Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0392674 (exhaustion)
 13,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the progression of Lewis lung carcinoma (LLC) in C57Bl/6 mice, a neutrophilia with granulocytosis develops. This heightened myeloid response is further reflected in a progressively increasing concentration of precursors CFU-GM (colony-forming unit, granulocyte-macrophage) in the marrow. However, during the final days of tumor growth (day 19) the cycling fraction of CFU-GM declines in LLC mice, although their concentration remains high. It was of interest to explore in the present study whether this decline in proliferation of committed myeloid progenitors was due to exhaustion of the pool of early and late pluripotential stem cells CFU-S (colony-forming unit, spleen). The results indicate that early stem cells experience an initial proliferative burst (day 14) during tumor growth, but fail to replenish their own pool by day 19, suggesting that their self-replicative ability may become exhausted during growth of this cancer. The implications of these findings to conditions of chronic hemopoietic stress are discussed.
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PMID:High proliferation of early hemopoietic progenitors in tumor-bearing mice. 157 Oct 93

We have studied the effects of GM-CSF on cell growth in Dexter's type normal human long-term bone marrow cultures. Non adherent and adherent cells were weekly harvested and studied all over the time of culture up to 10 weeks: number, cytology, hematopoietic granulocyte-macrophage progenitors content (CFU-GM). Control consisted of cultures without growth factor. GM-CSF (100 ng/ml) induced a significant increase in the number of non adherent and adherent cells, mainly increasing the number of cells of the granulocytic lineage. GM-CSF also induced a transient increase in the number of CFU-GM in the non adherent fraction, but as from week 6 of culture, there were no more CFU-GM. At last GM-CSF inhibited completely or partially the adipocyte growth in the adherent stromal cell layers. In conclusion, at this concentration, GM-CSF might be responsible for the accelerated aging, maybe linked to the hematopoietic stem cells exhaustion and to the almost exclusive presence of monocyte-macrophage cell types in the culture supernatant.
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PMID:[Modification of in vitro hematopoiesis induced by addition of GM-CSF in long term normal human bone marrow cultures]. 206 51

Lewis lung carcinoma (LLC) of C57BL/6 mice, a transplantable tumor widely metastatic by 6-7 days post implant (PI), caused hematopoietic alterations such as progressive anemia (hemoglobin: day 1 PI, 11.0 g/dl; day 19 PI, 7.8 g/dl), neutrophilia (neutrophils: day 1 PI, 2 X 10(3)/microliter; day 19 PI, 22 X 10(3)/microliter), and marrow and splenic myeloid hyperplasia (marrow myeloid-to-erythroid ratio: day 1 PI, 1:1; day 7 PI, 3:1). Accompanying these changes were an increased concentration of marrow granulocyte-macrophage colony-forming units (culture) (GM-CFUC) (day 3 PI, LLC 185 +/- 27% of control; day 19 PI, LLC 265 +/- 10% of control) and accelerated cycling of these myeloid progenitors [day 3 PI, LLC 45.3 +/- 6.5% GM-CFUC in cycle vs. sham (media) injected 17.5 +/- 10.5%; day 7 PI, LLC 52.2 +/- 2.5% vs. sham (media) injected 29.8 +/- 9.8%; day 11 PI, LLC 56.2 +/- 4.4% vs. sham (media) injected 22.2 +/- 14%]. This study questioned whether enhanced hematopoiesis was a result of progressive tumor growth or whether the injection of tumor cells could evoke the response. By use of groups of C57BL/6 mice given an injection of live LLC cells, x-irradiated killed LLC cells, or media, the hematopoietic response to live LLC cells versus dead LLC cells could be dissected. A biphasic colony-stimulating activity (CSA) response in the sera of tumor bearers was found to account for the myelopoietic changes. The first wave of CSA from days 1 to 3 PI stimulated 168 +/- 3.7% more GM-CFUC than control sera and was likely released by dead cells of the tumor inoculum; the second wave from day 7 onward stimulated 220 +/- 7.6% more colonies and was a result of the enlarging tumor mass. Tumor growth was necessary for GM-CFUC proliferation, and the declining growth fraction at day 19 in LLC-bearing mice suggested that hematopoietic exhaustion was a consequence of tumor growth.
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PMID:Early hematopoietic events during tumor growth in mice. 348 12

In groups of adults, and term and preterm neonates, we determined: the blood concentration, the proliferative rate, and the variety of progeny of committed granulocyte-macrophage progenitor cells (CFU-GM). In five of eight term neonates and in all premature infants, a potentially significant limitation of neutrophil production was detected. Unlike the slowly proliferating CFU-GM present in the blood of healthy adult subjects (7% thymidine suicide, range 0% to 32%), the circulating CFU-GM in the premature subjects were proliferating at a near maximal rate (55%, range 40% to 75%, P less than 0.001). Because CFU-GM proliferation is nearly maximal in the baseline, noninfected state, neonates may have restricted ability to increase neutrophil production from CFU-GM during times of increased neutrophil need, such as during bacterial infection. Such inability may predispose neonates to exhaustion of the neutrophil supply during bacterial infection.
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PMID:Granulocyte-macrophage progenitor cells in term and preterm neonates. 378 29

Cancer may affect hemopoiesis by altering the proliferative status of hemopoietic progenitor cells. In Lewis lung carcinoma (LLC), the proliferative rate of the granulocyte-macrophage colony-forming unit (culture) (GM-CFUc) was studied using in vivo hydroxyurea techniques. The disposal of mature elements to the periphery was also monitored during tumor growth. Neutrophilia, anemia, and splenic hypertrophy developed during the course of the disease. By Day 6 post-tumor implant, myeloid hyperplasia of the marrow was evident, but the content of GM-CFUc in LLC mice was similar to that of control. However, by Day 11, the marrow of LLC mice displayed an increased concentration of GM-CFUc, which tripled by Day 19. There was an increased percentage of proliferating GM-CFUc in LLC mice by Day 6 which was highest by Day 11 and thereafter declined. The level of colony-stimulating activity was higher in the serum of tumor bearers than in that of controls. The early increase in proliferative rate of these early hemopoietic precursors can account for the later accumulation of GM-CFUc and myeloid elements in the marrow. Increased cycling of hemopoietic stem cells raises questions concerning the potential for early exhaustion of hemopoietic progenitor cells in these animals.
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PMID:High proliferation of granulocyte-macrophage progenitors in tumor-bearing mice. 688 22

We have investigated the mechanism behind the hematopoietic stimulation mediated by AM5, a protein-associated polysaccharide that stimulates in vivo the murine hematopoietic system. A dose-dependent increase in hematopoietic progenitors was observed in long-term bone marrow cultures (LTBMCs) treated in vitro with AM5. The stimulatory effect was more marked in colony-forming units-granulocyte-macrophage (CFU-GM) than in CFU-spleen (CFU-S) progenitors and also more significant in the supernatant than in the adherent layer. This stimulatory effect was reversible, and continuous stimulation with high doses of AM5 was conductive to a progressive exhaustion of the culture. The analysis of the CFU-GM stimulating activity present in the supernatant of AM5-treated cultures revealed a dose-dependent induction of granulocyte-macrophage colony-stimulating activity (GM-CSA), in contrast with control cultures in which no CSA was detected. Northern blots of LTBMC-adherent layers obtained after in vitro treatment with AM5 revealed a significant mRNA expression for interleukin 1 alpha (IL-1 alpha), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage CSF (M-CSF) and granulocyte CSF (G-CSF), in contrast with adherent layers from untreated cultures which only expressed, in detectable levels, M-CSF and stem cell factor (SCF). The SCF expression was down-modulated in AM5-treated cultures. Our results strongly suggest that the hematopoietic stimulation induced by AM5 is mediated by the modulated expression of endogenous hematopoietic growth factors.
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PMID:AM5, a protein-associated polysaccharide, stimulates hematopoiesis and modulates the expression of endogenous hematopoietic growth factors in murine long-term bone marrow cultures. 754 Apr 71

The colony-stimulating factors (CSFs) have emerged as effective drugs in a variety of clinical situations. These drugs stimulate the production and activity of haematopoietic cells in vitro and in vivo. Two members of this group, granulocyte CSF (G-CSF) and granulocyte-macrophage CSF (GM-CSF), have been approved in the US and Europe for use following cytotoxic chemotherapy and autologous bone marrow transplantation. Other uses of the CSFs include myelodysplastic syndromes, aplastic anaemia, the acquired immunodeficiency syndrome (AIDS) and cyclic and congenital neutropenias. Although CSFs have generally been well tolerated in clinical use there are a number of theoretical concerns, including disease acceleration, biased stem cell commitment and bone marrow exhaustion. New CSFs are currently under development. Combinations of growth factors in the future may maximise effectiveness while minimising toxicity.
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PMID:Use and toxicity of the colony-stimulating factors. 768 34

In this paper we attempt to improve upon the methods of hematopoietic stem cell expansion. We evaluate the effects of recombinant human stem cell factor (SCF or c-kit ligand) alone and also in combination with recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 3 (IL-3), on cell proliferation and differentiation in human long term bone marrow cultures (LTBMC). Weekly addition of 5 ng/ml of SCF with 25% serum containing media resulted in increased recovery of total nonadherent cells, granulocyte-macrophage colony forming units (CFU-GM), and burst-forming units erythroid (BFU-E) at week 1, but the number of bone marrow (BM) progenitor cells fell below the level of untreated control cultures at weeks 3 (BFU-E) and 4 (CFU-GM). At week 8, when the cultures were terminated, the CFU-GM recovery was markedly reduced in flasks supplemented with SCF compared with the controls (p < 0.002). Moreover, SCF treatment induced the early disappearance of BFU-E. When LTBMC were supplemented with the combination of SCF plus GM-CSF (100 U/ml) and IL-3 (5 ng/ml), synergistic activity of the CSFs was observed at week 1. The number of BM colony forming cells (CFC) rapidly declined below the level of growth factor-free controls, leading to the early exhaustion of the culture when SCF was combined with GM-CSF. By comparison, GM-CSF and IL-3 alone induced a statistically significant increase above the controls (no growth factor) in the number of nonadherent cell colonies of CFU-GM and BFU-E. Analysis of adherent layer cells from cultures supplemented with SCF showed increased cellularity, no adipogenesis, and early disappearance of myeloid progenitors while the percentage of CFU-GM in S phase, assessed by cytosine arabinoside (Ara-C) suicide assay, was 9.2 +/- 5% SD versus 27.7 +/- 10% SD in control (no growth factor) samples (p < 0.01). SCF increased the number of fibroblast colony forming units (CFU-F) and also showed a synergistic activity (9.6-fold increase) when combined with IL-3. These findings suggest that SCF, GM-CSF and IL-3 exert their activity on different cell populations within the hematopoietic system. Further investigations are needed to optimize the use of SCF in supporting hematopoiesis.
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PMID:Effect of stem cell factor (c-kit ligand), granulocyte-macrophage colony stimulating factor and interleukin 3 on hematopoietic progenitors in human long-term bone marrow cultures. 769 21