Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor Have Differential Effects on Neonatal and Adult Neutrophil Survival and Function

Molloy, Eleanor J.; O’Neill, Amanda; Grantham, Julie J; Sheridan-Pereira, Margaret; Fitzpatrick, John M.; Webb, David; Watson, R.W.G.

doi:10.1203/01.pdr.0000156500.13600.b5

Cited by 42 publications

(24 citation statements)

References 39 publications

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“…Adding GM-CSF to the cultured neutrophil significantly delayed neutrophil apoptosis and increased neutrophil viability in both CKD and HD groups compared to corresponding cultured cells without GM-CSF. Similar results were observed in neutrophils from healthy individuals [29, 33, 34] and they suggested that the exact mechanisms that mediate the pro-survival effects of GM-CSF seem to happen through the mitochondrial pathway by preventing Bax translocation, cytochrome c release and subsequent caspase 3 activation.…”

Section: Discussionsupporting

confidence: 77%

Neutrophil apoptosis: impact of granulocyte macrophage colony stimulating factor on cell survival and viability in chronic kidney disease and hemodialysis patients

Zahran¹,

Sayed²,

William³

et al. 2013

aoms

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IntroductionAltered neutrophil apoptosis might be responsible for recurrent bacterial infections encountered in hemodialysis (HD) and chronic kidney disease (CKD) patients. This work was designed to assess the neutrophil apoptotic activity and the impact of implementation of granulocyte macrophage colony stimulating factor (GM-CSF), as a survival factor, on neutrophil apoptosis among these patients.Material and methodsTwenty-five patients on regular HD along with 34 CKD patients on conservative treatment, as well as 15 healthy controls, were investigated for apoptotic rate via assessment of neutrophil expression of Annexin-V by flow cytometry, before and after 20 h culture in absence and presence of GM-CSF. Neutrophil viability was determined using light microscopy. The preservation of neutrophil activation in these patients was analyzed by flow cytometric CD18 neutrophil expression. Chronic inflammatory state was evaluated by estimating C-reactive protein (CRP) and soluble intercellular adhesion molecule-1 (sICAM-1). Obtained data were statistically analyzed.ResultsCompared to controls, both HD and CKD groups had a significant increase of Annexin-V and CD18 expression and significant decrease in neutrophil viability. Culture of their neutrophils with GM-CSF showed significant decrease of apoptosis accompanied by improvement of neutrophil viability compared to their cultured cells without GM-CSF. These patients also showed significant elevation of CRP and sICAM-1.ConclusionsGranulocyte macrophage colony stimulating factor demonstrated an evident impact on improving in vitro neutrophil survival and viability in HD and CKD patients. Therefore, this may represent promising preventive and/or therapeutic strategies against infection frequently observed in these patients and causing morbidity and mortality.

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Section: Discussionsupporting

confidence: 77%

Neutrophil apoptosis: impact of granulocyte macrophage colony stimulating factor on cell survival and viability in chronic kidney disease and hemodialysis patients

Zahran¹,

Sayed²,

William³

et al. 2013

aoms

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“…GM-CSF was administered in a controlled trial in critically ill premature infants patients performed and failed to demonstrate protection against neonatal sepsis and did not significantly modify the outcome [46]. The reason of the relative inefficiency of GM-CSF in premature infants has been illustrated by the selective impaired anti-apoptotic effect (alteration of cytochrome C release and caspase-3 and -9 activity) of GM-CSF on newborn neutrophils [47]. Furthermore, the absence of a prophylactic effect of GM-CSF may have been explained by the already increased plasma levels measured in premature infants [48].…”

Section: Discussionmentioning

confidence: 99%

Innate Immune Deficiency of Extremely Premature Neonates Can Be Reversed by Interferon-γ

et al. 2012

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Background Bacterial sepsis is a major threat in neonates born prematurely, and is associated with elevated morbidity and mortality. Little is known on the innate immune response to bacteria among extremely premature infants. Methodology/Principal Findings We compared innate immune functions to bacteria commonly causing sepsis in 21 infants of less than 28 wks of gestational age, 24 infants born between 28 and 32 wks of gestational age, 25 term newborns and 20 healthy adults. Levels of surface expression of innate immune receptors (CD14, TLR2, TLR4, and MD-2) for Gram-positive and Gram-negative bacteria were measured in cord blood leukocytes at the time of birth. The cytokine response to bacteria of those leukocytes as well as plasma-dependent opsonophagocytosis of bacteria by target leukocytes was also measured in the presence or absence of interferon-γ. Leukocytes from extremely premature infants expressed very low levels of receptors important for bacterial recognition. Leukocyte inflammatory responses to bacteria and opsonophagocytic activity of plasma from premature infants were also severely impaired compared to term newborns or adults. These innate immune defects could be corrected when blood from premature infants was incubated ex vivo 12 hrs with interferon-γ. Conclusion/Significance Premature infants display markedly impaired innate immune functions, which likely account for their propensity to develop bacterial sepsis during the neonatal period. The fetal innate immune response progressively matures in the last three months in utero . Ex vivo treatment of leukocytes from premature neonates with interferon-γ reversed their innate immune responses deficiency to bacteria. These data represent a promising proof-of-concept to treat premature newborns at the time of delivery with pharmacological agents aimed at maturing innate immune responses in order to prevent neonatal sepsis.

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“…Among the mediators that prolong the life span of neutrophils, G-CSF is one of the most clinically relevant, and it is widely used in the treatment of various conditions associated with neutropenia [10]. Besides stimulation of neutrophil myeloid precursors in the bone marrow, G-CSF has a clear antiapoptotic effect on mature neutrophils [11, 12] via inhibition of mitochondrial-dependent caspase activation [9, 13] and re-expression of the antiapoptotic protein survivin [14]. …”

Section: Introductionmentioning

confidence: 99%

Biological Effects of Pegfilgrastim on Circulating Neutrophils in Breast Cancer Patients Undergoing Dose-Dense Chemotherapy

et al. 2008

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Pegfilgrastim is a covalent conjugate of filgrastim and polyethylene glycol that has proved to be effective in supporting myelopoiesis during chemotherapy. Since very limited information is available on the biological effects of pegfilgrastim on neutrophils exposed to chemotherapy, we analyzed the following parameters in neutrophils of patients undergoing dose-dense chemotherapy for breast cancer: apoptosis, by a TUNEL technique; actin polymerization, using FITC-labeled phalloidin, and alkaline phosphatase activity by cytochemistry. Peripheral blood buffy coat smears were obtained before starting treatment and immediately before each chemotherapy course. After pegfilgrastim stimulation we observed the following: (1) stability of the absolute neutrophil count for the whole duration of treatment and no infectious events; (2) a reduction in the neutrophil constitutive apoptosis rate in comparison with that observed in control patients treated with standard chemotherapy courses with no growth factor support; (3) persistent abnormalities of actin assembly in neutrophils, indicative of changes in cytoskeletal organization, and (4) a significant increase in the activity of leukocyte alkaline phosphatase, a sensitive marker of the later stages of neutrophil maturation. In conclusion, these results suggest that pegfilgrastim improves the neutrophil functions in patients exposed to chemotherapy by inhibition of constitutive apoptosis, thereby prolonging the survival of these cells.

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Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor Have Differential Effects on Neonatal and Adult Neutrophil Survival and Function

Cited by 42 publications

References 39 publications

Neutrophil apoptosis: impact of granulocyte macrophage colony stimulating factor on cell survival and viability in chronic kidney disease and hemodialysis patients

Neutrophil apoptosis: impact of granulocyte macrophage colony stimulating factor on cell survival and viability in chronic kidney disease and hemodialysis patients

Innate Immune Deficiency of Extremely Premature Neonates Can Be Reversed by Interferon-γ

Biological Effects of Pegfilgrastim on Circulating Neutrophils in Breast Cancer Patients Undergoing Dose-Dense Chemotherapy

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