2- and LTB4-releasing M phi in the spleens of control but not 89Sr mice. The incorporation and quantitative distribution of 3H-arachidonic acid into membrane lipids, however, were comparable in test and control mice. Neither zymosan nor any of the other stimulatory agents was able to effect significant release of PGE2 in vitro. No release of LTC4 by splenic M phi was detectable under experimental or control conditions. In contrast, the capacity of resident peritoneal M phi to release PGE2, LTC4, and LTB4 was apparently unaffected by 89Sr-induced bone marrow and monocyte depletion with virtually no demonstrable elicitation. Resident peritoneal M phi removed after CP in such mice showed a dramatic decrease in PGE2 release when incubated in vitro with zymosan, A23187, or PMA. These results, taken with earlier findings, demonstrate characteristically different phenotypic expression of metabolism of certain eicosanoids by splenic M phi from the spleen and the peritoneal cavity and suggest in addition that the induction of PGE2-synthesizing M phi in the spleen by CP is dependent on either an immigrant cell originating in the bone marrow or a regulatory agent derived from a bone marrow cell.

Animals↗

Antimicrobial activity of various immunomodulators: independence from normal levels of circulating monocytes and natural killer cells.

The effects of 89Sr treatment on the natural host resistance of CD-1 mice and the enhancement of resistance by immunomodulators to infection with Listeria monocytogenes or herpes simplex virus type 2 (HSV-2) were determined. In the CD-1 mouse, single-dose treatment with 89Sr caused a profound decrease in the number of circulating monocytes (Mo), lymphocytes, and polymorphonuclear leukocytes (PMN) within 1 week. There was also marked functional impairment of the Mo inflammatory response, as well as markedly decreased spontaneous and activatable cytotoxicity by splenic natural killer (NK) cells. Despite this profound cellular suppression, there was no significant change in natural resistance of CD-1 mice to L. monocytogenes or HSV-2 infection. Furthermore, prophylactic treatment of mice with the biologic immunomodulator Corynebacterium parvum or the synthetic immunomodulators maleic anhydride-divinyl ether or avridine in liposomes resulted in comparable enhancement of resistance in 89Sr-treated and normal mice. These data indicate that natural and immunomodulator-enhanced resistance of CD-1 mice to microbial infections do not depend on normal levels of Mo, PMN, or NK cells. The resistance enhancement may rely on activated tissue macrophages (M phi). In contrast to the early changes in circulating leukocytes, the resident peritoneal cell populations were not markedly altered until after day 30. There then was a distinct decline in lymphocytes and a gradual decline in M phi; the change in M phi was apparently due to the lack of an age-related increase in the peritoneal M phi population in 89Sr-treated mice in comparison with a slight increase in resident M phi in normal mice. After CD-1 mice were treated with 89Sr, the number of PMN and the function of NK cells generally recovered by about day 50 and was followed by partial recovery of circulating Mo, unless a second dose of 89Sr was administered.

Animals↗

Selectively eliminated blood monocytes and splenic suppressor macrophages in mice depleted of bone marrow by strontium 89.

The contribution of specific activity to the effects of the bone-seeking isotope, strontium 89 on radiosensitive components of mononuclear phagocyte populations was investigated in mice. CBA/J mice received a fixed dose of 2 microCi/g body weight of 89Sr with three different specific activities, 6 Ci, 100 microCi and 20 microCi per mg Sr. The estimated radioactivity located in the bone surface was 4,200, 3,000 and 2,400 cpm/mg bone when measured 2 days after the administration of 89Sr, and was lost with an estimated biological half-life of 27, 25, and 23 days, respectively. Bone marrow suppression was assessed by quantitation of the depletion of macrophage-colony forming cells (M-CFC) grown in vitro in the presence of macrophage growth factor. The decline in M-CFC closely paralleled the level of radioactivity in the bone. These effects were clearly reflected by the depletion of monocytes in the blood, which were reduced to 14%, 14%, and 21% of control levels corresponding to SA's of 6 Ci/mg, 100 microCi/mg and 20 microCi/mg when counted on day 10. By day 30 the respective monocyte levels were 15%, 31%, and 77%. Furthermore, the induction of prostaglandin E producing suppressor macrophages (M phi) by Corynebacterium parvum administration was found to vary inversely with the effects of radioactivity in the bone, with initial impairment followed by quantitative recovery. Resident-type M phi in peritoneal cavity, however, appear to be unaffected by 89Sr-treatment. These data suggest, as before, that the monocytes and suppressor M phi are dependent on radiosensitive marrow cells. The observations also lead to the conclusion that the specific activity of 89Sr preparations is an important determinant of the degree of suppression and of the rate of recovery of bone marrow from the effects of irradiation that follow the administration of this isotope.

Animals↗

The effect of bone marrow depletion on prostaglandin E-producing suppressor macrophages in mouse spleen.

The i.p. injection of Corynebacterium parvum (CP) into CBA/J mice effected increases in macrophage colony-forming cells (M-CFC) when spleen cells were cultured with L cell culture filtrate as a source of colony-stimulating factor. Significant increases in phagocytic macrophages (M phi) with Fc receptors for IgG2a and IgG2b immune complexes were additionally noted among the spleen cells in these mice. These M phi effectively inhibited Con A-induced lymphocyte proliferation, probably reflecting a 10-fold increase above normal controls in prostaglandin E to 47 ng/3 X 10(6) spleen cells/ml. To determine whether the suppressor M phi are immediate derivatives of splenic M-CFC, we tried to induce suppressor M phi by the injection of CP into mice depleted of bone marrow M-CFC by the earlier administration of the bone-seeking isotope, 89Sr. This procedure reduced M-CFC in the bone marrow to less than 1% of normal for more than 30 days. Monocytes in the blood fell to 5% of normal by day 10 and were 30% on day 30. Levels of resident peritoneal M phi showed relatively little change in this period. By contrast, splenic M-CFC increased to 20-fold higher than the "cold" 88Sr controls. CP-induced suppressor M phi activity, however, was sharply reduced in 89Sr marrow-depleted mice on day 10, despite the striking increase in M-CFC. There was a threefold increase in the number of phagocytic M phi binding IgG2a immune complexes, with no significant increase in IgG2b binding M phi. The kinetics of recovery of suppressor M phi activity showed that on days 20, 30, and 50 after 89Sr injection the activities reached 20%, 30%, and 70% of the "cold" control, respectively, and correlated with the recovery of significant levels of M-CFC in the bone marrow. Taken together, these observations suggest that splenic M-CFC are not an immediate source of PGE-suppressor M phi in vivo. It appears more likely that the CP-inducible suppressor M phi, in particular, originate from radiosensitive bone marrow cells or require for differentiation a microenvironment provided by bone marrow cells. The data also suggest that the expression of the Fc gamma 2b receptor and of suppressor activity by CP-induced splenic M phi are related phenomena.

Animals↗

The effect of hemopoietic microenvironment on splenic suppressor macrophages in congenitally anemic mice of genotype Sl/Sld.

Mechanisms underlying mononuclear phagocyte specialization are being probed by studying suppressor macrophages (M phi) as a reference population in mouse models with impaired blood monocyte formation. Splenic suppressor M phi, defined by PGE-mediated inhibition of Con A-induced T lymphocyte proliferation are induced by the i.p. administration of Corynebacterium parvum (CP). Mice severely depleted of bone marrow and blood monocytes by treatment with 89Sr fail to show this suppressor M phi response to CP, although M phi-forming stem cells, assessed as splenic M-CFC in vitro, are increased 20-fold. These observations suggest that radiosensitive bone marrow stem cells are necessary for the generation of both suppressor M phi and monocytes and that one such stem cell may be common to both types of mononuclear phagocytes. This notion was explored further by employing congenitally anemic mice of the genotype S1/S1d in which the hemopoietic microenvironment is genetically defective and thus unable to support the proliferation, differentiation, and function of stem cells. The congenital defect was found to be additionally expressed in the S1/S1d mouse by a monocytopenia of less than 10% of the values in normal congenic littermate controls and by the failure of splenic M-CFC to increase in response to CP. PGE-producing suppressor M phi expressing Fc gamma 2b receptors, however, were induced by CP in S1/S1d mice with no significant diminution of suppressor activity. These data establish the fact that significant impairment of the formation of monocytes is part of the overall hemopoietic defect in S1/S1d mice. PGE-producing suppressor M phi, however, were inducible at normal functional levels in the presence of a profound monocytopenia, and therefore appear to be independent of the mechanisms that regulate blood monocyte formation. Ablation of the bone marrow with 89Sr resulted in failure of CP to induce suppressor M phi in the spleens of the S1/S1d mice as in the littermate controls. Other observations in the present study, when taken with data from the 89Sr model, show the additional independence of these suppressor M phi from splenic M-CFC. In aggregate, these findings delineate three functionally definable populations of mononuclear phagocytes that appear to be independently regulated.

Anemia, Hemolytic, Congenital↗

Qualitative and quantitative differences between resident peritoneal mononuclear phagocytes of beige and control mice.

A qualitative and quantitative comparison of resident peritoneal macrophages (RPM) from beige (C57BL6Jbg/bg), (bg), and control black (C57BL/6J), (BL), mice has been made. Giant anomalous lysosomes as described for other leukocytes are inconsistently demonstrable. The principal morphological expression of the bg phenotype in RPM is the presence of elongated dumbbell-shaped, horseshoe-shaped, and ring-formed cytoplasmic lysosomes demonstrable by electron microscopy. Detailed analysis indicates that these are probably variations of the same basic structure, a deformed biconcave disc with differences in form resulting from their being cut in various planes of section. Additional structural complexity results from fusion between adjacent lysosomes. Thus the distinctive lysosomes of bg mouse RPM are not totally analogous to those structures described in other cell types. A morphometric analysis of control RPM compared to those from bg animals shows a significant decrease in the lysosomal volume proportion from 5.8% to 5.0% (P less than 0.02) with a corresponding increase in the mitochondrial volume proportion in cells from bg animals (P less than 0.05). There are no differences between bg and controls in regard to cellular profile areas, nuclear profile areas, nuclear volume proportions, and the volume to surface ratios of either the average cell or nucleus. This study represents the first compilation by morphometric methods of total granule content in the bg animal and demonstrates the ability of these techniques to detect significant quantitative changes in cells as structurally complex as mononuclear phagocytes.

Animals↗

Differential effects of chronic monocyte depletion on macrophage populations.

The administration of the bone-seeking isotope, 89Sr, to mice results in severe monocytopenia without any apparent effect on the numbers of resident peritoneal macrophages (Mphi). An explanation for this dichotomy was sought by determining whether the residual blood monocytes were still an effective source of Mphi after 89Sr treatment. Stem cell enumeration showed that a 90% fall in bone marrow macrophage colony-forming cells after 89Sr was accompanied by a 10-fold rise in splenic M-CFC. Splenectomy performed before 89Sr treatment, however, resulted in little additional monocytopenia and had no affect on the numbers of resident peritoneal Mphi even when sampling was extended to 31 days, an interval beyond the accepted half-time for peritoneal Mphi. Intraperitoneal injections of thioglycollate or Corynebacterium parvum elicited few or no monocyte-Mphi during respective intervals of 4 and 7 days. Elicitation with thioglycollate was attempted in tritiated thymidine-labeled mice 26 days after 89Sr. Four days later only a 2-fold increase in labeled peritoneal Mphi was found in the 89Sr-treated mice compared with a 150-fold increase in the controls. Studies of the ectoenzymes 5'-nucleotidase, alkaline phosphodiesterase I, and leucine aminopeptidase in such elicitation experiments suggested that the observed changes in activities reflected the direct stimulation of resident Mphi rather than monocyte immigration. Overall, the results indicate that treatment with 89Sr distinguishes two large populations of Mphi on the basis of their dependence on bone marrow. Mphi of inflammation reflect the monocytopenia and are severely and rapidly depleted by such treatment. The maintenance of resident type Mphi, on the other hand, appears to be independent of both the state of the bone marrow and the level of monocytes in the blood.

Animals↗