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PubMed1994

Restoration of murine cytomegalovirus (MCMV) induced myelosuppression by AS101.

Infection with cytomegalovirus (CMV) continues to be one of the most common complications following allogeneic bone marrow transplantation. The gravest danger for the host occurs when the virus is reactivated as a result of immunosuppression. In this report we studied the effects of sublethal murine cytomegalovirus (MCMV) infection on the hemopoietic system including bone marrow (BM) cellularity, production of colony stimulating factor (CSF) and interleukin-6 (IL-6) and the development of granulocyte-macrophage colony forming units (CFU-GM), and BM stromal cell viability. Our findings show that the virus infection led to a significant decrease in the number of BM cells and in the production levels of CSF and IL-6. There was also a decrease in the number of stromal cells, as reflected by the number of colony forming unit fibroblasts (CFU-F), and in the relative number of CFU-GM progenitors. Treatment of MCMV infected mice with the immunomodulator AS101 [ammonium trichloro (dioxyethylene 0-0')tellurate] restored significantly CSF and IL-6 production by BM cells to levels of uninfected control mice as well as the number of CFU-F and stromal cell elements which consequently led to the restoration of the total number of BM cells. Results presented here indicate that AS101 may have immunomodulatory effects on MCMV mediated myelosuppression. Administration of AS101 to patients with CMV associated BM damage may improve the restoration of their BM function.

Adjuvants, Immunologic↗
PubMed1988

Hypoplastic myelodysplastic syndrome.

Over a period of 8 years 11 of 64 patients seen at Loyola University Medical Center with the diagnosis of myelodysplastic syndrome (MDS) also exhibited bone marrow hypoplasia (marrow cellularity of 25% or less) at presentation. The other 53 had normocellular or hypercellular marrow. Clinical features, hemograms, chromosome analysis, incidence of progression to acute leukemia or aplastic anemia, and survival in each group were compared. Using the French-American-British (FAB) classification, there were seven patients with refractory anemia (RA), one refractory anemia with ringed sideroblasts (RARS), and three refractory anemia with excess blasts (RAEB) in the hypoplastic MDS group. Those with normocellular or hypercellular marrow included 22 with RA, nine with RARS, 12 with RAEB, three with chronic myelomonocytic leukemia, and four with RAEB in transformation; one had chronic diGuglielmo syndrome and two patients were not classified. Patients with hypoplastic MDS had lower hemoglobin levels (median, 8 g/dl versus 9 g/dl), more severe leucopenia (median 3100/microliter versus 4200/microliter) and thrombocytopenia (median, 28,000/microliter versus 75,000/microliter), and marked macrocytosis (mean corpuscular volume (MCV), 107 mu 3 versus 97 mu 3). Nine patients with hypoplastic MDS had a chromosome analysis of the bone marrow, and all were normal. In those with normocellular or hyperplastic bone marrow, 22 such analyses were done, and seven (23%) were abnormal. One patient (11%) from the hypoplastic group and 11 (23%) from the normocellular or hyperplastic MDS transformed into acute leukemia. None progressed to aplastic anemia. With a mean follow-up time of 33 months in the hypoplastic MDS, eight patients (72%) are alive. In the group with normal or hyperplastic MDS, the mean follow up was 47 months, and 27 patients (50%) have survived. The two groups differ significantly in leukocyte count (P less than 0.0015), platelet count (P less than 0.0001), and MCV (P less than 0.0023). There may be a possible difference between these groups related to abnormal karyotype, but it is not statistically significant (P = 0.06). Therapy with pyridoxine, folic acid, prednisone, anabolic steroids, retinoids, or low-dose cytosine arabinoside was not beneficial in hypoplastic MDS. Hypoplastic MDS appears to be a distinct clinicopathologic entity characterized by marrow hypoplasia, macrocytosis, severe leucopenia and thrombocytopenia, low incidence of progression to acute leukemia, and unresponsiveness to conventional therapy.

Adult↗
PubMed1992

Administration of recombinant human interleukin-7 alters the frequency and number of myeloid progenitor cells in the bone marrow and spleen of mice.

The administration of greater than or equal to 5 micrograms interleukin-7 (IL-7) twice a day to mice for 4 to 7 days increased by twofold to fivefold the total number of splenic and peripheral blood leukocytes, but did not appreciably increase bone marrow (BM) cellularity. This regimen of IL-7 administration also resulted in a greater than 90% reduction in the frequency and total number of single lineage colony-forming unit-culture (CFU-c) and multilineage CFU-granulocyte, erythroid, monocyte, megakaryocyte colonies that could be cultured from the BM, but a fivefold to 15-fold increase in the number of these progenitors that could be cultured from the spleen. All of these effects were reversible with progenitor and white blood cell numbers returning to near normal by day 6. Morphologic analysis of cells obtained from the BM of IL-7-treated mice showed an increase in lymphoid cells. Surface phenotype analysis showed that most of this IL-7-induced increase in lymphocytes was attributable to an increase in immature B cells (B220+, sIg-), while cells expressing the myelomonocytic markers 8C5 and MAC-1 decreased by twofold to threefold. Further studies showed that the administration of IL-7 to mice that had been rendered leukopenic by the injection of cyclophosphamide (Cy) or 5-fluorouracil (5FU) exhibited a more rapid recovery and/or overshoot in their peripheral blood lymphocytes when compared with mice treated with Cy or 5FU alone. These results show that IL-7 can differentially regulate myelopoiesis in the BM and spleen, while stimulating lymphopoiesis.

Animals↗
PubMed1977

The effect of dimethylbenz(a) anthracene on murine hematopoiesis.

DMBA was given p.o. to young adult female CBA/J mice in two regimens, a single dose of 1 mg and 4 doses of 1 mg in weekly intervals. In the peripheral blood only a transient reticulocytopenia and thrombocytopenia was observed in both groups. After 4 doses the thymus and spleen weights were reduced up to 4 weeks after the last dose. In the bone marrow the cellularity was lower in treated animals than in controls. After 1 mg DMBA pluripotent stem cells (CFUc) in the marrow were reduced to about 50--70% over a 2- to 3-week period, in the spleen the CFUs concentration was reduced to 10% at day 3 with about normal levels after 3 to 4 weeks. The compartment of granulocytic committed stem cells (CFUs) in both organs followed the same pattern with an overshoot in CFUc concentration in the spleen after 3 to 4 weeks. After 4 doses CFUs and CFUc were more depressed, regeneration began about 2 weeks after the last dose in both organs. CFUc in the marrow had normal and in the spleen supra-normal concentrations 3 and 4 weeks after the last dose.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1992

Combined differentiation therapy in myelodysplastic syndrome with retinoid acid, 1 alpha,25 dihydroxyvitamin D3, and prednisone.

The myelodysplastic syndrome (MDPS) provides an opportunity for identifying host factors (genetic, endocrine, immune) involved in initiation and progression of preleukemia into frank acute myeloid leukemia. The aim of this study was to identify bone marrow (BM) cellular and humoral dysfunctions central to the development of MDPS and useful in therapeutic follow-up studies. Our preclinical studies have shown that (1) the characteristic stromal cell composition of the normal BM microenvironment was impaired in MDPS and in AML in 67 and 86% of the cases, respectively; (2) the 1 alpha,25(OH)2D3 concentration in BM plasma was abnormal in 50% of MDPS and 30% of AML; and (3) an inverse correlation existed in MDPS between the 1 alpha,25(OH)2D3 concentration and the frequency of F-CFU, (r = 0.41, p < 0.02), suggestive of a regulatory interaction between this secosteroid hormone and BM stromal cells. The analysis of clonal extinction of BM blast cells in response to all trans retinoic acid (RA), 1 alpha,25(OH)2D3, and colony stimulating factors (PHA-LCM), either alone or in various combinations, revealed individual patterns of responses in the cases of MDPS or AML. The results indicate the necessity for preclinical studies to select patients for combined differentiation therapy. Our ongoing clinical trials suggest that RA (Roaccutan, 20 mg/day continuously) as induction therapy, followed at weeks 6 to 8 by prednisone (40 mg/day for 15 days) and 1 alpha,25(OH)2D3 (Rocaltrol, 3 x 0.25 micrograms/day for 3 months) may induce a long-lasting hematological remission in MDPS.

Bone Marrow↗
PubMed2005

Benzo(a)pyrene and 7,12-dimethylbenz(a)anthrecene differentially affect bone marrow cells of the lymphoid and myeloid lineages.

Polycyclic aromatic hydrocarbons (PAHs) are common environmental contaminants that are carcinogenic and immunosuppressive. Benzo(a)pyrene (BP) and 7,12-dimethylbenz(a)anthracene (DMBA) are two prototypic PAHs known to impair the cell-mediated and humoral immune responses. We have previously shown that, in C57BL/6J mice, total bone marrow (BM) cellularity decreased two-fold following intraperitoneal DMBA treatment but not BP treatment. Here, we have used flow cytometry to demonstrate that BP and DMBA differentially alter the lymphoid and myeloid lineages. Following DMBA treatment, the pro/pre B-lymphocytes (B220(lo)/IgM(-)) and the immature B-lymphocytes (B220(lo)/IgM(+)) significantly decreased, while the mature B-lymphocytes (B220(hi)/IgM(+)) remained unaffected. In contrast, BP treatment decreased the pro/pre B-lymphocytes, and did not affect the immature B-lymphocytes or mature B-lymphocytes. The Gr-1(+) cells of the myeloid lineage were depleted 50% following DMBA treatment and only minimally depleted following BP treatment. Interestingly, the monocytes (7/4(+)1A8(lo)) and neutrophils (7/4(+)1A8(hi)) within this Gr-1(+) population were differentially affected by these PAHs. Monocytes and neutrophils were depleted following DMBA treatment whereas neutrophils decreased and monocytes increased following BP treatment. Although TNFalpha and CYP1B1 are implicated as essential mediators of hypocellularity, the similar induction of TNFalpha mRNA and CYP1B1 mRNA in the BM by BP and DMBA suggests that they are not limiting factors in mediating the different effects of these PAHs. Given that similar amounts of BP and DMBA reach the BM when administered intraperitoneally, their differential effects on the lymphoid and myeloid lineages probably stem from differences in reactive metabolites such as PAH quinones and PAH-dihydrodiol-epoxides.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1997

Virus-induced transient bone marrow aplasia: major role of interferon-alpha/beta during acute infection with the noncytopathic lymphocytic choriomeningitis virus.

The hematologic consequences of infection with the noncytopathic lymphocytic choriomeningitis virus (LCMV) were studied in wild-type mice with inherent variations in their interferon (IFN)-alpha/beta responder ability and in mutant mice lacking alpha/beta (IFN-alpha/beta R0/0) or gamma IFN (IFN-gamma R0/0) receptors. During the first week of infection, wild type mice demonstrated a transient pancytopenia. Within a given genetic background, the extent of the blood cell abnormalities did not correlate with the virulence of the LCMV isolate but variations were detected between different mouse strains: they were found to depend on their IFN-alpha/beta responder phenotype. Whereas IFN-gamma R0/0 mice were comparable to wild-type mice, IFN-alpha/beta R0/0 mice exhibited unchanged peripheral blood values during acute LCMV infection. In parallel, the bone marrow (BM) cellularity, the pluripotential and committed progenitor compartments were up to 30-fold reduced in wild type and IFN-gamma R0/0, but remained unchanged in IFN-alpha/beta R0/0 mice. Viral titers in BM 3 d after LCMV infection were similar in these mice, but antigen localization was different. Viral antigen was predominantly confined to stromal BM in normal mice and IFN-gamma R0/0 knockouts, whereas, in IFN-alpha/beta R0/0 mice, LCMV was detected in > 90% of megakaryocytes and 10-15% of myeloid precursors, but not in erythroblasts Although IFN-alpha/beta efficiently prevented viral replication in potentially susceptible hematopoietic cells, even in overwhelming LCMV infection, unlimited virus multiplication in platelet and myeloid precursors in IFN-alpha/beta R0/0 mice did not interfere with the number of circulating blood cells. Natural killer (NK) cell expansion and activity in the BM was comparable on day 3 after infection in mutant and control mice. Adaptive immune responses did not play a major role because comparable kinetics of LCMV-induced pancytopenia and transient depletion of the pluripotential and committed progenitor compartments were observed in CD8(0/0) and CD4(0/0) mice, in mice depleted of NK cells, in lpr mice, and in perforin-deficient (P0/0) mice lacking lytic NK cells. Thus, the reversible depression of hematopoiesis during early LCMV infection was not mediated by LCMV-WE-specific cytotoxic T lymphocyte, cytolysis, or secreted IFN-gamma from virally induced NK cells but was a direct effect of IFN-alpha/beta.

Acute Disease↗
PubMed2005

Hypocellular myelodysplastic syndromes: clinical and biological significance.

The article is concerned with incidence, clinical features, response to therapy, and prognosis of patients with hypocellular myelodysplastic syndromes. Bone marrow (BM) cellularity <30% (or <20% in patients >70 yr) was found in 24 of 236 (10.2%) trephine biopsies. Median age was 61 yr, with significant male predominance (M/F=3.0) At diagnosis, median hemoglobin was 83 g/L, median platelet and neutrofil counts were 31x109/L and 1.2x109/L, respectively. According to FAB classification, 17 patients had RA, 6 had RAEB, and only 1 had RAEB-t. Beside marrow hypoplasia, the most prominent PH finding was megakaryocyte hypoplasia and dysplasia, found in two-thirds of cases, each. Comparison between hypocellular and normo/hypercellular MDS cases regarding clinicopathological features showed younger age, more severe cytopenia, less blood and BM blast infiltration, MK hypoproliferation, and more pronounced stromal reactions in former cases. Karyotypic abnormalities were present in 12.5% hypocellular cases, in contrast to 44.6% normo/hypercellular cases (p=0.0025). Eleven patients were treated with supportive therapy alone, six with danazol or androgens, six with immunosuppressive therapy, and one with LDARAC. However, complete or partial response was achieved in only four patients treated with danazol or androgens. None of the patients developed leukemia. Eleven patients died, so marrow insufficiency was the main cause of death. Median survival was 33 mo for hypocellular MDS, and 19 mo for normo/hypercellular MDS (p=0.09). The results confirm the existence of hypocellular variant of MDS, which seems to have better prognosis than those patients with normo/hypercellular disease.

Adolescent↗
PubMed1987

Infusion-rate independent cellular adriamycin concentrations and cytotoxicity to human bone marrow clonogenic cells (CFU-GM).

The effect of adriamycin (ADM) infusion-rate on cellular ADM concentrations and on clonogenicity of human haematopoietic cells was studied in vivo and in vitro. In patients an ADM dose of 30 mg m-2 was administered as a bolus injection, or as a 4 h or a 24 h infusion. In vitro the effect of ADM on clonogenic cell growth was determined after exposure during 5 min, 2 h and 24 h of human bone marrow cells to increasing ADM concentrations. ADM showed rapid intracellular accumulation, to levels 100-fold the plasma concentration in vivo or the incubation medium concentration in the in vitro experiments. After a bolus injection or 5 min exposure only approximately 10% of the cellular peak ADM was retained after elimination of the drug from the plasma or the incubation medium. Ninety percent of the ADM was apparently 'loosely' bound. After 4 h and 24 h constant-rate infusions and also after 2 h and 24 h incubations in vitro, the cells accumulated ADM gradually, and the subsequent washing-out of the cellular ADM was substantially less, most of the ADM being 'tightly' bound. Despite these different patterns of uptake and retention after in vivo short- and long-lasting infusion of the same total dose, the 'tightly-bound' cellular ADM concentrations were the same. Moreover, comparable cellular ADM concentrations, retained after efflux of the 'loosely-bound' cellular ADM fraction were equally cytotoxic to normal human clonogenic cells. Short-lasting cellular peak ADM concentrations which occur after a bolus injection or after short exposure to high ADM concentrations are not essential for the cytotoxic effect, in contrast to the retained, 'tightly-bound' cellular ADM levels.

Bone Marrow↗
PubMed2002

Overexpression of vascular endothelial growth factor (VEGF) and its cellular receptor KDR (VEGFR-2) in the bone marrow of patients with acute myeloid leukemia.

Vascular endothelial growth factor (VEGF) and its cellular receptor VEGFR-2 have been implicated as the main endothelial pathway required for tumor neovascularization. However, the importance of the VEGF/VEGFR-2 system for angiogenesis in hematologic malignancies such as AML remains to be elucidated. In 32 patients with newly diagnosed untreated AML, we observed by immunohistochemical analysis of bone marrow biopsies significantly higher levels of VEGF and VEGFR-2 expression than in 10 control patients (P <0.001). In contrast, VEGFR-1 staining levels in AML patients were in the same range as in the controls. Expression of VEGF and VEGFR-2 was significantly higher in patients with a high degree of microvessel density compared to those with a low degree (VEGF: P =0.024; VEGFR-2: P =0.040) and correlated well with bone marrow microvessel density (r(s)=0.566 and 0.609, respectively; P <0.001). Furthermore, in patients who achieved a complete remission following induction chemotherapy VEGFR-2 staining levels decreased into the normal range. In conclusion, our results provide evidence for increased expression of VEGF/VEGFR-2 of leukemic blasts and correlation with angiogenesis in the bone marrow of AML patients. Thus, VEGF/VEGFR-2 might constitute promising targets for antiangiogenic and antileukemic treatment strategies in AML.

Acute Disease↗
PubMed1983

Histomorphologic study of bone marrow in acute leukemia following chemotherapy and autologous bone marrow transplantation.

Twenty-six patients with acute myeloid leukemia, acute lymphoid leukemia and chronic granulocytic leukemia in blast crisis were studied by means of multiple biopsies during a polychemotherapeutic or autologous bone marrow transplant protocol. Following chemotherapy, 3 main phases were observed: leukemic cellular depletion, stromal bone marrow reconstruction, and bone marrow hemopoietic restoration. Following intensive chemotherapy (in 2 patients after cyclophosphamide and total body irradiation) and autologous bone marrow transplantation, the 3 phases appeared to be shorter. A focal or diffuse increase in marrow fibrosis was a common finding in leukemia. An effective antileukemic therapy resulted in a decrease in fibrosis, whereas in some cases a further increase was a precocious sign of leukemia relapse.

Adolescent↗
PubMedDate not supplied

[Regulation of fibroblast-like cell proliferation in human bone marrow].

The influence of growth factors (GF) and some other biological active molecules on the human bone marrow fibroblast (HBMF) proliferation was studied in the monolayer system. The proliferation of HBMF, like other connective tissue cells, was serum- and GF-dependent. GF tested (EGF, FGF, insulin) produced both positive and negative effects on HBMF proliferation. It was also shown that phorbol ester, which activates protein kinase C, usually inhibited HBMF proliferation. It has been proposed that this feature of HBMF is the cause of GF bifunctional action. It has been suggested that the ability of GF to inhibit HBMF proliferation in some cases permits one to maintain cellular homeostasis in GF rich human bone marrow. HBMF of different hematological patients were characterized by individual differences in GF sensitivity. This may be secondary to the bone marrow cellular composition. For example, HBMF obtained from the bone marrow rich in total cells or megakaryocytes were more responsive to proliferation stimulating effect of GF.

Bone Marrow↗
PubMed2006

Critically short telomeres in acute myeloid leukemia with loss or gain of parts of chromosomes.

Telomeres, nucleoprotein complexes at chromosome ends, protect chromosomes against end-to-end fusion. Previous in vitro studies in human fibroblast models indicated that telomere dysfunction results in chromosome instability. Loss of telomere function can result either from critical shortening of telomeric DNA or from loss of distinct telomere-capping proteins. It is less clear whether telomere dysfunction has an important role in human cancer development in vivo. Acute myeloid leukemia (AML) is a good model to study mechanisms that generate chromosome instability in human cancer development because distinct groups of AML are characterized either by aberrations that theoretically could result from telomere dysfunction (terminal deletions, gains/losses of chromosome parts, nonreciprocal translocations), or aberrations that are unlikely to result from telomere dysfunction (e.g., reciprocal translocations or inversions). Here we demonstrate that AML with multiple chromosome aberrations that theoretically could result from telomere dysfunction is invariably characterized by critically short telomeres. Short telomeres in this group are not associated with low telomerase activity or decreased expression of essential telomeric capping proteins TRF2 and POT1. In contrast, telomerase activity levels are significantly higher in AML with short telomeres. Notably, short telomeres in the presence of high telomerase may relate to significantly higher expression of TRF1, a negative regulator of telomere length. Our observations suggest that, consistent with previous in vitro fibroblast models, age-related critical telomere shortening may have a role in generating chromosome instability in human AML development.

Acute Disease↗
PubMed1994

The present and future of hematopoietic cytokines in clinical practice.

Hematologic toxicities can be a major problem in the delivery of some chemotherapy regimens. The way clinicians manage myelosuppression has evolved from a symptomatic approach to the use of cytokines to ameliorate or prevent anemia and neutropenia. Soon, new cytokines will be commercially available to manage thrombocytopenia. Cytokines are transforming oncology by permitting dose intensification through delivery of chemotherapy at the full dose and on time, as well as permitting high-dose chemotherapy. Clinical trials are also exploring the benefits of cytokines for myeloablative chemotherapy with cellular support (bone marrow transplantation or peripheral blood progenitor cell transplantation). Future applications of cytokines include ex vivo expansion and gene transfer therapy. For cancer patients, the ability to receive intensive doses of chemotherapy might mean improved survival rates.

Antineoplastic Agents↗
PubMed1997

Hematopoietic transplantation: state of the art.

Bone marrow transplantation has developed from an experimental therapy for a small group of patients to a well-established form of treatment with well-defined indications for a large group of patients with hematological and non-hematological neoplasia. The availability of suitable donors has more than doubled due to large registries of persons volunteering for marrow donation. With improved techniques for histocompatibility typing, it has become possible to study the role of specific histoincompatibilities for graft-versus-host disease and graft-versus-leukemia reactions. The source of hematopoietic stem cells now comprises not only bone marrow, but also stem cells mobilized into the peripheral blood and stem cells from cord blood. Hematopoietic growth factors have found a large distribution in the mobilization of stem cells and support for hematological reconstitution. They are studied for the expansion of pools of stem cells. Reconstitution of antileukemia and antiviral activity has been achieved by adoptive immunotherapy using lymphocytes and dendritic cells cultured in vitro. The way from transplantation of bone marrow to cellular and genetic engineering leads to new indications such as treatment of severe autoimmune disease. Hematopoietic transplantation has come a long way and it still has possible new areas of application.

Graft vs Host Disease↗
PubMed1995

Investigation of a screening battery for immunotoxicity of pharmaceuticals within a 28-day oral toxicity study using azathioprine and cyclosporin A as model compounds.

The authors have investigated a panel of parameters for immunotoxicity that may be incorporated in routine screening for toxicity of pharmaceuticals. This panel comprises serum immunoglobulin concentrations, cellularity of bone marrow, weights and histopathology of thymus, spleen, and lymph nodes, histopathology of Peyers' patches, and FACScan analysis of lymphocyte subpopulations in the spleen, in addition to parameters of toxicity to other systems. To study the value of these assays for pharmaceuticals, the authors used the immunosuppressants azathioprine (AZP) and cyclosporin A (CsA) as model compounds with known immunotoxic activity. In two separate experiments, rats were treated by daily gastric intubation with 0, 5, 12.5, and 25 mg AZP/kg body wt or 0, 1.25, 5, and 20 mg CsA/kg body wt. In the AZP study, the histopathology of the thymus and the spleen were valuable parameters of immunotoxicity, since these organs showed microscopic alterations at relatively low dose levels. In the CsA experiment, both the histopathology of the thymus and the data provided by FACScan analysis were sensitive indicators of immunotoxicity detecting effects at the lowest dose level employed. The data indicate that the lymphoid system is the most sensitive target of toxicity after AZP or CsA administration. The authors conclude that their test battery yielded immunotoxicity profiles of AZP and CsA in rats that were consistent with published findings in the literature, indicating the usefulness of the test battery employed.

Administration, Oral↗
PubMed1995

A morphological analysis of the short-term effects of benzene on the development of the hematological cells in the bone marrow of mice and the effects of interleukin-1 alpha on the process.

Chronic exposure of humans to benzene (BZ), a widely used industrial chemical and a ubiquitous environmental pollutant, causes aplastic anemia and acute myeloid leukemia. The purpose of the studies reported here was to determine whether the observed depression of bone marrow (BM) cellularity in mice administered benzene was reflected in a suppression of development of all of the hematopoietic lineages and to confirm the ability of interleukin-1 alpha (IL-1 alpha) to prevent BZ-induced BM cell depression. We report that BZ, administered twice per day for 2 days to C57B1/6J mice at a dose of 600 mg/kg body weight, caused a significant depression of the total number of nucleated BM cells per femur when measured on day 3. The observed depression reflects a complex situation that represents the net effect of a decrease in the total number of cells of the lymphocytic and erythroid lineages, along with an increase in the number of intermediate and terminally differentiated cells of the granulocytic lineage. An experiment to monitor the effects of BZ over a 7-day period showed a progressive depressive effect on the lymphocytes and an initial depression of the erythroid cells at day 3 that remained constant until day 7. Conversely, the numbers of intermediate and terminally differentiated granulocytes progressively increased over the 7 days. The BM appeared to recover from the depressive effects of BZ immediately upon cessation of exposure, as the number of nucleated BM cells began to rise by day 5 and was equal to that of the control group by day 7. The results expand our earlier finding (Renz and Kalf 1991) that the overall depression of BM cellularity occurs because of an inability of the stromal fibroblast to produce colony-stimulating factors essential for stem and progenitor cell survival. This results from inhibition by the BZ metabolite, hydroquinone (HQ), of the processing of pre-IL-1 alpha to the mature cytokine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗