Plasma Granulocyte Colony-stimulating Factor Research Articles

Granulocyte colony-stimulating factor expression as a prognostic biomarker in non-small cell lung cancer

Hematologic paraneoplastic alternations may not be very common, but they have been observed in a small number of patients. Granulocytosis has been described in several malignancies and its common mechanism may be associated with granulocyte colony-stimulating factor (G-CSF) production by the tumor. High neutrophilia (150,000-240,000 white blood cell count) observed in two patients with non-small cell lung cancer led us to run the present trial. The purpose of this study was to compare the white blood cell counts and the G-CSF plasma levels of the patients and classify the results into groups, as well as to determine the survival rates of the patients in each of the groups. The histological specimens and plasma of two patients as well as the plasma of another 87 patients with several malignancies, were examined. The plasma G-CSF levels were determined using a quantitative sandwich immunoassay technique (Quantikine; RySD systems) according to the manufacturer's instructions and all samples were tested in triplicate. It was found that 12 patients had a white blood cell count increased beyond normal as well as a high G-CSF plasma level and the survival of these patients was shorter as compared to the rest of the patients. We assume that these findings may indicate that increased G-CSF levels may function as a biomarker of survival.

The role of granulocyte colony-stimulating factor in the neutrophilia observed in the fetal inflammatory response syndrome.

Fetal neutrophilia is present in two-thirds of cases with the fetal inflammatory response syndrome (FIRS). The mechanisms responsible for this finding have not been elucidated. Granulocyte colony-stimulating factor (G-CSF) is the primary physiologic regulator of neutrophil production and plays a key role in the rapid generation and release of neutrophils in stressful conditions (i.e., infection). The objective of this study was to determine: 1) whether FIRS was associated with changes in fetal plasma G-CSF concentrations; and 2) if fetal plasma G-CSF concentrations correlated with fetal neutrophil counts, chorioamnionitis, neonatal morbidity/mortality and cordocentesis-to-delivery interval. Percutaneous umbilical cord blood sampling was performed in a population of patients with preterm labor (n=107). A fetal plasma interleukin-6 (IL-6) concentration >11 pg/mL was used to define FIRS. Cord blood G-CSF was measured by a sensitive and specific immunoassay. An absolute neutrophil count was determined and corrected for gestational age. Receiver operating characteristic (ROC) curve, survival analysis and Cox proportional hazard model were employed. 1) G-CSF was detected in all fetal blood samples; 2) fetuses with FIRS had a higher median fetal plasma G-CSF concentration than those without FIRS (P<0.001); 3) a fetal plasma G-CSF concentration ≥134 pg/mL (derived from an ROC curve) was associated with a shorter cordocentesis-to-delivery interval, a higher frequency of chorioamnionitis (clinical and histological), intra-amniotic infection, and composite neonatal morbidity/mortality than a fetal plasma concentration below this cut-off; and 4) a fetal plasma G-CSF concentration ≥134 pg/mL was associated with a shorter cordocentesis-to-delivery interval (hazard ratio 3.2; 95% confidence interval 1.8-5.8) after adjusting for confounders. 1) G-CSF concentrations are higher in the peripheral blood of fetuses with FIRS than in fetuses without FIRS; and 2) a subset of fetuses with FIRS with elevated fetal plasma G-CSF concentrations are associated with neutrophilia, a shorter procedure-to-delivery interval, chorio-amnionitis and increased perinatal morbidity and mortality.

Contribution of Granulocyte Colony-Stimulating Factor to the Acute Mobilization of Endothelial Precursor Cells by Vascular Disrupting Agents

Vascular disrupting agents (VDA) cause acute shutdown of abnormal established tumor vasculature, followed by massive intratumoral hypoxia and necrosis. However, a viable rim of tumor tissue invariably remains from which tumor regrowth rapidly resumes. We have recently shown that an acute systemic mobilization and homing of bone marrow-derived circulating endothelial precursor (CEP) cells could promote tumor regrowth following treatment with either a VDA or certain chemotherapy drugs. The molecular mediators of this systemic reactive host process are unknown. Here, we show that following treatment of mice with OXi-4503, a second-generation potent prodrug derivative of combretastatin-A4 phosphate, rapid increases in circulating plasma vascular endothelial growth factor, stromal derived factor-1 (SDF-1), and granulocyte colony-stimulating factor (G-CSF) levels are detected. With the aim of determining whether G-CSF is involved in VDA-induced CEP mobilization, mutant G-CSF-R(-/-) mice were treated with OXi-4503. We found that as opposed to wild-type controls, G-CSF-R(-/-) mice failed to mobilize CEPs or show induction of SDF-1 plasma levels. Furthermore, Lewis lung carcinomas grown in such mice treated with OXi-4503 showed greater levels of necrosis compared with tumors treated in wild-type mice. Evidence for rapid elevations in circulating plasma G-CSF, vascular endothelial growth factor, and SDF-1 were also observed in patients with VDA (combretastatin-A4 phosphate)-treated cancer. These results highlight the possible effect of drug-induced G-CSF on tumor regrowth following certain cytotoxic drug therapies, in this case using a VDA, and hence G-CSF as a possible therapeutic target.

Stem Cell-Like Human Endothelial Progenitors Show Enhanced Colony-Forming Capacity After Brief Sevoflurane Exposure: Preconditioning of Angiogenic Cells by Volatile Anesthetics

Endothelial progenitor cells play a pivotal role in tissue repair, and thus are used for cell replacement therapies in "regenerative medicine." We tested whether the anesthetic sevoflurane would modulate growth or mobilization of these angiogenic cells. In an in vitro model, mononuclear cells isolated from peripheral blood of healthy donors were preconditioned with sevoflurane (3 times 30 min at 2 vol% interspersed by 30 min of air). Colony-forming units were determined after 9 days in culture and compared with time-matched untreated control. Using magnetic cell sorting, CD133+/CD34+ endothelial progenitors were enriched from human umbilical cord blood, and vascular endothelial growth factor (VEGF), VEGFR2 (KDR), granulocyte colony-stimulating factor (G-CSF), STAT3, c-kit, and CXCR4 expressions were determined in sevoflurane-treated and untreated cells by real-time reverse transcriptase polymerase chain reaction. In a volunteer study with crossover design, we tested whether sevoflurane inhalation (<1 vol% end-tidal concentration) would mobilize endothelial progenitor cells from the bone marrow niche into the circulation using flow cytometry of peripheral blood samples. VEGF and G-CSF plasma levels were also measured. In vitro sevoflurane exposure of mononuclear cells enhanced colony-forming capacity and increased VEGF mRNA levels in CD133+/CD34+ cord blood cells (P = 0.017). Sevoflurane inhalation in healthy volunteers did not alter the number of CD133+/CD34+ or KDR+/CD34+ endothelial progenitors in the circulation, but increased the number of colony-forming units (P = 0.034), whereas VEGF and G-CSF plasma levels remained unchanged. Sevoflurane preconditioning promotes growth and proliferation of stem cell-like human endothelial progenitors. Hence, it may be used to promote perioperative vascular healing and to support cell replacement therapies.

Acupuncture for chemotherapy-induced neutropenia in patients with gynecologic malignancies: a pilot randomized, sham-controlled clinical trial.

The objective of this study was to investigate the effect of acupuncture administered during myelosuppressive chemotherapy on white blood cell (WBC) count and absolute neutrophil count (ANC) in patients with ovarian cancer. This study is a pilot, randomized, sham-controlled clinical trial. Patients received active acupuncture versus sham acupuncture while undergoing chemotherapy. A standardized acupuncture protocol was employed with manual and electrostimulation. The frequency of treatment was 2-3 times per week for a total of 10 sessions, starting 1 week before the second cycle of chemotherapy. The setting was two outpatient academic centers for patients with cancer. Twenty-one (21) newly diagnosed and recurrent ovarian cancer patients were the subjects. WBC count, ANC, and plasma granulocyte colony-stimulating factor (G-CSF ) were assessed weekly. The median leukocyte value in the acupuncture arm at the first day of the third cycle of chemotherapy was significantly higher than in the control arm after adjusting for baseline value (8600 cells/microL, range: 4800-12,000 versus 4400 cell/microL, range: 2300-10,000) (p = 0.046). The incidence of grade 2-4 leukopenia was less in the acupuncture arm than in the sham arm (30% versus 90%; p = 0.02). However, the median leukocyte nadir, neutrophil nadir, and recovering ANC were all higher but not statistically significantly different (p = 0.116-0.16), after adjusting for baseline differences. There were no statistically significant differences in plasma G-CSF between the two groups. We observed clinically relevant trends of higher WBC values during one cycle of chemotherapy in patients with ovarian cancer, which suggests a potential myeloprotective effect of acupuncture. A larger trial is warranted to more definitively determine the efficacy of acupuncture on clinically important outcomes of chemotherapy-induced neutropenia.

Decreased Plasma Levels of Granulocyte-Colony Stimulating Factor (G-CSF) in Patients with Early Alzheimer's Disease

Alzheimer's disease (AD) is characterized by massive neuronal cell loss in the brain. Granulocyte-colony stimulating factor (G-CSF) is a hematopoietic growth factor that promotes neuroprotective effects and supports neurogenesis in the brain. In the present study, we found significantly lower G-CSF plasma levels in 50 early AD patients in comparison with 50 age-matched healthy controls. In AD patients, G-CSF levels showed a significant inverse correlation with amyloid-beta (Abeta1-42) levels in cerebrospinal fluid, but not with levels of tau protein in cerebrospinal fluid or Mini-Mental Status Examination scores. In addition, G-CSF plasma levels were significantly inversely correlated with age in AD patients and healthy controls. In conclusion, decreased G-CSF plasma levels in early AD patients may contribute to a deficient hematopoietic brain support with putative pathogenic relevance. Further studies are needed to examine whether a modulation of hematopoietic growth factors such as G-CSF could be a promising new therapeutic strategy for AD.

Plasma granulocyte colony-stimulating factor levels correlate with clinical outcomes in patients with acute lung injury.

To evaluate the association between plasma granulocyte colony-stimulating factor (G-CSF) levels and clinical outcomes including mortality in patients with acute lung injury (ALI), and to determine whether lower tidal volume ventilation was associated with a more rapid decrease in plasma G-CSF over time in patients with ALI. Retrospective measurement of G-CSF levels in plasma samples that were collected prospectively as part of a large multicenter clinical trial. Intensive care units in ten university centers. The study included 645 patients enrolled in the National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Clinical Network trial of lower tidal volumes compared with traditional tidal volumes for ALI. Baseline plasma levels of G-CSF were associated with an increased risk of death and a decrease in ventilator-free days and organ failure-free days in multivariate analyses controlling for ventilation strategy, age, and sex (Odds ratio death 1.2/log10 increment G-CSF, 95% confidence interval 1.01 to 1.4). Stratification of G-CSF levels into quartiles revealed a strong association between the highest levels of G-CSF and an increased risk of death and decreased ventilator-free days and organ failure-free days in multivariate analyses controlling for ventilation strategy, Acute Physiology and Chronic Health Evaluation III score, Pao2/Fio2 ratio, creatinine, and platelet count (p < 0.05). Subgroup multivariate analysis of patients with sepsis as their risk factor for ALI revealed a U-shaped association between mortality and G-CSF levels such that risk increased linearly from the second through fourth (highest) quartiles, yet also increased in the first (lowest) quartile. G-CSF levels decreased over time in both tidal volume groups, and there was no statistical difference in the extent of decrease between ventilator strategies. In patients with ALI, plasma G-CSF levels are associated with morbidity and mortality, but these levels are not influenced by tidal volume strategy. In patients with sepsis-related ALI, a bimodal association between baseline plasma G-CSF levels and subsequent morbidity and mortality from this disease was found.

Timing of granulocyte-colony stimulating factor treatment after acute myocardial infarction and recovery of left ventricular function: Results from the STEMMI trial

Background Granulocyte-colony stimulating factor (G-CSF) therapy after ST-elevation myocardial infarction (STEMI) have not demonstrated impact on systolic recovery compared to placebo. However, recent studies suggest that timing of G-CSF therapy is crucial. Methods Timing of G-CSF treatment was analyzed in the STEMMI MRI subpopulation including 54 patients with STEMI treated with primary percutaneous coronary intervention (PCI) < 12 h after symptom onset. Patients were randomized to double blind treatment with G-CSF (10 µg/kg/day) or placebo. Treatment was initiated from 17 to 65 h (mean 30) after PCI. Left ventricular ejection fraction (LVEF) was evaluated with MRI. Results Recovery of LVEF from baseline to 6 months was not associated with time from PCI to G-CSF. An identical improvement in LVEF was found in the placebo group and the G-CSF group ( p = 0.8). There was no correlation between time from PCI to G-CSF and maximum plasma concentration of CD34+ cells ( r = − 0.3, p = 0.1). Similar results were found from data on recovery of the infarction size and change in the systolic wall thickening. Conclusions In the time window from 17 to 65 h after STEMI treated with PCI, the timing of G-CSF treatment does not seem to affect the recovery of LVEF. It remains to be determined if very early, or very late G-CSF treatment might be effective.

Effects of social isolation and environmental enrichment on atherosclerosis in ApoE−/− mice

Social support and a stimulating environment have been suggested to reduce stress reactions and cardiovascular risk. The aim of this study was to assess the role of environmental enrichment and social interaction for development of atherosclerosis in atherosclerosis prone mice. Male ApoE− / − mice were divided into four groups and followed during 20 weeks: (i) enriched environment (E, n = 12), (ii) deprived environment (ED, n = 12), (iii) enriched environment with exercise (E-Ex, n = 12) and (iv) socially deprived by individual housing (SD, n = 10). Plasma lipid and cytokine concentrations were measured. Atherosclerosis was quantified in cross-sections of innominate artery and en face in thoracic aorta. Plaque area was significantly increased in SD mice in the innominate artery (P < 0.05 vs. all other groups), but not in the thoracic aorta. Plasma lipids were increased in SD mice (P < 0.001 vs. all for total cholesterol, P < 0.05 vs. E and P < 0.01 vs. ED for triglycerides). Plasma concentration of granulocyte-colony stimulating factor (G-CSF) was decreased in SD mice compared to E mice (P < 0.05). Thus, social isolation increased atherosclerosis and plasma lipids in ApoE− / − mice. Reduction in plasma G-CSF levels may hamper endothelial regeneration in the atherosclerotic process. While environmental enrichment did not affect atherosclerosis, social isolation accelerated atherosclerosis.

Abstract 2670: Time to Granulocyte-Colony Stimulating Factor Treatment after Acute Myocardial Infarction Does Not Affect Left Ventricular Recovery: Results from the STEMMI Trial

Introduction: Granulocyte-colony stimulating factor (G-CSF) therapy after a STEMI does not affect left ventricular systolic function when compared to placebo. However, recent human and animal studies suggest that the timing of G-CSF therapy is crucial. Hypothesis: G-CSF improves recovery of left ventricular ejection fraction if administered very early after a STEMI. Methods: The STEMMI trial MRI-subpopulation was analyzed. The trial included 58 patients (47 men; 56 [SD 9] years) with STEMI treated with primary PCI &lt;12 hours after symptom onset. Patients were randomized to double blind treatment with G-CSF (10 μg/kg/day) or placebo for 6 days. Treatment with G-CSF (time to G-CSF) was initiated 30 hours (range 17 – 65) after PCI. Left ventricular function was evaluated with cardiac MRI and analyzed by an independent blinded core laboratory. Results: Circulating CD34+ cells increased during G-CSF therapy. However, there was no correlation between time to G-CSF and maximum plasma concentration of CD34+ cells (r=-0.3, p=0.2). Baseline ejection fraction was independent of time to G-CSF. The recovery of ejection fraction from baseline to 6 months was not associated with time to G-CSF (regression coefficient 0.2/hour, 95% CI -0.2 to 0.5), an identical improvement was found in the placebo group (p=0.8). There was no association between plasma concentrations of CD34+ cells and improvement in left ventricular function. Conclusions: We found no indication that early initiation of treatment with G-CSF improves recovery of left ventricular ejection fraction as compared to both late G-CSF and placebo. It remains to be determined if treatment initiation &lt;17 hours after PCI improves recovery.

The Effect of Brief Exercise on Circulating CD34+ Stem Cells in Early and Late Pubertal Boys

We tested the hypothesis that exercise could stimulate CD34+ peripheral blood hematopoietic stem cells (PBSC) in children. Fourteen early pubertal boys (EP, age 10.3 +/- 0.3 y) and 13 late pubertal boys (LP, age 16.5 +/- 0.4 y) performed 20 min of moderate-to-vigorous cycle ergometer exercise. Blood was drawn before and after exercise. Cells were stained for surface CD34+. Plasma granulocyte colony stimulating factor (G-CSF), Fms-like tyrosine kinase-3 (FLT-3), and stromal cell-derived factor-1 (SDF-1) were measured using ELISA. Exercise substantially increased PBSC (in EP from 112 +/- 21 to 182 +/- 30 cells/microL, p=0.0007; in LP from 63 +/- 8 to 152 +/- 21, p=0.0008), and to a smaller extent FLT-3 (in EP from 98 +/- 5 to 110 +/- 6 pg/mL, p<0.0001; in LP from 73 +/- 6 to 92 +/- 6, p<0.0001) and G-CSF (in EP from 26 +/- 4 to 29 +/- 4 pg/mL, p<0.0001; in LP from 14 +/- 1 to 18 +/- 1, p<0.0001). Baseline levels of PBSC, FLT-3, and G-CSF were significantly higher in EP. Exercise increased SDF-1 alpha only in LP, and the FLT-3 increase was greater in LP than EP. Brief exercise affects PBSC and PBSC mediators in children.

Endothelial Progenitor Cells are Mobilized After Cardiac Surgery

There is evidence that endothelial progenitor cells (EPCs) are mobilized into the circulation after coronary artery bypass grafting (CABG) with cardiopulmonary bypass. However, there is little known about EPC mobilization after off-pump CABG or valve surgery. We aimed to establish the response of EPCs to various forms of cardiac surgery and examine the role of well-known mobilizing cytokines on EPC levels. One hundred and ten patients were studied: 54 elective CABG (30 on-pump, 24 off-pump); 23 urgent CABG; and 33 non-CABG. The EPC functional status was assessed using the colony forming unit assay (EPC-CFU) and plasma levels of granulocyte colony-stimulating factor (G-CSF), stromal cell-derived factor 1-alpha, matrix metalloproteinase, and vascular endothelial growth factor were assessed by enzyme-linked immunosorbent assay. Samples were taken preoperatively and on days 1 and 5 after surgery. Patients requiring urgent CABG and non-CABG patients had significantly higher numbers of EPC-CFU prior to surgery than elective CABG patients. All elective patients showed a significant increase in postoperative EPC-CFU levels: on-pump CABG 10.4 +/- 3.8 to 53.9 +/- 11.9, p = 0.001; off-pump CABG 9.5 +/- 3.5 to 65.7 +/- 17.3, p = 0.006; non-CABG 23.5 +/- 6.8 to 84.6 +/- 27.2, p = 0.05. The postoperative EPC rise in elective patients correlated with plasma G-CSF levels (r = 0.387, p < 0.01). Urgent patients demonstrated a significant increase in G-CSF levels but this was not associated with an increase in EPC-CFU level. Patients undergoing elective cardiac surgery demonstrated an increase in EPC-CFU postoperatively, which correlated with increased plasma G-CSF level. Urgent patients did not have an increase in EPC-CFU despite a plasma G-CSF rise. Endogenously mobilized EPCs present a potential therapeutic target.

Sustained G-CSF plasma levels following administration of pegfilgrastim fasten neutrophil reconstitution after high-dose chemotherapy and autologous blood stem cell transplantation in patients with multiple myeloma

Pegfilgrastim has shown to decrease the duration of severe neutropenia after conventional chemotherapy, but its use after high-dose chemotherapy and autologous blood stem cell transplantation has not been established yet. Therefore we studied the efficacy and the pharmacokinetic profile of pegfilgrastim in patients with multiple myeloma undergoing high-dose chemotherapy. In total, 21 patients received a single subcutaneous injection of 6 mg pegfilgrastim on day +1 after transplantation and pegfilgrastim plasma levels were measured daily by enzyme-linked immunosorbent assay. Clinical outcome was compared with pegfilgrastim levels of 282 plasma samples and data of a historical control group of patients without granulocyte colony-stimulating factor (G-CSF) support. Pegfilgrastim levels showed an inverse correlation (r = -0.68, p < 0.01) with neutrophil counts. Peak levels were reached at day +4 (94 ng/mL; range: 37-205) and were maintained until day +7 (85 ng/mL; range: 35-186). Comparison with the control group without G-CSF support showed that time to neutrophil reconstitution was significantly shorter in the pegfilgrastim group with 10 vs 15 days, respectively (p < 0.001). There was no correlation of pegfilgrastim levels and the duration of neutropenia, although patients with a fivefold increase in neutrophil counts the day after pegfilgrastim administration had a significantly shorter median duration of neutropenia in comparison to patients who were less susceptible to G-CSF stimulation (5 vs 7 days, p < 0.01). Neutrophil reconstitution after high-dose chemotherapy could be accelerated by the use of pegfilgrastim in patients with myeloma. Responsiveness of neutrophils to pegfilgrastim before neutropenia was correlated with faster neutrophil reconstitution, whereas G-CSF levels had no impact on neutrophil recovery.

G-CSF, but not corticosterone, mediates circulating neutrophilia induced by febrile-range hyperthermia

We previously showed that sustained exposure to febrile-range hyperthermia (FRH) for 24 h caused an increase in circulating granulocyte colony-stimulating factor (G-CSF) levels and a peripheral neutrophilia in mice (Hasday J, Garrison A, Singh I, Standiford T, Ellis G, Rao S, He JR, Rice P, Frank M, Goldblum S, and Viscardi R. Am J Pathol 162: 2005-2017, 2003). In this study, we utilized a conscious temperature-clamped mouse model to analyze the kinetics of G-CSF expression and peripheral neutrophil expansion and the contributions of FRH-induced G-CSF expression, glucocorticoid generation, and catecholamine-induced neutrophil demargination. In conscious mice housed at an ambient temperature of 34.5 degrees C, core temperature rapidly equilibrated at 39.5-40 degrees C. Peripheral neutrophil counts increased 2-fold after 24-h exposure to hyperthermia, peaked at 3.6-fold baseline levels after 36-h exposure to FRH, and returned to baseline levels after 42 h of sustained hyperthermia. Plasma G-CSF levels were increased by 6.8-fold after 24 h and peaked at 40-fold baseline levels after 36 h in the hyperthermic mice. Plasma corticosterone levels peaked at 3.3-fold baseline levels after 30-h sustained hyperthermia and returned to baseline by 42 h. Immunoneutralization of G-CSF blocked FRH-induced peripheral neutrophilia, but blockade of the glucocorticoid receptor with mifepristone failed to modify FRH-induced neutrophilia. Epinephrine induced similar increases in peripheral blood absolute neutrophil counts in euthermic mice (2.2-fold increase) and mice exposed to FRH for 36 h (1.8-fold increase). Collectively, these data suggest that FRH-induced expression of G-CSF drives the sustained peripheral neutrophilia that occurs during sustained (36 h) hyperthermia, whereas glucocorticoid generation and catecholamine-induced demargination play little role in this response.

Effect of recombinant human GH on circulating granulocyte colony-stimulating factor and neutrophils in patients with adult GH deficiency

We previously reported that short-term continuous subcutaneous infusion (CSI) of recombinant human growth hormone (rhGH) increased plasma erythropoietin levels and hemoglobin concentrations in patients with adult GH deficiency. In the present study, we investigated the effect of rhGH on plasma granulocyte colony-stimulating factor (G-CSF) levels and neutrophil counts in patients with adult GH deficiency. rhGH was administrated for 1 year in six patients with adult GH deficiency (age range, 24-69 years; mean +/- S.E.M., 51.7 +/- 5.8 years; two males and four females) by means of CSI at a rate of 0.25 U/kg per week. Blood samples were obtained in the morning after overnight fasting every month before and after the start of rhGH administration. Plasma GH, insulin-like growth factor I (IGF-I) and G-CSF levels, and neutrophil counts, were measured. Mean ( +/- S.E.M.) plasma GH levels increased from 0.26 +/- 0.14 to 2.28 +/- 0.20 microg/l 1 month after the start of rhGH administration. An increase of the plasma GH levels was accompanied by an increase in the plasma IGF-I levels from 64.7 +/- 8.5 to 293.3 +/- 80.6 microg/l. Plasma G-CSF levels increased at 2, 3, 8, 9 and 10 months after the start of rhGH administration compared with 28.6 +/- 11.0 ng/l at time 0. The neutrophil counts increased at 2, 3, 7, 8, 9, 11 and 12 months after the start of rhGH administration compared with 2822 +/- 377 neutrophils/microl at time 0. rhGH administration increased plasma G-CSF levels and neutrophil counts. GH and/or IGF-I might stimulate neutrophil production and/or release via G-CSF.

Effects of Carbon Monoxide Poisoning on Neutrophil Responses in Patients Treated with Hyperbaric Oxygen

Background Carbon monoxide (CO) poisoning can cause tissue injury. Neutrophil granulocytes have been proposed to contribute to the injury, which may be ameliorated by hyperbaric oxygen (HBO2) treatment. We sought to assess the relationship between acute CO poisoning and blood neutrophil count, plasma cytokine, and Cortisol responses, as well as the mechanism behind the observed beneficiary effects of HBO2 treatment. Methods Eight patients (age 26–82 years) with severe acute CO poisoning were enrolled, concomitant with eight healthy controls (age 27–42 years), in a prospective, controlled, clinical study. The patients were given three HBO2 treatments (2.8 atmospheres absolute, 100 minutes) within the first 24 hours. The controls were given identical simultaneous HBO2 treatments. Venous blood samples were taken before and after each treatment. Results At the start of the HBO2 treatment, patients displayed significantly higher blood neutrophil counts ( p &lt; .0001) and plasma Cortisol levels (p = .020) than controls, but the two groups had similar values for interleukin-8, granulocyte colony-stimulating factor (G-CSF), neutrophil H2O2 generation, and CD16 and CD18 surface expression. During the observation time, neutrophil H2O2 accumulation declined in patients and in controls ( p = .031), whereas the up-regulation of CD18 expression increased ( p = .002) in both groups. Moreover, G-CSF levels became significantly higher in patients than in controls ( p = .015). G-CSF levels also correlated significantly with neutrophil counts. Conclusion CO poisoning was associated with discrete changes of blood neutrophil counts, Cortisol, and G-CSF plasma concentrations. HBO2 treatment modulated neutrophil generation of H2O2 and surface expression of CD18. These changes may be part of the cascade of events leading to the sequelae of CO poisoning and their attenuation by HBO2.

Effects of Carbon Monoxide Poisoning on Neutrophil Responses in Patients Treated with Hyperbaric Oxygen

BackgroundCarbon monoxide (CO) poisoning can cause tissue injury. Neutrophil granulocytes have been proposed to contribute to the injury, which may be ameliorated by hyperbaric oxygen (HBO2) treatment. We sought to...

Escherichia coli pneumonia enhances granulopoiesis and the mobilization of myeloid progenitor cells into the systemic circulation.

The process by which hematopoietic tissues respond to a pulmonary infection remains poorly understood. This study investigated the potential role of lung-derived granulopoietic cytokines in facilitating this response. Laboratory investigation. University laboratory. Male Balb/c mice. Mice were challenged with intratracheal Escherichia coli or granulocyte colony-stimulating factor (G-CSF). Bone marrow cells were isolated from normal mice and treated in vitro with G-CSF. Bronchoalveolar lavage fluid concentrations of G-CSF, macrophage inflammatory protein-2, and keratinocyte-derived chemokine were elevated 3 and 6 hrs after intratracheal E. coli. The increases in intrapulmonary G-CSF and keratinocyte-derived chemokine were associated with increases of their concentrations in the plasma. The numbers of granulocyte-macrophage colony forming units in bone marrow, spleen, and blood were increased 48 hrs after intratracheal E. coli or G-CSF. In addition, plasma G-CSF and the number of progenitor cells (lin-ckit+Sca-1(-)) in the blood were increased at 30 mins and 48 hrs, respectively, following intratracheal G-CSF. Signal transducer and activator of transcription-3 in bone marrow cells was activated following intratracheal E. coli or G-CSF in addition to activation by in vitro G-CSF stimulation. During pulmonary infection, locally produced cytokines enter the circulation and may play an important role in initiating a granulopoietic response.

Transient leukocytosis, granulocyte colony-stimulating factor plasma concentrations, and apoptosis determined by binding of annexin V by peripheral leukocytes in patients with severe sepsis.

This study was undertaken to clarify the relation between transient increases in the numbers of leukocytes and granulocyte colony-stimulating factor (G-CSF) plasma concentrations as well as the degree of apoptosis, as determined by binding of annexin V by these cells in patients with severe sepsis and septic shock. Over a 6-month period, annexin V binding by leukocytes was determined daily using flow cytometry and FITC-labeled annexin V in 33 postoperative patients with severe sepsis or septic shock during their intensive care unit stay. The percentage of annexin V binding neutrophils, monocytes, and lymphocytes was significantly lower, and G-CSF plasma concentrations were higher in patients than in controls on most days. Nine, 19, and 18 peaks in neutrophil, monocyte, and lymphocyte counts (increase of >/=30% within 2 days, followed by a decrease of >/=30% within 2 days) occurred in 6, 11, and 16 patients. During leukocyte peaks, the absolute numbers of annexin V binding neutrophils, monocytes, and lymphocytes paralleled those of neutrophil, monocyte, and lymphocyte numbers. However, the percentage of annexin V binding neutrophils, monocytes, and lymphocytes did not differ significantly from one day to another. Increased G-CSF serum concentrations preceded neutrophil and monocyte peaks. In conclusion, apoptosis of leukocytes is lowered during severe sepsis and septic shock in critically ill patients. Moreover, the degree of apoptosis does not increase during transient leukocytosis. G-CSF might contribute to the low degree of apoptosis of neutrophils and monocytes in those patients.

Bactericidal activity response of blood neutrophils from critically ill patients to in vitro granulocyte colony-stimulating factor stimulation.

Neutrophil function impairment is common in nonneutropenic critically ill patients. Whether granulocyte colony-stimulating factor (G-CSF) may be useful for preventing nosocomial infection in these patients is debated. The response of blood neutrophils from critically ill patients to G-CSF was investigated in vitro. Prospective study, laboratory investigation in two intensive care units. 52 critically ill patients without immunosuppression. Neutrophils obtained from 52 patients on the 5th day of their intensive care unit stay were incubated with and without G-CSF (1, 10, 100 ng/ml). Reactive oxygen species (ROS) release and bactericidal activity against Staphylococcus aureus and Pseudomonas aeruginosa were evaluated. Plasma cytokines (interleukin 10, tumor necrosis factor alpha, and G-CSF) were measured. Median values (25th-75th percentiles) indicated no stimulatory effect of G-CSF on neutrophil bactericidal activity against either organism: S. aureus, 100% (95-109) of the unstimulated condition with 1 ng/ml G-CSF, and P. aeruginosa, 102% (98-109) with 1 ng/ml G-CSF. However, wide interindividual variability was found, ranging from marked inhibition to marked stimulation. Similar variability was found for ROS release. No correlations were found between ROS release and bactericidal activities against either bacterial strain. Inhibition of neutrophil bactericidal activity by G-CSF was associated with significantly higher plasma interleukin 10 concentrations. Plasma G-CSF levels were significantly higher in patients whose neutrophil bactericidal activity was unresponsive to G-CSF, suggesting G-CSF receptor downregulation. The effect of G-CSF on in vitro neutrophil bactericidal activity varied widely, depending on endogenous levels of G-CSF and was not predictable based on severity scores.