Effects Of Granulocyte Colony-stimulating Factor Treatment Research Articles

Development and content validation of the Satisfaction and Experience Questionnaire for Granulocyte Colony-Stimulating Factor (SEQ-G-CSF)

BackgroundSeveral options for granulocyte colony-stimulating factor (G-CSF) prophylaxis of chemotherapy-induced febrile neutropenia are available to patients worldwide. We have developed a novel patient-reported outcome measure, the Satisfaction and Experience Questionnaire for G-CSF (SEQ-G-CSF), to help understand patients’ perspectives of and satisfaction with different G-CSF options.ResultsThree oncology nurses and 40 adult oncology patients in the United States were enrolled and participated in focus group discussions to develop and refine the SEQ-G-CSF. Nurses had ≥ 5 years of experience treating oncology patients and were currently involved in the management of oncology patients receiving G-CSF prophylaxis. The patients had breast cancer, lung cancer, non-Hodgkin lymphoma, or prostate cancer (10 patients in each group) and were receiving G-CSF prophylaxis via injection or the on-body injector (OBI) device. The preliminary SEQ-G-CSF contained an item relevance questionnaire and three SEQ modules (sociodemographic, medical history, and G-CSF–related healthcare characteristics questionnaires). Twenty-one patients (53% of total sample size) discussed their experience and satisfaction with G-CSF. Their most common experiences were G-CSF effectiveness, convenience and benefits of the OBI, and relationships with healthcare providers. Side effects and having to undergo additional treatment were also reported. Satisfaction with aspects of G-CSF included the OBI and effectiveness of G-CSF treatment; dissatisfaction included inconvenience (having to return to the clinic the next day and administration of the injection) and the insurance approval process. The SEQ-G-CSF was finalized after three rounds of cognitive interviews and includes five domains related to general satisfaction (one item), treatment burden (four items), travel burden (two items), time burden (four items), and treatment compliance (two items).ConclusionsThe SEQ-G-CSF is a novel instrument that quantifies a patient’s experience and satisfaction with different G-CSF options using 13 easy-to-understand items. This study provides evidence for the content validity of SEQ-G-CSF. Although further psychometric testing is required, the SEQ-G-CSF may be a useful addition to clinical trials, observational studies, and clinical practice.

G-CSF attenuates neuroinflammation and neuronal apoptosis via the mTOR/p70SK6 signaling pathway in neonatal Hypoxia-Ischemia rat model

BackgroundHypoxic-ischemic encephalopathy (HIE) is an important cause of permanent damage to the central nervous system, associated with long-lasting neurological disabilities and neurodevelopmental impairment in neonates. Granulocyte-colony stimulating factor (G-CSF) has been shown to have neuroprotective activity in a variety of experimental brain injury models and G-CSF is a standard treatment in chemotherapeutic-induced neutropenia. The underlying mechanisms are still unclear. The mTOR (mammalian target of rapamycin) signaling pathway is a master regulator of cell growth and proliferation in the nervous system. However, the effects of G-CSF treatment on the mTOR signaling pathway have not been elucidated in neonates with hypoxic-ischemic (HI) brain injury. Our study investigated the neuroprotective effect of G-CSF on neonates with hypoxic-ischemic (HI) brain injury and the possible mechanism involving the mTOR/p70S6K pathway. MethodsSprague-Dawley rat pups at postnatal day 7 (P7) were subjected to right unilateral carotid artery ligation followed by hypoxic (8% oxygen and balanced nitrogen) exposure for 2.5 h or sham surgery. Pups received normal saline, G-CSF, G-CSF combined with rapamycin or ethanol (vehicle for rapamycin) intraperitoneally. On postnatal day 9 (P9), TTC staining for infarct volume, and Nissl and TUNEL staining for neuronal cell injury were conducted. Activation of mTOR/p70S6K pathway, cleaved caspase-3 (CC3), Bax and Bcl-2 and cytokine expression levels were determined by western blotting. ResultsThe G-CSF treated group was associated with significantly reduced infarction volume and decreased TUNEL positive neuronal cells compared to the HI group treated with saline. The expression levels of TNF-α and IL-1ß were significantly decreased in the G-CSF treated group, while IL-10 expression level was increased. The relative immunoreactivity of p-mTOR and p-p70S6K was significantly reduced in the HI group compared to sham. The HI group treated with G-CSF showed significant upregulated protein expression for p-mTOR and p-p70S6K levels compared to the HI group treated with saline. Furthermore, G-CSF treatment increased Bcl-2 expression levels and decreased CC3 and Bax expression levels in the ipsilateral hemispheres of the HI brain. The effects induced by G-CSF were all reversed by rapamycin. ConclusionTreatment with G-CSF decreases inflammatory mediators and apoptotic factors, attenuating neuroinflammation and neuronal apoptosis via the mTOR/p70S6K signalling pathway, which represents a potential target for treating HI induced brain damage in neonatal HIE.

Very Small Embryonic-Like Stem Cells, Endothelial Progenitor Cells, and Different Monocyte Subsets Are Effectively Mobilized in Acute Lymphoblastic Leukemia Patients after G-CSF Treatment.

Background Acute lymphoblastic leukemia (ALL) is a malignant disease of lymphoid progenitor cells. ALL chemotherapy is associated with numerous side effects including neutropenia that is routinely prevented by the administration of growth factors such as granulocyte colony-stimulating factor (G-CSF). To date, the effects of G-CSF treatment on the level of mobilization of different stem and progenitor cells in ALL patients subjected to clinically effective chemotherapy have not been fully elucidated. Therefore, in this study we aimed to assess the effect of administration of G-CSF to ALL patients on mobilization of other than hematopoietic stem cell (HSCs) subsets, namely, very small embryonic-like stem cells (VSELs), endothelial progenitor cells (EPCs), and different monocyte subsets. Methods We used multicolor flow cytometry to quantitate numbers of CD34+ cells, hematopoietic stem cells (HSCs), VSELs, EPCs, and different monocyte subsets in the peripheral blood of ALL patients and normal age-matched blood donors. Results We showed that ALL patients following chemotherapy, when compared to healthy donors, presented with significantly lower numbers of CD34+ cells, HSCs, VSELs, and CD14+ monocytes, but not EPCs. Moreover, we found that G-CSF administration induced effective mobilization of all the abovementioned progenitor and stem cell subsets with high regenerative and proangiogenic potential. Conclusion These findings contribute to better understanding the beneficial clinical effect of G-CSF administration in ALL patients following successful chemotherapy.

Effects of filgrastim on gene expression of cholinergic system in the rat hippocampus

Background: Filgrastim is a granulocyte colony-stimulating factor (G-CSF), which also showed effects on memory and cognation. Although recent studies have begun to explore G-CSF-related mechanisms of action in memory, little is known about its effects on cholinergic system. Since the cholinergic system has a key role in memory and some studies reported effects of G-CSF on cholinergic activity. Choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) gene expression was examined in the rat frontal cortex and hippocampus. Aims and Objectives: This study was designed to investigate the effect of G-CSF treatment on gene expression of AChE and ChAT in the frontal cortex and hippocampus during learning. Materials and Methods: In this study, male Wistar rats were treated for 2 week with filgrastim intraperitoneally at doses of 10, 50, 70 μg/kg/day. All rats received Morris water maze training (4 trials/day for 5 days). Moreover, ChAT and AChE gene expression was assessed by real-time polymerase chain reaction in the rat frontal cortex and hippocampus. Results: Over 5 days of training, filgrastim at doses 10, 50 and 70 μg/kg/day did not change the gene expression of ChAT and AChE in frontal cortex and hippocampus although at dose of 50 ug/kg a little changes but not significant observed. Conclusions: The findings observed in this study propose that G-CSF memory enhancer effects doesn’t only cholinergic and other mechanism may be involve.

Adjuvant granulocyte colony-stimulating factor therapy results in improved spatial learning and stimulates hippocampal neurogenesis in a mouse model of pneumococcal meningitis.

Despite the development of new antibiotic agents, mortality of pneumococcal meningitis remains high. In addition, meningitis results in severe long-term morbidity, most prominently cognitive deficits. Granulocyte colony-stimulating factor (G-CSF) stimulates proliferation and differentiation of hematopoietic progenitor cells and increases the number of circulating neutrophil granulocytes. This study investigated the effect of adjuvant G-CSF treatment on cognitive function after pneumococcal meningitis. C57BL/6 mice were infected by subarachnoid injection of Streptococcus pneumoniae serotype 3 and treated with ceftriaxone and G-CSF subcutaneously or ceftriaxone alone for 5 days. Clinical scores, motor performance, and mortality during bacterial meningitis were unaffected by adjuvant G-CSF treatment. No effect of G-CSF treatment on production of proinflammatory cytokines or activation of microglia or astrocytes was observed. The G-CSF treatment did, however, result in hippocampal neurogenesis and improved spatial learning performance 6 weeks after meningitis. These results suggest that G-CSF might offer a new adjuvant therapeutic approach in bacterial meningitis to reduce long-term cognitive deficits.

G-CSF displays restricted ability to promote Sca-1(+) cardiac stem cell proliferation in vitro.

Granulocyte colony-stimulating factor (G-CSF) is a controversial chemical in cardiac cell therapy. Myocardial homing of mobilized bone marrow-derived cells is thought to play a critical role in observed G-CSF-induced cardiac repair; meanwhile, the activation of proliferative potential of cardiac stem cells (CSCs) residing in the heart is a significant challenge. The present study aims to investigate whether G-CSF receptor is expressed in adult resident Sca-1(+) CSCs and determine the effect of G-CSF treatment on the proliferation of CSCs. For cardiac cells isolation, 12-week-old male C57BL/6 mice were anesthetized in a chamber containing 2.5% isoflurane in oxygen, euthanized by CO2 inhalation and then sacrificed by cervical dislocation. Magnetic-activated cell sorting was employed to acquire highly purified Sca-1(+) CSCs. We found that G-CSF receptor was expressed in adult resident Sca-1(+) CSCs by immunofluorescence staining and Western blotting. Exposure of Sca-1(+) cells to G-CSF in the culture medium for 72 h induced time-dependent but self-limiting cell cycle acceleration with a restricted effect on the CSC proliferation. As a result, it has provided a new insight to focus on the association between cardiac G-CSF therapy and adult resident stem cell activation. It may suggest gaining a deeper insight into the mechanisms of the interaction between CSCs and G-CSF to develop a synergistic strategy based on resident stem cell and G-CSF therapy for heart disease.

Anti-obesity effects of granulocyte-colony stimulating factor in Otsuka-Long-Evans-Tokushima fatty rats.

Granulocyte-colony stimulating factor (G-CSF) has molecular structures and intracellular signaling pathways that are similar to those of leptin and ciliary neurotropic factor (CNTF). It also has immune-modulatory properties. Given that leptin and CNTF play important roles in energy homeostasis and that obesity is an inflammatory condition in adipose tissue, we hypothesized that G-CSF could also play a role in energy homeostasis. We treated 12 38-week-old male Otsuka-Long-Evans-Tokushima fatty rats (OLETF, diabetic) and 12 age-matched male Long-Evans-Tokushima rats (LETO, healthy) with 200 µg/day G-CSF or saline for 5 consecutive days. Body weight reduction was greater in G-CSF-treated OLETF (G-CSF/OLETF) than saline-treated OLETF (saline/OLETF) following 8 weeks of treatment (−6.9±1.6% vs. −3.1±2.2%, p<0.05). G-CSF treatment had no effect on body weight in LETO or on food intake in either OLETF or LETO. Body fat in G-CSF/OLETF was more reduced than in saline/OLETF (−32.2±3.1% vs. −20.8±6.2%, p<0.05). Energy expenditure was higher in G-CSF/OLETF from 4 weeks after the treatments than in saline/OLETF. Serum levels of cholesterol, triglyceride, interleukin-6 and tumor necrosis factor-α were lower in G-CSF/OLETF than in saline/OLETF. Uncoupling protein-1 (UCP-1) expression in brown adipose tissue (BAT) was higher in G-CSF/OLETF than in saline/OLETF, but was unaffected in LETO. Immunofluorescence staining and PCR results revealed that G-CSF receptors were expressed in BAT. In vitro experiments using brown adipocyte primary culture revealed that G-CSF enhanced UCP-1 expression from mature brown adipocytes via p38 mitogen-activated protein kinase pathway. In conclusion, G-CSF treatment reduced body weight and increased energy expenditure in a diabetic model, and enhanced UCP-1 expression and decreased inflammatory cytokine levels may be associated with the effects of G-CSF treatment.

Granulocyte colony-stimulating factor receptor signalling via Janus kinase 2/signal transducer and activator of transcription 3 in ovarian cancer

Background:Ovarian cancer remains a major cause of cancer mortality in women, with only limited understanding of disease aetiology at the molecular level. Granulocyte colony-stimulating factor (G-CSF) is a key regulator of both normal and emergency haematopoiesis, and is used clinically to aid haematopoietic recovery following ablative therapies for a variety of solid tumours including ovarian cancer.Methods:The expression of G-CSF and its receptor, G-CSFR, was examined in primary ovarian cancer samples and a panel of ovarian cancer cell lines, and the effects of G-CSF treatment on proliferation, migration and survival were determined.Results:G-CSFR was predominantly expressed in high-grade serous ovarian epithelial tumour samples and a subset of ovarian cancer cell lines. Stimulation of G-CSFR-expressing ovarian epithelial cancer cells with G-CSF led to increased migration and survival, including against chemotherapy-induced apoptosis. The effects of G-CSF were mediated by signalling via the downstream JAK2/STAT3 pathway.Conclusion:This study suggests that G-CSF has the potential to impact on ovarian cancer pathogenesis, and that G-CSFR expression status should be considered in determining appropriate therapy.

Mitigating effects of hUCB-MSCs on the hematopoietic syndrome resulting from total body irradiation

This study evaluated the clinical and pathologic effects of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in the recovery from total body irradiation by comparing it with the effects of granulocyte-colony stimulating factor (G-CSF), an efficacious drug in the treatment of acute bone marrow radiation syndrome. BALB/c mice were treated with G-CSF or hUCB-MSCs after they were irradiated with 7 Gy cobalt-60 γ-rays. Circulating blood counts, histopathologic changes in the bone marrow, and plasma level of Flt-3L and transforming growth factor (TGF-β1) were monitored in the postirradiation period. Hematologic analysis revealed that the peripheral leukocyte counts were markedly increased in the hUCB-MSCs-treated group, whereas G-CSF-treated mice did not recover significantly. Moreover, differential counts showed that hUCB-MSC treatment has regenerative effects on white blood cells, lymphocytes, and monocytes compared with the irradiated group. Treatment with hUCB-MSCs or G-CSF significantly increased immunoreactivity of Ki-67 until 3 weeks after total body irradiation. However, at 3 weeks, the number of Ki-67 immunoreactive cells significantly increased in the hUCB-MSCs-treated group compared with the G-CSF-treated group. Furthermore, hUCB-MSC treatment significantly modulated plasma levels of the hematopoietic cytokines Flt-3L and TGF-β1, whereas G-CSF treatment failed to decrease the plasma Flt-3L levels at 2 weeks after irradiation. Based on the differences in circulating blood cell reconstitution and cell density of bone marrow, the authors suggest that MSC treatment is superior to G-CSF treatment for hematopoietic reconstitution following sublethal dose radiation exposure.

Investigating the Possibility of Intervertebral Disc Regeneration Induced by Granulocyte Colony Stimulating Factor-Stimulated Stem Cells in Rats

Intervertebral disc (IVD) degeneration is a multifactorial process that is influenced by contributions from genetic predisposition, the aging phenomenon, lifestyle conditions, biomechanical loading and activities, and other health factors (such as diabetes). Attempts to decelerate disc degeneration using various techniques have been reported. However, to date, there has been no proven technique effective for broad clinical application. Granulocyte colony-stimulating factor (GCSF) is a growth factor cytokine that has been shown to enhance the availability of circulating hematopoietic stem cells to the brain and heart as well as their capacity for mobilization of mesenchymal bone marrow stem cells. GCSF also exerts significant increases in circulating neutrophils as well as potent anti-inflammatory effects. In our study, we hypothesize that GCSF can induce bone marrow stem cells differentiation and mobilization to regenerate the degenerated IVD. We found that GCSF had no contribution in disc regeneration or maintenance; however, there were cell proliferation within end plates. The effects of GCSF treatment on end plates might deserve further investigation.

Myocardial regeneration induced by granulocyte-colony-stimulating factor mobilization of stem cells in patients with acute or chronic ischaemic heart disease: a non-invasive alternative for clinical stem cell therapy?

Mobilization of stem cells into the peripheral circulation for myocardial regeneration using subcutaneous injections of granulocyte-colony-stimulating factor (G-CSF) has been tested in both patients with acute myocardial infarction (AMI) and patients with chronic myocardial ischaemia. G-CSF treatment seems to be safe and unblinded trials in patients with AMI were encouraging. However, larger double-blind placebo-controlled trials have not been able to demonstrate effect of G-CSF treatment. In patients with chronic myocardial ischaemia, small-unblinded G-CSF trials did not show effect on myocardial perfusion and function. In both patient populations, G-CSF did mobilize stem cells of known importance to myocardial regeneration, but there seemed to be a general lack of homing of the stem cells into the ischaemic myocardium. In AMI, factors of importance to homing of stem cells, stem cell derived factor-1, are maximally elevated in plasma 3 weeks after infarction, suggesting that this time point could be the optimal time for stem cell mobilization treatment. The known complex interaction of stem cells and cytokines for induction of vasculogenesis should be implemented in future clinical trials, to elucidate whether G-CSF mobilization of stem cells might be useful as a new regenerative treatment in patients with ischaemic heart disease.

Effect of Bovine Granulocyte Colony-Stimulating Factor on the Development of Pneumonia Caused by Mannheimia haemolytica

The role of recruited neutrophils in Mannheimia haemolytica infection is controversial. We hypothesized that the neutrophilia induced by recombinant bovine granulocyte colony-stimulating factor (GCSF) would lead to rapid bacterial clearance and less severe lesions after infection with M. haemolytica. Two experiments (A and B) were conducted in which four calves per experiment were treated daily with 5 microg/kg GCSF and four calves per experiment were treated with saline. All 16 calves were challenged with 5 x 10(9) colony-forming units (cfu)/ml (experiment A) or 4.5 x 10(8) cfu/ml (experiment B) of M. haemolytica bacteria, into the right bronchus by bronchoscope-placed catheter. The mean maximal blood neutrophil counts in non-GCSF-treated and GCSF-treated calves before bacterial challenge were 5.6 +/- 0.7 x 10(9)/liter and 25.4 +/- 2.7 x 10(9)/liter, respectively. Two untreated calves became neutropenic and were euthanatized 2 days after infection because of severe respiratory distress. GCSF-treated calves had a 37% reduction in lung lesions compared with nontreated calves, and this difference was significant (P=0.04) when the effect of previous antibody titre to leukotoxin was considered. The effect of GCSF treatment on the severity of clinical signs seemed to be influenced by the antibody titre to M. haemolytica leukotoxin, although this effect could not be conclusively addressed. In conclusion, GCSF induced neutrophilia and partially protected calves against experimental infection with M. haemolytica. These results imply that increased numbers of neutrophils may, under some circumstances, protect against severe pneumonia caused by M. haemolytica.

The Effect of Granulocyte Colony-Stimulating Factor in the Treatment of Escherichia coli Peritonitis With or Without Ceftriaxone in a Nonneutropenic Rat Model

To investigate the effect of granulocyte colony-stimulating factor (G-CSF) in the treatment of Escherichia coli peritonitis with and without ceftriaxone in a nonneutropenic rat model. The rats were divided into five groups: control group (C) receiving physiological saline; peritonitis group (P) infected intraperitoneally with a live bacterial suspension of E. coli; peritonitis and antibiotic group (PA) receiving ceftriaxone 3 h after being infected; peritonitis, antibiotic, and G-CSF group (PAG) receiving G-CSF and antibiotic 3 h after infection; and peritonitis and G-CSF group (PG). All rats in group C survived. Any animals which did not survive died within 24h after inoculation. A significantly higher rate of survival, 95%, was observed with antibiotic treatment alone (PA), in comparison to the G-CSF-treated groups, PAG and PG, 52% and 57%, respectively. No beneficial effect of G-CSF treatment was seen in the E. coli peritonitis and antibiotic therapy remains the basic treatment for this disease.

The Effects of G-CSF Treatment and Starvation on Bacterial Translocation in Hemorrhagic Shock

Background.Bacterial translocation is thought to be responsible for infectious complications after hemorrhagic shock. The aim of this study is to investigate the effects of granulocyte colony-stimulating factor (G-CSF) treatment on bacterial translocation in starved or fed animals subjected to hemorrhagic shock.Materials and Methods.Fifty Wistar albino rats (200–275 g) were divided into six groups such as naive control (n= 7), G-CSF treatment (n= 7), hemorrhagic shock in starved rats (n= 9), hemorrhagic shock in fed rats (n= 9), G-CSF treatment 24 h before hemorrhagic shock in starved rats (n= 9), and G-CSF treatment 20 min after hemorrhagic shock in fed rats (n= 9). Hemorrhagic shock was induced by withdrawal of 2.1 ml/100 g blood via a carotid arterial cannulae placed under sodium pentobarbital anesthesia. Twenty-four hours later, mesenteric lymph nodes, liver, spleen, and peripheral blood samples were evaluated by using a quantitative microbiological technique and the numbers of colony-forming units were compared between groups.Results.No bacteria was detected in samples from naive controls or G-CSF-treated unshocked rats. In animals subjected to hemorrhage,Escherichia coliwas the predominant pathogen together withStreptococcus faecalis, Pseudomonas,andLactobacillusspecies. In this model, starvation augmented the magnitude of bacterial translocation while G-CSF treatment has virtually abolished it.Conclusion.Under experimental conditions, preshock starvation increases gut-derived bacterial translocation and administration of G-CSF before or after hemorrhagic insult significantly reduces it.

Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are clonal disorders of haemopoietic stem cells which are characterised by peripheral cytopenia and, usually, by an increased bone marrow cellularity. Transfusions of red blood cells and platelets comprise the basis of supportive care for anaemia and thrombocytopenia. In patients who progress to acute myeloid leukaemia, cytotoxic chemotherapy is used. In MDS, haemopoietic growth factors can enhance: proliferation and differentiation of normal and myelodysplastic haemopoietic progenitor cells, and prevent premature apoptosisacceleration of haemopoietic recovery after intensive chemotherapy and amelioration of mature cell function; and sensitisation of malignant cells for the cytotoxic action of chemotherapeutic agents. There is widespread clinical experience with the use of epoetin (EPO), granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF). A meta-analysis of 17 trials with EPO showed a stimulation of erythropoiesis, resulting in a discontinuation of the need for transfusions or an increase in haemoglobin levels of at least 15 g/L in 16% of 205 patients. Favourable factors for the response were an initial absence of a need for transfusion and a serum EPO level <200 U/L. In clinical phase I/II studies of GM-CSF administration, a dose-dependent increase in the absolute neutrophil count was seen in >80% of patients, as well as a decrease in the infection rate. The effect on survival could not be assessed. Lower platelet counts, with a risk of bleeding, bone pain, local erythema at the subcutaneous injection site and phlebitis during intravenous infusion, were observed. The combined administration of GM-CSF and EPO to a small number of patients resulted in an increase in haemoglobin levels or a decrease in the need for transfusion, with an overall response rate of 46%, but is not a proven treatment. The use of G-CSF increased the absolute neutrophil count in about 90% of patients with MDS, and was accompanied by an improvement of neutrophil function, which is frequently impaired in these patients. However, contradictory data exist on the influence of prophylactic G-CSF treatment on the infection rate. Bone pain and thrombocytopenia were the most important adverse effects of G-CSF treatment. Synergism of G-CSF and EPO has not yet been proven in randomised phase III trials, although selected patients showing no response to EPO alone may achieve normal haemoglobin levels after receiving additional G-CSF. Treatment in vivo with EPO, GM-CSF or G-CSF has not been shown to change the percentage of bone marrow cells carrying cytogenetic aberrations. However, individual patients have shown a reversal from a monoclonal to a polyclonal pattern with GM-CSF therapy.