scholarly journals Production of granulocyte colony-stimulating factor in vitro by monocytes from preterm and term neonates [see comments]

Blood ◽  
1993 ◽  
Vol 82 (8) ◽  
pp. 2478-2484 ◽  
Author(s):  
KR Schibler ◽  
KW Liechty ◽  
WL White ◽  
RD Christensen
Keyword(s):  
Newborn Infants ◽  
Preterm Neonates ◽  
Granulocyte Colony Stimulating Factor ◽  
Serum Concentrations ◽  
Colony Stimulating Factor ◽  
Term Infants ◽  
Term Neonates ◽  
And Function ◽  
Stimulating Factor

Abstract We postulated that defective generation of granulocyte colony- stimulating factor (G-CSF) by cells of newborn infants might underlie their deficiencies in upregulating neutrophil production and function during bacterial infection. To test this, we isolated monocytes from the blood of preterm neonates, term neonates, and adults and, after stimulation with various concentrations of interleukin-1 alpha (IL-1 alpha) or lipopolysaccharide (LPS), quantified G-CSF concentrations in cell supernatants and G-CSF mRNA in cell lysates. When stimulated with plateau concentrations of IL-1 alpha for 24 hours, G-CSF concentrations were higher in supernatants of adult cells (8,699 +/- 5,529 pg/10(6) monocytes) than in those from term infants (2,557 +/- 442 pg, P < .05) or from preterm infants (879 +/- 348 pg, P < .05 v adults). When stimulated with plateau concentrations of LPS, supernatants of monocytes from preterm neonates had less G-CSF than did those from term neonates or adults. G-CSF mRNA content was low in cells from preterm infants, higher in those from term infants, and highest in those from adults. On the basis of the in vitro studies, we speculated that serum G-CSF concentrations might be less elevated in neutropenic neonates than in neutropenic adults. Indeed, serum concentrations were relatively low in all nonneutropenic subjects; 92 +/- 34 pg/mL (mean +/- SEM) in 10 preterm neonates, 114 +/- 21 pg/mL in 16 term neonates, and 45 +/- 13 pg/mL in 11 healthy adults. Serum concentrations were not elevated in 7 neutropenic neonates (39 +/- 17 pg/mL) but were in 8 neutropenic adults (2101 +/- 942 pg/mL, P < .05 v healthy adults). Other studies suggested that the lower G-CSF production in neonates is not counterbalanced by a heightened sensitivity of G-CSF--responsive progenitors to G-CSF. Therefore, we speculate that newborn infants, particularly those delivered prematurely, generate comparatively low quantities of G-CSF after inflammatory stimulation, and that this might constitute part of the explanation for their defective upregulation of neutrophil production and function during infection.

Production of granulocyte colony-stimulating factor in vitro by monocytes from preterm and term neonates [see comments]

Blood ◽  
1993 ◽  
Vol 82 (8) ◽  
pp. 2478-2484 ◽  
Author(s):  
KR Schibler ◽  
KW Liechty ◽  
WL White ◽  
RD Christensen
Keyword(s):  
Newborn Infants ◽  
Preterm Neonates ◽  
Granulocyte Colony Stimulating Factor ◽  
Serum Concentrations ◽  
Colony Stimulating Factor ◽  
Term Infants ◽  
Term Neonates ◽  
And Function ◽  
Stimulating Factor

We postulated that defective generation of granulocyte colony- stimulating factor (G-CSF) by cells of newborn infants might underlie their deficiencies in upregulating neutrophil production and function during bacterial infection. To test this, we isolated monocytes from the blood of preterm neonates, term neonates, and adults and, after stimulation with various concentrations of interleukin-1 alpha (IL-1 alpha) or lipopolysaccharide (LPS), quantified G-CSF concentrations in cell supernatants and G-CSF mRNA in cell lysates. When stimulated with plateau concentrations of IL-1 alpha for 24 hours, G-CSF concentrations were higher in supernatants of adult cells (8,699 +/- 5,529 pg/10(6) monocytes) than in those from term infants (2,557 +/- 442 pg, P < .05) or from preterm infants (879 +/- 348 pg, P < .05 v adults). When stimulated with plateau concentrations of LPS, supernatants of monocytes from preterm neonates had less G-CSF than did those from term neonates or adults. G-CSF mRNA content was low in cells from preterm infants, higher in those from term infants, and highest in those from adults. On the basis of the in vitro studies, we speculated that serum G-CSF concentrations might be less elevated in neutropenic neonates than in neutropenic adults. Indeed, serum concentrations were relatively low in all nonneutropenic subjects; 92 +/- 34 pg/mL (mean +/- SEM) in 10 preterm neonates, 114 +/- 21 pg/mL in 16 term neonates, and 45 +/- 13 pg/mL in 11 healthy adults. Serum concentrations were not elevated in 7 neutropenic neonates (39 +/- 17 pg/mL) but were in 8 neutropenic adults (2101 +/- 942 pg/mL, P < .05 v healthy adults). Other studies suggested that the lower G-CSF production in neonates is not counterbalanced by a heightened sensitivity of G-CSF--responsive progenitors to G-CSF. Therefore, we speculate that newborn infants, particularly those delivered prematurely, generate comparatively low quantities of G-CSF after inflammatory stimulation, and that this might constitute part of the explanation for their defective upregulation of neutrophil production and function during infection.

scholarly journals Serum concentrations of granulocyte colony-stimulating factor in healthy term and preterm neonates and in those with various diseases including bacterial infections

Blood ◽  
1993 ◽  
Vol 82 (10) ◽  
pp. 3177-3182 ◽  
Author(s):  
P Gessler ◽  
N Kirchmann ◽  
R Kientsch-Engel ◽  
N Haas ◽  
P Lasch ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Assay Method ◽  
Preterm Neonates ◽  
Enzyme Linked Immunosorbent Assay ◽  
Granulocyte Colony Stimulating Factor ◽  
Serum Concentrations ◽  
Colony Stimulating Factor ◽  
Csf Levels ◽  
Stimulating Factor

Abstract The neonate is uniquely susceptible to severe and overwhelming bacterial infections. One of the most important deficits in the neonatal host defense system seems to be a quantitative and qualitative deficiency of the myeloid and the phagocytic system. Future optimal therapy of neonatal sepsis may include the use of adjuvant immunologic therapy. Granulocyte colony-stimulating factor (G-CSF) has been shown to induce neutrophilia and to enhance mature effector neutrophil function. To evaluate the role of G-CSF with respect to infection, we examined serum levels of G-CSF in term and preterm neonates, using an enzyme-linked immunosorbent assay method. G-CSF levels in healthy neonates showed peak levels up to 7 hours after birth, followed by an increase in total neutrophil cell (TNC) counts. Both G-CSF levels determined between 4 and 7 hours after birth and peak TNC counts correlated with the gestational age of the neonates. The state of nutrition, maternal treatment with glucocorticoids, maternal infection and hypertension, and the mode of delivery influenced peak G-CSF levels. Neonates with signs of infection between 4 and 7 hours after birth had higher levels of G-CSF than did healthy neonates (1,312 +/- 396 pg/mL v 176 +/- 19 pg/mL). In conclusion, the presented results of serum concentrations of G-CSF in relation to TNC counts and various diseases suggests an important role of G-CSF in the regulation of granulopoiesis during the neonatal period.

scholarly journals Serum concentrations of granulocyte colony-stimulating factor in healthy term and preterm neonates and in those with various diseases including bacterial infections

Blood ◽  
1993 ◽  
Vol 82 (10) ◽  
pp. 3177-3182
Author(s):  
P Gessler ◽  
N Kirchmann ◽  
R Kientsch-Engel ◽  
N Haas ◽  
P Lasch ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Assay Method ◽  
Preterm Neonates ◽  
Enzyme Linked Immunosorbent Assay ◽  
Granulocyte Colony Stimulating Factor ◽  
Serum Concentrations ◽  
Colony Stimulating Factor ◽  
Csf Levels ◽  
Stimulating Factor

The neonate is uniquely susceptible to severe and overwhelming bacterial infections. One of the most important deficits in the neonatal host defense system seems to be a quantitative and qualitative deficiency of the myeloid and the phagocytic system. Future optimal therapy of neonatal sepsis may include the use of adjuvant immunologic therapy. Granulocyte colony-stimulating factor (G-CSF) has been shown to induce neutrophilia and to enhance mature effector neutrophil function. To evaluate the role of G-CSF with respect to infection, we examined serum levels of G-CSF in term and preterm neonates, using an enzyme-linked immunosorbent assay method. G-CSF levels in healthy neonates showed peak levels up to 7 hours after birth, followed by an increase in total neutrophil cell (TNC) counts. Both G-CSF levels determined between 4 and 7 hours after birth and peak TNC counts correlated with the gestational age of the neonates. The state of nutrition, maternal treatment with glucocorticoids, maternal infection and hypertension, and the mode of delivery influenced peak G-CSF levels. Neonates with signs of infection between 4 and 7 hours after birth had higher levels of G-CSF than did healthy neonates (1,312 +/- 396 pg/mL v 176 +/- 19 pg/mL). In conclusion, the presented results of serum concentrations of G-CSF in relation to TNC counts and various diseases suggests an important role of G-CSF in the regulation of granulopoiesis during the neonatal period.

scholarly journals Prevention of Thrombocytopenia and Neutropenia in a Nonhuman Primate Model of Marrow Suppressive Chemotherapy by Combining Pegylated Recombinant Human Megakaryocyte Growth and Development Factor and Recombinant Human Granulocyte Colony-Stimulating Factor

Blood ◽  
1997 ◽  
Vol 89 (1) ◽  
pp. 155-165 ◽  
Author(s):  
Laurence A. Harker ◽  
Ulla M. Marzec ◽  
Andrew B. Kelly ◽  
Ellen Cheung ◽  
Aaron Tomer ◽  
...  
Keyword(s):  
Platelet Count ◽  
Neutrophil Count ◽  
Growth And Development ◽  
Granulocyte Colony Stimulating Factor ◽  
Serum Concentrations ◽  
Colony Stimulating Factor ◽  
Platelet Counts ◽  
Development Factor ◽  
Trough Serum ◽  
Stimulating Factor

Abstract This report examines the effects on hematopoietic regeneration of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF ) (2.5 μg/kg/d) alone and in combination with recombinant human granulocyte colony stimulating factor (rHu-GCSF ) (10 μg/kg/d) for 21 days in rhesus macaques receiving intense marrow suppression produced by single bolus injections of hepsulfam (1.5 g/m2). In six hepsulfam-only control animals thrombocytopenia (platelet count <100 × 109/L) was observed between days 12 and 25 (nadir 39 ± 20 × 109/L on day 17), and neutropenia (absolute neutrophil count <1 × 109/L) occurred between days 8 and 30 (nadir 0.167 ± 0.120 × 109/L on day 15). PEG-rHuMGDF (2.5 μg/kg/d) injected subcutaneously into four animals from day 1 to day 22 following hepsulfam administration produced trough serum concentrations of 1.9 ± 0.2 ng/mL and increased the platelet count twofold over basal prechemotherapy levels (856 ± 594 × 109/L v baseline of 416 ± 88 × 109/L; P = .01). PEG-rHuMGDF alone also shortened the period of posthepsulfam neutropenia from 22 days to 12 days (P = .01), although the neutropenic nadir was not significantly altered (neutrophil count 0.224 ± 0.112 × 109/L v 0.167 ± 0.120 × 109/L; P < .3). rHu-GCSF (10 μg/kg/d) injected subcutaneously into four animals from day 1 to day 22 following hepsulfam administration produced trough serum concentrations of 1.4 ± 1.1 ng/mL, and reduced the time for the postchemotherapy neutrophil count to attain 1 × 109/L from 22 days to 4 days (P = .005). The postchemotherapy neutropenic nadir was 0.554 ± 0.490 × 109neutrophils/L (P = .3 v hepsulfam-only control of 0.167 ± 0.120 × 109/L). However, thrombocytopenia of <100 × 109 platelets/L was not shortened (persisted from day 12 to day 25), or less severe (nadir of 56 ± 32 × 109 platelets/L on day 14; P = .7 compared with untreated hepsulfam animals). The concurrent administration of rHu-GCSF (10 μg/kg/d) and PEG-rHuMGDF (2.5 μg/kg/d) in four animals resulted in postchemotherapy peripheral platelet counts of 127 ± 85 × 109/L (P = .03 compared with 39 ± 20 × 109/L for untreated hepsulfam alone, and P = .02 compared with 856 ± 594 × 109/L for PEG-rHuMGDF alone), and shortened the period of neutropenia <1 × 109/L from 22 days to 4 days (P = .8 compared with rHu-GCSF alone). Increasing PEG-rHuMGDF to 10 μg/kg/d and maintaining the 21-day schedule of coadministration with rHu-GCSF (10 μg/kg/d) in another four animals produced postchemotherapy platelet counts of 509 ± 459 × 109/L (P < 10−4compared with untreated hepsulfam alone, and P = .04 compared with 2.5 μg/kg/d PEG-rHuMGDF alone), and 4 days of neutropenia. Coadministration of rHu-GCSF and PEG-rHuMGDF did not significantly alter the pharmacokinetics of either agent. The administration of PEG-rHuMGDF (2.5 μg/kg/d) from day 1 through day 22 and rHu-GCSF (10 μg/kg/d) from day 8 through day 22 in six animals produced peak postchemotherapy platelet counts of 747 ± 317 × 109/L (P < 10−4 compared with untreated hepsulfam alone, and P = .7 compared with PEG-rHuMGDF alone), and maintained the neutrophil count < 3.5 × 109/L (P = .008 v rHu-GCSF therapy alone). Thus, both thrombocytopenia and neutropenia are eliminated by initiating daily PEG-rHuMGDF therapy on day 1 and subsequently adding daily rHu-GCSF after 1 week in the rhesus model of hepsulfam marrow suppression. This improvement in platelet and neutrophil responses by delaying the addition of rHu-GCSF to PEG-rHuMGDF therapy demonstrates the importance of optimizing the dose and schedule of cytokine combinations after severe myelosuppressive chemotherapy.

scholarly journals G-CSF receptor activation of the Src kinase Lyn is mediated by Gab2 recruitment of the Shp2 phosphatase

Blood ◽  
2011 ◽  
Vol 118 (4) ◽  
pp. 1077-1086 ◽  
Author(s):  
Muneyoshi Futami ◽  
Quan-sheng Zhu ◽  
Zakary L. Whichard ◽  
Ling Xia ◽  
Yuehai Ke ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Src Kinase ◽  
Receptor Activation ◽  
Phosphorylation Sites ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Stimulating Factor ◽  
In Cells

Abstract Src activation involves the coordinated regulation of positive and negative tyrosine phosphorylation sites. The mechanism whereby receptor tyrosine kinases, cytokine receptors, and integrins activate Src is not known. Here, we demonstrate that granulocyte colony-stimulating factor (G-CSF) activates Lyn, the predominant Src kinase in myeloid cells, through Gab2-mediated recruitment of Shp2. After G-CSF stimulation, Lyn dynamically associates with Gab2 in a spatiotemporal manner. The dephosphorylation of phospho-Lyn Tyr507 was abrogated in Shp2-deficient cells transfected with the G-CSF receptor but intact in cells expressing phosphatase-defective Shp2. Auto-phosphorylation of Lyn Tyr396 was impaired in cells treated with Gab2 siRNA. The constitutively activated Shp2E76A directed the dephosphorylation of phospho-Lyn Tyr507 in vitro. Tyr507 did not undergo dephosphorylation in G-CSF–stimulated cells expressing a mutant Gab2 unable to bind Shp2. We propose that Gab2 forms a complex with Lyn and after G-CSF stimulation, Gab2 recruits Shp2, which dephosphorylates phospho-Lyn Tyr507, leading to Lyn activation.

Granulocyte-colony stimulating factor promotes invasion by human lung cancer cell lines in vitro

1996 ◽  
Vol 14 (4) ◽  
pp. 351-357 ◽  
Author(s):  
Xin-Hai Pei ◽  
Yoichi Nakanishi ◽  
Koichi Takayama ◽  
Jun Yatsunami ◽  
Feng Bai ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Lung ◽  
Human Lung Cancer ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Lung Cancer Cell ◽  
Stimulating Factor

scholarly journals Granulocyte colony-stimulating factor protects cardiac mitochondria in the early phase of cardiac injury

2009 ◽  
Vol 296 (3) ◽  
pp. H823-H832 ◽  
Author(s):  
Yoshimi Hiraumi ◽  
Eri Iwai-Kanai ◽  
Shiro Baba ◽  
Yoshihiro Yui ◽  
Yuri Kamitsuji ◽  
...  
Keyword(s):  
Diastolic Function ◽  
Early Phase ◽  
Cardiac Injury ◽  
Left Ventricular ◽  
Cardiac Mitochondria ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Stimulating Factor ◽  
Cellular Fate

Although granulocyte colony-stimulating factor (G-CSF) reportedly plays a cardioprotective role in several models of cardiac injury, clinical use of this drug in cardiac patients has been controversial. Here, we tested, in vivo and in vitro, the effect of G-CSF on cardiac mitochondria, which play a key role in determining cardiac cellular fate and function. Mild stimulation of C57/BL6 mice with doxorubicin (Dox) did not induce cardiac apoptosis or fibrosis but did induce damage to mitochondrial organization of the myocardium as observed through an electron microscope. Cardiac catheterization and echocardiography revealed that Dox did not alter cardiac systolic function or left ventricular size but did reduce diastolic function, an early sign of cardiac damage. Treatment with G-CSF attenuated significantly the damage to mitochondrial organization and rescued diastolic function. In an in vitro model for rat neonatal cardiomyocytes, a subapoptotic dose of Dox induced severe mitochondrial damage, including marked swelling of the cardiac mitochondria and/or decreased mitochondrial membrane potential. These mitochondrial changes were completely blocked by pretreatment with G-CSF. In addition, G-CSF dramatically improved ATP generation, which rescued Dox-impaired mitochondrial electron transport and oxygen consumption mainly through complex IV. These findings clearly indicate that G-CSF protects cardiac mitochondria, which are key organelles in the determination of cardiac cellular fate, in the early phase of cardiac injury.

Sign in / Sign up

Export Citation Format

Share Document