Exacerbation with granulocyte colony-stimulating factor of prior acute lung injury during neutropenia recovery in rats

OBJECTIVE: Neutropenia recovery may be associated with an increased risk of respiratory function deterioration. A history of pneumonia complicating neutropenia has been identified as the leading cause of adult respiratory distress syndrome during neutropenia recovery in patients receiving anticancer chemotherapy, suggesting that neutropenia recovery may worsen prior lung injury. DESIGN: Controlled animal study. SETTING: Research laboratory of an academic institution. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: We studied the effect of recovery from cyclophosphamide-induced neutropenia on endotoxin (lipopolysaccharide)- or hydrochloric acid-induced acute lung injury in rats. We also studied the effects of adding granulocyte colony-stimulating factor. MEASUREMENTS AND MAIN RESULTS: Compared with noncyclophosphamide-treated rats, rats undergoing neutropenia recovery had a higher wet/dry lung weight ratio after hydrochloric acid-induced but not lipopolysaccharide-induced acute lung injury. Granulocyte colony-stimulating factor significantly increased both alveolar cell recruitment (bronchoalveolar lavage fluid counts) and pulmonary edema (wet/dry lung ratio) in both acute lung injury models during neutropenia recovery. Furthermore, in an experiment in hydrochloric acid-instilled rats, exacerbation by granulocyte colony-stimulating factor of hydrochloric acid-induced acute lung injury was inhibited by lidocaine, which prevents adhesion of neutrophils to endothelial cells. Tumor necrosis factor-alpha and interleukin-1 beta concentrations in supernatants of lipopolysaccharide-stimulated alveolar macrophages from rats undergoing neutropenia recovery with granulocyte colony-stimulating factor treatment were significantly increased compared with rats undergoing neutropenia recovery without granulocyte colony-stimulating factor. CONCLUSION: Neutropenia recovery can worsen acute lung injury, and this effect is exacerbated by granulocyte colony-stimulating factor.     

Effect of granulocyte colony-stimulating factor on bleomycin-induced acute lung injury and pulmonary fibrosis

OBJECTIVE: Potentially fatal pulmonary toxicity is a dreaded complication of bleomycin. Increased use of granulocyte colony-stimulating factor in patients receiving chemotherapy has been paralleled by an increased incidence of bleomycin-induced pulmonary toxicity. We investigated whether granulocyte colony-stimulating factor (25 microg x kg(-1) x day(-1), 4 days) enhanced endotracheal bleomycin-induced (5 mg/kg) acute lung injury and fibrosis in rats. SETTING: University laboratory. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: We compared the effects of alveolar instillation of bleomycin in rats treated with either granulocyte colony-stimulating factor or saline. MEASUREMENTS AND MAIN RESULTS: Mortality was 25% with bleomycin only and 50% with bleomycin + granulocyte colony-stimulating factor. Granulocyte colony-stimulating factor increased alveolar neutrophil recruitment, pulmonary edema, and lung myeloperoxidase activity on day 4. Lung static compliance on day 15 was severely decreased with bleomycin alone and showed a further significant decrease when granulocyte colony-stimulating factor was added (controls, 3.85 +/- 0.14 mL/kPa; bleomycin, 1.44 +/- 0.06 mL/kPa; and bleomycin + granulocyte colony-stimulating factor, 0.65 +/- 0.09 mL/kPa; control vs. bleomycin, p <.0001; and bleomycin vs. bleomycin + granulocyte colony-stimulating factor, p =.0003). Lung morphology with bleomycin + granulocyte colony-stimulating factor showed, in addition to the changes observed with bleomycin alone, four patterns indicating more severe disease: honeycomb foci, pleural thickening with hyaline fibrosis, interstitial granuloma with increased number of macrophages but not neutrophils, and established interstitial fibrosis. Lidocaine, which prevents neutrophil adhesion to endothelial cells, inhibited granulocyte colony-stimulating factor-related exacerbation of acute lung injury (bronchoalveolar lavage fluid cells and pulmonary edema) and pulmonary fibrosis (lung static compliance and morphologic changes). CONCLUSIONS: Granulocyte colony-stimulating factor enhances bleomycin-induced lung toxicity by a mechanism that probably involves neutrophils.     

急性肺损伤炎性细胞凋亡异常及粒细胞集落刺激因子调控的研究

目的 探讨急性肺损伤时支气管肺泡灌洗液(BALF)中的中性粒细胞(PMN)凋亡发生规律及其与粒细胞集落刺激因子调控关系.方法 豚鼠30只,分为3组:组1为生理盐水正常对照组,组2为油酸致病组,组3为油酸+粒细胞集落刺激因子组.组2、组3分别由尾静脉注射油酸(0.12 ml/kg)造成豚鼠急性肺损伤模型.组1则注入生理盐水.组3在实验造模前2 d由皮下注射粒细胞集落刺激因子1.0μg/kg,1次/d.组1、组2、组3分别于注射后2 h用生理盐水进行全肺支气管肺灌洗,收集BALF.用梯度密度法离心收集PMN.用原位末端标记法检测BALF中PMN凋亡.结果 组2、组3和组1BALF中PMN凋亡百分比分别为(2.500±1.080)%、(3.500±0.850)%、(6.400±1.505)%.组2、组3较组1 BALF中PMN凋亡均显著降低(均P＜0.01).结论 急性肺损伤炎性细胞PMN凋亡延迟,PMN持续激活和释放毒性内容物与肺损伤有密切关系.粒细胞集落刺激因子能调控干预急性肺损伤时PMN凋亡延迟.     

Modulation of neutrophil apoptosis by granulocyte colony-stimulating factor and granulocyte/macrophage colony-stimulating factor during the course of acute respiratory distress syndrome

OBJECTIVE: To determine whether bronchoalveolar lavage fluid (BALF) from patients either at risk for the acute respiratory distress syndrome (ARDS) or with sustained ARDS modulates neutrophil apoptosis; to measure the BALF concentrations of the apoptosis inhibitors granulocyte colony-stimulating factor (G-CSF) and granulocyte/macrophage colony-stimulating factor (GM-CSF) before and after the onset of ARDS; and to determine whether the BALF concentrations of G-CSF and/or GM-CSF are associated with clinical outcome. DESIGN: Prospective cohort study. SETTING: Tertiary university hospital. PATIENTS: Twenty patients at risk for ARDS and 45 patients with established ARDS. INTERVENTIONS: Patients at risk for ARDS underwent bronchoalveolar lavage within 24 hrs of being identified, then again 72 hrs later. Patients with ARDS underwent bronchoalveolar lavage within 24 hrs of meeting ARDS criteria, then again on days 3, 7, and 14 of the disease. MEASUREMENTS AND MAIN RESULTS: Normal peripheral blood neutrophil were incubated overnight in BALF from normal volunteers, from patients at risk for ARDS, or from patients with ARDS. neutrophil apoptosis was determined by flow cytometric analysis of annexin V binding. G-CSF and GM-CSF were measured in BALF by immunoassays. Compared with normal BALF, BALF from patients on days 1 and 3 of ARDS inhibited neutrophil apoptosis, but BALF from patients at later stages of ARDS, or from patients at risk for ARDS, did not. The BALF concentrations of both G-CSF and GM-CSF were elevated early in ARDS and decreased toward later stages. Patients who lived had significantly higher concentrations of GM-CSF in the BALF than those who died. CONCLUSIONS: We conclude that the antiapoptotic effect of ARDS BALF on normal neutrophil is highest during early ARDS, and decreases during late ARDS. G-CSF and GM-CSF are present in BALF from patients with ARDS, and their concentrations parallel the antiapoptotic effect of ARDS BALF. These data support the concept that the life-span of neutrophil in the air spaces is modulated during acute inflammation. GM-CSF in the air spaces is associated with improved survival in patients with ARDS.     

Detection of the granulocyte colony-stimulating factor receptor using biotinylated granulocyte colony-stimulating factor: presence of granulocyte colony-stimulating factor receptor on CD34-positive hematopoietic progenitor cells

Granulocyte colony-stimulating factor (G-CSF) was linked to NHS-biotin to yield biotinylated G-CSF (b-G-CSF), which retained the ability to stimulate colony formation by normal bone marrow (BM) cells in methylcellulose. The use of streptivadin-phycoerythrin conjugate in conjunction with flow cytometry demonstrated that the binding of biotnylated G-CSF to its receptor is saturable, competitive, and specific. A 100-fold molar excess of unlabeled G-CSF almost completely inhibited the binding of the biotinylated G-CSF to the human leukemia cell line U937, which is known to posses the G-CSF receptor. G-CSF receptors were clearly detected by flow cytometry on adult human peripheral granulocytes and monocytes, but not on lymphocytes. Using this method, the expression of G-CSF receptors on hematopoietic progenitor cells in bone marrow and umbilical cord blood, detected as CD34-positive (CD34⁺) cells, were examined. A small but significant number of CD34⁺ cells were detected among the bone marrow mononuclear cells and umbilical-cord-blood mononuclear cells (4.28%±0.31%, 1.09%±0.20%, respectively). The percentage of CD34⁺ BM mononuclear cells was significantly higher than for cord blood mononuclear cells (P<0.01). These CD34⁺ cells were then analyzed by biotinylated G-CSF binding. CD34⁺ cells from bone marrow contained 25.8%±7.9% G-CSF receptor positive cells and those from cord blood possessed 29.2% ±7.0% of G-CSF receptor-positive cells. The difference was not statistically significant.     

粒细胞集落刺激因子受体在急性白血病中的表达及临床意义

目的探讨粒细胞集落刺激因子受体(GCSFR)在急性白血病(AL)中的表达及临床意义。方法选初诊或难治复发的急性髓性白血病(AML)患者30例,急性淋巴细胞白血病(ALL)患者20例,正常对照20例。化疗前留取骨髓5ml,用GCSFR、CD34单抗,采用流式细胞技术(FCM)检测GCSFR、CD34在AL细胞的表达情况。同时制备骨髓单个核细胞(MNC)悬液,并分别加入不同浓度的GCSF(5、10、15、20和25ng/ml),培养24h后用FCM检测其DNA倍体的量。结果GCSFR、CD34的表达率:AML为(76.5±12.8)%和(45.15±4.22)%;ALL为(6.12±1.98)%和(46.75±3.15)%;对照组为(80.5±10.8)%和(3.15±0.22)%。骨髓MNC培养24h后DNA倍体量在AML随着GCSF浓度的增加有上升的趋势,在ALL和对照组无明显变化。结论GCSFR主要表达于AML细胞,并促进其增殖;不表达于ALL细胞,不促进其增殖;也表达于成熟粒细胞,但不促进其增殖。     

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

OBJECTIVE: 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. DESIGN AND SETTING: Prospective study, laboratory investigation in two intensive care units. PATIENTS: 52 critically ill patients without immunosuppression. MEASUREMENTS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Colchicine-induced bone marrow suppression: treatment with granulocyte colony-stimulating factor

Bone marrow aplasia is a frequent complication of colchicine poisoning. This typically occurs on day 3 to 5 postexposure, and the blood cell counts remain depressed for a week or more. Unfortunately, because patients suffering from colchicine toxicity develop multiple organ complications and sepsis, the morbidity and mortality associated with bone marrow depression is high. In this article, we present three cases of colchicine toxicity in which granulocyte colony-stimulating factor (G-CSF) was used to treat bone marrow depression. In all three cases, there was a dramatic increase in the white cell count and, to a lesser extent, the platelet count. In view of the critical nature of the bone marrow depression and multi-organ toxicity induced by colchicine, we believe that consideration of the use of G-CSF to shorten the duration of neutropenia is warranted.     

The effects of granulocyte colony-stimulating factor in preclinical models of infection and acute inflammation

The cytokine granulocyte colony-stimulating factor (G-CSF) is a potent endogenous trigger for the release of neutrophils from bone marrow stores and for their activation for enhanced antimicrobial activity. G-CSF has been widely evaluated in preclinical models of acute illness, with generally promising though divergent results. A recombinant G-CSF molecule has recently undergone clinical trials to assess its efficacy as an adjuvant therapy in community-acquired and nosocomial pneumonia, however, these studies failed to provide convincing evidence of benefit. We undertook a systematic review of the published literature reporting the effects of modulation of G-CSF in preclinical in vivo models to determine whether evidence of differential efficacy might explain the disappointing results of human studies and point to disease states that might be more likely to benefit from G-CSF therapy. G-CSF has been evaluated in 86 such studies involving a variety of different models. The strongest evidence of benefit was seen in studies involving intraperitoneal challenge with live organisms; benefit was evident whether the agent was given before or after challenge. G-CSF demonstrates anti-inflammatory activity in models of systemic challenge with viable organisms or endotoxin, but only when the agent is given before challenge; evidence of benefit after challenge was minimal. Preclinical models of intrapulmonary challenge only show efficacy when the cytokine is administered before the infectious challenge, and suggested harm in gram-negative pneumonia resulting from challenge with Escherichia coli or Klebsiella. There is little evidence for therapeutic efficacy in noninfectious models of acute illness. We conclude that the most promising populations for evaluation of G-CSF are neutropenic patients with invasive infection and patients with intra-abdominal infection, particularly those with the syndrome of tertiary, or recurrent, peritonitis. Significant variability in the design and reporting of studies of preclinical models of acute illness precludes more sophisticated data synthesis.     

Effect of granulocyte colony-stimulating factor on the candidacidal activity of polymorphonuclear neutrophils and their collaboration with fluconazole.

The effect of granulocyte colony-stimulating factor (GCSF) treatment of polymorphonuclear neutrophils (PMN) in vitro was studied with respect to their candidacidal activity. The candidacidal activity of PMN was found to be significantly increased when they were pretreated with GCSF. Fluconazole (1 microg/ml) was found to be highly fungistatic (90%) for Candida albicans Sh27 and collaborated with PMN for significantly increased killing. Collaborative killing by PMN significantly increased when they were treated with GCSF before and after fungal exposure. The enhancing activities of GCSF required optimization of the GCSF dose and were thus inoculum and strain dependent.     

Pegfilgrastim: a granulocyte colony-stimulating factor with sustained duration of action

Granulocyte colony-stimulating factors such as filgrastim (Neupogen, Amgen, Inc.) and pegfilgrastim (Neulasta, Amgen, Inc.) are frequently used in clinical practice for the prevention of chemotherapy-induced neutropenia and its potentially life-threatening complications. Due to its unique neutrophil-mediated clearance, pegfilgrastim can be administered once per chemotherapy cycle. Clinical trials have shown that a single, fixed subcutaneous dose of pegfilgrastim 6 mg is comparable in safety and efficacy to daily injections of filgrastim for decreasing the incidence of infection following myelosuppressive chemotherapy in patients with cancer. Postregistrational trials have been conducted to evaluate the use of pegfilgrastim with emerging dose-dense regimens, in myeloid cancers and for mobilisation and engraftment of autologous stem cells. Ongoing clinical trials continue to explore further potential uses for pegfilgrastim.     

Pegfilgrastim: a granulocyte colony-stimulating factor with sustained duration of action

Granulocyte colony-stimulating factors such as filgrastim (Neupogen^®, Amgen, Inc.) and pegfilgrastim (Neulasta^®, Amgen, Inc.) are frequently used in clinical practice for the prevention of chemotherapy-induced neutropenia and its potentially life-threatening complications. Due to its unique neutrophil-mediated clearance, pegfilgrastim can be administered once per chemotherapy cycle. Clinical trials have shown that a single, fixed subcutaneous dose of pegfilgrastim 6 mg is comparable in safety and efficacy to daily injections of filgrastim for decreasing the incidence of infection following myelosuppressive chemotherapy in patients with cancer. Postregistrational trials have been conducted to evaluate the use of pegfilgrastim with emerging dose-dense regimens, in myeloid cancers and for mobilisation and engraftment of autologous stem cells. Ongoing clinical trials continue to explore further potential uses for pegfilgrastim.     

Monocyte deactivation in neutropenic acute respiratory distress syndrome patients treated with granulocyte colony-stimulating factor

Introduction

In severely neutropenic septic acute respiratory distress syndrome (ARDS) patients, macrophages and monocytes are the last potentially remaining innate immune cells. We have previously shown, however, a deactivation of the alveolar macrophage in neutropenic septic ARDS patients. In the present study, we tried to characterize in vitro monocyte baseline cytokine production and responsiveness to lipopolysaccharide exposure.

Methods

Twenty-two consecutive patients with cancer were prospectively enrolled into a prospective observational study in an intensive care unit. All patients developed septic ARDS and were divided into two groups: neutropenic patients (n = 12) and non-neutropenic patients (n = 10). All of the neutropenic patients received granulocyte colony-stimulating factor whereas no patient in the non-neutropenic group received granulocyte colony-stimulating factor. We compared monocytes from neutropenic patients with septic ARDS with monocytes from non-neutropenic patients and healthy control individuals (n = 10). Peripheral blood monocytes were cultured, and cytokine levels (TNFα, IL-1β, IL-6, IL-10, and IL-1 receptor antagonist) were assayed with and without lipopolysaccharide stimulation.

Results

TNFα, IL-6, IL-10 and IL-1 receptor antagonist levels in unstimulated monocytes were lower in neutropenic patients compared with non-neutropenic patients. Values obtained in the healthy individuals were low as expected, comparable with neutropenic patients. In lipopolysaccharide-stimulated monocytes, both inflammatory and anti-inflammatory cytokine production were significantly lower in neutropenic patients compared with non-neutropenic patients and control individuals.

Conclusion

Consistent with previous results concerning alveolar macrophage deactivation, we observed a systemic deactivation of monocytes in septic neutropenic ARDS. This deactivation participates in the overall immunodeficiency and could be linked to sepsis, chemotherapy and/or the use of granulocyte colony-stimulating factor.     

Potentiation by granulocyte macrophage colony-stimulating factor of lipopolysaccharide toxicity in mice.

GM-CSF is known to prime leukocytes for inflammatory stimuli in vitro. The objective of this study was to investigate the role of GM-CSF in vivo in a systemic inflammatory reaction syndrome. The results demonstrate a potentiation of LPS toxicity by GM-CSF in a mortality model as well as in a septic liver failure model in mice. Pretreatment of animals with 50 micrograms/kg GM-CSF induced lethality within 24 h in mice challenged with a subtoxic dose of LPS while controls survived > 72 h. A monoclonal anti-GM-CSF antibody significantly protected against a lethal LPS dose. Serum GM-CSF was inducible by LPS and peaked at 2 h. GM-CSF pretreatment dramatically potentiated systemic TNF release and hepatotoxicity induced by a subtoxic dose of LPS in galactosamine-sensitized mice. Potentiation of LPS hepatotoxicity was possible until 30 min after LPS challenge. Polyclonal anti-GM-CSF IgG protected against septic liver failure in this model and attenuated serum TNF concentrations. In vitro an ex vivo experiments revealed that after GM-CSF pretreatment LPS-induced IL-1 release from bone marrow or spleen cells was also enhanced. These findings suggest that GM-CSF represents an endogenous enhancer of LPS-induced organ injury, possibly by potentiating the release of proinflammatory cytokines such as TNF and IL-1.     

Recent developments in the cell biology of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor: activities on endothelial cells

Summary Granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor were considered as growth and differentiation factors restricted to hematopoietic cells. It was recently found that non-hematopoietic cells, including endothelial cells, respond to these cytokines. In this review we describe their effects on endothelial cells, underlining their role in the behavior and survival of the microenvironment of bone marrow, in the angiogenesis process related to the progression of solid tumors and of vascular tumors, and in the homing of lymphocytes.     

Role of activated neutrophils in chest trauma-induced septic acute lung injury

More than 50% of severely injured patients have chest trauma. Second insults frequently result in acute lung injury (ALI), with sepsis being the main underlying condition. We aimed to develop a standardized, reproducible, and clinically relevant double-hit mouse model of ALI induced by chest trauma and polymicrobial sepsis and to investigate the pathophysiologic role of activated neutrophils. Lung contusion was applied to C57Bl/6 mice via a focused blast wave. Twenty-four hours later, sepsis was induced by cecal ligation and puncture. For polymorphonuclear leukocyte (PMN) depletion, animals received intravenous injections of PMN-depleting antibody. In response to blunt chest trauma followed by sepsis as well as after sepsis alone, a significant local and systemic inflammatory response with increased cytokine/chemokine levels in lung and plasma was observed. In contrast, lung apoptosis was markedly elevated only after a double hit. Intra-alveolar neutrophils and total bronchoalveolar lavage protein concentrations were markedly increased following isolated chest trauma or the combined insult, but not after sepsis alone. Lung myeloperoxidase activity was enhanced only in response to the double hit accompanied by histological disruption of the alveolar architecture, lung congestion, and marked cellular infiltrates. Neutrophil depletion significantly diminished lung interleukin 1β and interleukin 6 concentrations and reduced the degree of septic ALI. Here we have established a novel and highly reproducible mouse model of chest trauma-induced septic ALI characterizing a clinical relevant double-hit scenario. In particular, the depletion of neutrophils substantially mitigated the extent of lung injury, indicating a pathomechanistic role for neutrophils in chest trauma-induced septic ALI.     

Adjunctive granulocyte colony-stimulating factor therapy for diabetic foot infections

OBJECTIVE: To evaluate the role of granulocyte colony-stimulating factor (G-CSF) as adjunctive therapy for the treatment of diabetic foot infections in non-neutropenic patients. DATA SOURCES: Clinical literature was accessed through MEDLINE (1965-April 2004). Key search terms included G-CSF, infection, and diabetes. In addition, relevant references from primary and secondary article bibliographies were extracted. DATA SYNTHESIS: Three clinical trials evaluating G-CSF for diabetic foot infections were identified. These data demonstrated positive effects of G-CSF on improvement of foot infections and risk of amputations. CONCLUSIONS: Controlled trials are necessary to validate the role of adjunctive G-CSF at reducing amputations in patients with diabetic foot infections.     

Activation of polymorphonuclear neutrophils by immune complex: possible involvement in development of transfusion-related acute lung injury

Transfusion-related acute lung injury (TRALI) is a serious side-effect of transfusion. We presumed that immune complex (IC)-activated polymorphonuclear neutrophils (PMNs) are involved in the development of TRALI. The aim of this study is to examine the various effects of ICs on normal human PMNs. ICs used here were artificially formed by combining soluble human leucocyte antigen (HLA) class II-positive serum and anti-HLA class II antiserum. The abilities of ICs to trigger PMNs and induce the production of soluble mediators and the involvement of the Fc receptor (FcR) in the activation of PMNs by ICs were investigated. Moreover, the ability of the culture supernatant of PMNs incubated with ICs regarded to induce the apoptosis of lung microvascular endothelial (LME) cells was examined. The results proved that PMNs are triggered by ICs resulting in the acceleration of the production of tumour necrosis factor-alpha (TNF-alpha), perforin and Fas ligand, in which FcR on PMNs appears to be involved. Furthermore, the culture supernatants of PMNs cultured with ICs were revealed to induce the apoptosis of LME cells. In conclusion, the ICs used here were proved to induce PMNs to release cytotoxic factors upon activation. These results suggest that ICs are mediators of the development of TRALI.     

Effect of granulocyte colony-stimulating factor on functional and histopathologic outcome after traumatic brain injury in mice

OBJECTIVE: Granulocyte colony-stimulating factor has been used to reduce the risk of sepsis in patients with traumatic brain injury. However, granulocyte colony-stimulating factor exerts potent pro- and anti-inflammatory effects that could influence secondary injury, and outcome, after traumatic brain injury. Our objective was to determine the effect of granulocyte colony-stimulating factor on histopathologic, motor, and cognitive outcome after experimental traumatic brain injury in mice. DESIGN: Experimental study. SETTING: Research laboratory at the Massachusetts General Hospital, Boston, MA. SUBJECTS: Forty-eight adult male C57Bl/6 mice. INTERVENTIONS: Mice (8 wks of age, n = 16/group) were administered granulocyte colony-stimulating factor or saline subcutaneously twice per day for 7 days after controlled cortical impact or sham injury (n = 16). Absolute neutrophil counts, motor function, Morris water maze performance, and lesion volume were determined after controlled cortical impact or sham injury. MEASUREMENTS AND MAIN RESULTS: At the time of controlled cortical impact, body weight, brain and body temperature, and systemic absolute neutrophil counts did not differ between groups. Compared with control, systemic absolute neutrophil count was increased more than ten-fold in granulocyte colony-stimulating factor-treated mice on posttrauma days 2 and 7 (p < .05, repeated-measures analysis of variance) but did not differ between groups by day 14. There were no differences between groups in tests of motor function or histopathologic outcome. However, compared with control, mice given granulocyte colony-stimulating factor had improved Morris water maze performance after controlled cortical impact (p < .05, repeated-measures analysis of variance) but not sham injury. CONCLUSIONS: The data suggest a small beneficial effect of granulocyte colony-stimulating factor on functional outcome after traumatic brain injury in adult mice but do not show differences in histopathology or motor outcome between treated and control groups.