Evidence for a renal-dependent factor in the control of muramidase (lysozyme) formation

1969 ◽  
Vol 47 (9) ◽  
pp. 831-832 ◽  
Author(s):  
R. Keeler
Keyword(s):  
Bone Marrow ◽  
Plasma Flow ◽  
Enzyme Production ◽  
Fold Increase ◽  
Renal Tissue ◽  
Inhibitory Influence ◽  
Bilateral Nephrectomy ◽  
Total Body ◽  
Dependent Factor

After bilateral nephrectomy the total body muramidase in the rat increases by about 50% in 6 h. Since there was no evidence to suggest that this increase was the result of failure to remove or inactivate muramidase, experiments were performed to measure the rate of muramidase formation in the bone marrow of normal and nephrectomized rats. The enzyme production was measured as the product of the plasma flow and the arterio–venous difference. Results showed that 6 h after bilateral nephrectomy there was a 14-fold increase in muramidase production. It is suggested that renal tissue may normally exert an inhibitory influence upon muramidase formation.

The effect of bilateral nephrectomy on the production and distribution of muramidase (lysozyme) in the rat

1970 ◽  
Vol 48 (2) ◽  
pp. 131-138 ◽  
Author(s):  
R. Keeler
Keyword(s):  
Kidney Tissue ◽  
High Plasma ◽  
Renal Tissue ◽  
Inhibitory Influence ◽  
Bilateral Nephrectomy ◽  
Venous Anastomosis ◽  
Rate Of Increase ◽  
Total Body ◽  
High Level

After bilateral nephrectomy total body muramidase in the rat increased by more than 50%. The mean rate of increase was 340 μg/h per 100 g. Skin and bone showed the greatest increase. Although the lungs contain a high level of muramidase there was no significant change in the level of enzyme activity after nephrectomy. Rats with sectioned ureters or with a uretero–venous anastomosis did not develop high plasma levels of muramidase. The response to nephrectomy is therefore not a response to uremia. Pretreatment of the animals with cortisone or DL-ethionine had no effect on the enzyme response to nephrectomy. This was taken to indicate that the response was not to antigenic material and did not depend upon hepatic synthesis of the enzyme. Pretreatment with the cytotoxic agent cyclophosphamide reduced the plasma and total body level of muramidase and blocked the response to nephrectomy. Direct measurement demonstrated a large increase in the rate of muramidase production by bone marrow. Since the in vitro inactivation of muramidase by kidney tissue could not be demonstrated, it is concluded that nephrectomy causes an increase in the rate of enzyme production rather than a failure of catabolism. Renal tissue might normally exert an inhibitory influence upon muramidase formation.

scholarly journals Endothelial progenitor cell infusion induces hematopoietic stem cell reconstitution in vivo

Blood ◽  
2009 ◽  
Vol 113 (9) ◽  
pp. 2104-2107 ◽  
Author(s):  
Alice B. Salter ◽  
Sarah K. Meadows ◽  
Garrett G. Muramoto ◽  
Heather Himburg ◽  
Phuong Doan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Blood Cells ◽  
Progenitor Cell ◽  
White Blood Cells ◽  
Fold Increase ◽  
Endothelial Progenitor ◽  
Hematopoietic Stem ◽  
Hematopoietic Reconstitution ◽  
Total Body

Hematopoietic stem cells (HSCs) reside in association with bone marrow (BM) sinusoidal vessels in vivo, but the function of BM endothelial cells (ECs) in regulating hematopoiesis is unclear. We hypothesized that hematopoietic regeneration following injury is regulated by BM ECs. BALB/c mice were treated with total body irradiation (TBI) and then infused with C57Bl6-derived endothelial progenitor cells (EPCs) to augment endogenous BM EC activity. TBI caused pronounced disruption of the BM vasculature, BM hypocellularity, ablation of HSCs, and pancytopenia in control mice, whereas irradiated, EPC-treated mice displayed accelerated recovery of BM sinusoidal vessels, BM cellularity, peripheral blood white blood cells (WBCs), neutrophils, and platelets, and a 4.4-fold increase in BM HSCs. Systemic administration of anti–VE-cadherin antibody significantly delayed hematologic recovery in both EPC-treated mice and irradiated, non–EPC-treated mice compared with irradiated controls. These data demonstrate that allogeneic EPC infusions can augment hematopoiesis and suggest a relationship between BM microvascular recovery and hematopoietic reconstitution in vivo.

5-Androstene-3b,17b-Diol Administration of Mice Exposed to Total Body Irradiation Results in Rapid Reconstitution of Immature Bone Marrow Progenitor Cells and Synergizes with Thrombopoietin but Not with Granulocyte-Colony Stimulating Factor.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2327-2327
Author(s):  
Fatima SF Aerts Kaya ◽  
Trudi P Visser ◽  
James M Frincke ◽  
Dwight R. Stickney ◽  
Chris L Reading ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Total Body Irradiation ◽  
Blood Cells ◽  
Fold Increase ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Total Body ◽  
Marrow Cellularity ◽  
Immature Cells ◽  
Stimulating Factor

Abstract 5-AED (5-androstene-3β,17β-diol) is a naturally occurring adrenal cortical steroid, which displays radioprotective effects in both rodents and non-human primates, resulting in accelerated multilineage hematopoiesis and enhanced survival after total body irradiation (TBI), including a 1-log accelerated CD34+ cell reconstitution in bone marrow of non-human primates. Pegylated granulocyte-colony stimulating factor (Peg-G-CSF) is known to stimulate lineage-specific recovery of neutrophils, whereas the effects of thrombopoietin (TPO) are broader and include protection of short-term spleen repopulating immature cells as well as platelet recovery. To gain insight into the mechanism of 5-AED on immature hematopoietic cells, the effects of 5-AED on multilineage hematopoiesis and recovery of specific repopulating stem and progenitor cell subsets after TBI was evaluated in combination with and relative to either Peg-G-CSF or TPO. For direct measurements of the radioprotective effect of 5-AED, BALB/c mice were exposed to a midlethal dose of 6 Gy TBI. Two hours after TBI, mice were injected IM with 40 mg/kg 5-AED or the carrier, with or without 0.225 mg TPO or 10 mg Peg-G-CSF IP. Radioprotective effects of 5-AED on immature repopulating cell subsets were assessed by exposing BALB/c donor mice to 3 fractions of 2 Gy TBI, separated by 24 hours, and treatment with 40 mg/kg/d 5-AED or the carrier IM, or 0.7 mg TPO IP after each fraction or a single injection of 10 mg Peg-G-CSF IP after the first fraction. Twenty four hours after the last fraction, bone marrow of donor mice was examined for immature cell content per femur using the marrow repopulating ability (MRA day 13) assay and the CFU-S day 12 after transplantation in 8 Gy irradiated mice. After 6 Gy TBI, BALB/c mice treated with 5-AED displayed an accelerated multilineage recovery with increased white blood cells (p<0.001), blood platelets (p<0.0001) and red blood cells (p<0.03), as well as increased bone marrow cellularity (p<0.0001) and elevated numbers of bone marrow colony forming cells (p<0.00001) at 14 days post-TBI in comparison to placebo-treated animals. Increasing the 5-AED dose up to 200 mg/kg did not augment this effect. Combined treatment with 5-AED and Peg-G-CSF or TPO treatment did not result in an additive effect in this setting. However, after the fractionated 3x2 Gy, a 5- and 7- fold increase in CFU-S relative to radiation controls was observed in the 5-AED and TPO groups, respectively, and a synergistic 20-fold increase in CFU-S day 12 was observed when 5-AED and TPO were used simultaneously. Consistent with earlier observations, Peg-GCSF alone did not affect CFU-S day 12 and appeared to dampen the effect of 5-AED. MRA, expressed as GM-CFU per femur at 13 days after transplantation, was found to be increased 5- to 6-fold with 1002 colonies (range 0-5785) for 5-AED versus 174 (5-360) for radiation controls. This is in contrast to TPO, which promotes CFU-S reconstitution at the expense of the more immature MRA (Neelis et al. 1998: Blood92, 1586). Thus, 5-AED as a single agent stimulates multilineage hematopoiesis and increases bone marrow cellularity following TBI. This effect is mediated by increased survival and/or reconstitution of immature repopulating cells in a pattern distinct from that of TPO. Consistently, 5-AED strongly synergizes with TPO at the level of immature cells from which reconstitution originates, thus revealing a novel mechanism of bone marrow protection in cytoreductive therapy.

The CXCR4 Inhibitor Plerixafor Effectively Mobilizes Primary AML in NODscid IL2Rγc−/− Xenografts and Markedly Reduces but Does Not Eradicate Leukemia in Combination with Cytarabine +/− Clofarabine Chemotherapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1432-1432
Author(s):  
Sylvia Chien ◽  
Xin Zhao ◽  
Thalia Papayannopoulou ◽  
Frederick R. Appelbaum ◽  
Pamela S. Becker
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Fold Increase ◽  
White Blood Count ◽  
Saline Control ◽  
Immunodeficient Mice ◽  
Human Cd34 ◽  
Cd34 Cells ◽  
Significant Difference ◽  
Total Body

Abstract Abstract 1432 Background: The origin of relapse in AML is believed to be related to persistence of resistant “leukemia stem cells.” in the bone marrow microenvironment where adhesion confers drug resistance. Engraftment of human AML in immunodeficient mice is dependent on CXCR4 (Tavor et al 2004). CXCR4 inhibitors, such as AMD3100 (plexiglass,hereafter P), overcome adhesion mediated chemotherapy resistance (Zeng et al 2006) and mobilize human leukemia engrafted in immunodeficient mice (Zeng et al 2009). P also mobilized leukemia in an APL murine model and in combination with chemotherapy reduced tumor burden (Nervi et al 2009). Methods: We studied the combination of P 5mg/kg daily sc X 3, cytarabine (araC=A) 300mg/kg IP X 3 and clofarabine (C), 20mg/kg IP X 3 in the NODscid IL2R γc−/− mouse engrafted with primary patient AML CD34+ cells after 350 cGy total body irradiation. We could first detect circulating human CD45+ or human CD34+ cells, denoting engraftment, by flow cytometry as early as 5–13 weeks. We then injected plerixafor to assess mobilization capability at 8–16 weeks, followed by the combination of plerixafor and chemotherapy. Animals were sacrificed by 14–38 days after chemotherapy, and assessed for AML in blood, marrow, and spleen. Results: A single 5mg/kg dose of P, produced a 2.26 ± 0.94 (SD) fold increase in peak mobilization (at 2 hours) compared to saline control, p=0.026. P-induced mobilization was directly related to expression of CXCR4, with a patient exhibiting 10.3% CXCR4 showing 0.86× baseline, as compared to a patient with 24.7% CXCR4 exhibiting a 2.2-fold increase, and 84.9% CXCR4, a 3-fold increase. Chemotherapy,described above, was given 2 hours after plerixafor. For animals that received P/A vs. P/A/C, there was no statistically significant difference in leukemic burden (in millions of human CD34+ AML cells ± SD) of the animals sacrificed 14 days after initiation of treatment: bone marrow six bones 116.3 ± 33.7 vs. 111.7 ± 29.2 (p=0.86), spleen 50.8 ± 10 vs. 43.7 ± 19.1 (p=0.59), blood 10.9 ± 9.6 vs. 3.1 ± 1.4 (p=0.16), or estimated total body burden 178.0 ± 45.3 vs. 158.5 ± 30 (p=0.52). A comparison of 4 groups of animals, P/A/C vs. P/A vs. A/C vs. A demonstrated a statistically significant difference between certain groups, at certain time points. For example, on day 10, P/A/C treated animals had a lower human PB CD34+ count than P/A, 0.07 vs. 0.24 × 109/L (p=0.034). On day 14, P/A/C had a lower CD34+ count than A/C, 0.08 vs. 0.16 (p=0.047). But at day 38, the leukemia had already recurred, and there was no statistically significant difference in the organ or total body involvement by the leukemia. There was a very low white blood count days 5–24 post chemotherapy, with only minimal residual disease detectable by flow cytometry (analogous to a period of remission in humans), but by day 38, the leukemia had recurred (Figure 1), and there was no statistically significant difference in the organ or total body involvement by the leukemia amongst the groups (Figure 2). Conclusion: This model demonstrates the efficacy of chemotherapy in reducing circulating leukemia, but resistant cells appear to remain sheltered and give rise to relapse. Despite the beneficial effects of CXCR4 inhibitors in vitro and in vivo in a murine APL model, the combination of plerixafor with chemotherapy did not prevent or postpone leukemic relapse. These results could be attributed to either inefficient scheduling of plerixafor (for example, continuous infusion may have worked better), or non-cycling cells may be preferentially mobilized (Bonig H et al., 2009), and thus less susceptible to cytarabine treatment. These concepts are currently being explored. Alternatively, concomitant inhibition of other adhesion receptors may be necessary to prevent leukemia from homing back to the marrow. Precise timing and degree of mobilization in combination with chemotherapy may be required to optimize this approach in the clinic. Disclosures: Becker: Sanofi-Oncology (Genzyme): Research Funding.

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