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(Chest. 2004;125:212-219.)
© 2004 American College of Chest Physicians

Alveolar Granulocyte Colony-Stimulating Factor and {alpha}-Chemokines in Relation to Serum Levels, Pulmonary Neutrophilia, and Severity of Lung Injury in ARDS*

Franz J. Wiedermann, MD; Andreas J. Mayr, MD; Nicole C. Kaneider, MD; Dietmar Fuchs, PhD; Norbert J. Mutz, MD and Wolfgang Schobersberger, MD

* From the Departments of Anesthesiology and Critical Care Medicine (Drs. Wiedermann, Mayr, Mutz, and Schobersberger), Internal Medicine (Dr. Kaneider), and Chemistry and Biochemistry (Dr. Fuchs), Leopold-Franzens-University of Innsbruck, Innsbruck, Austria.

Correspondence to: Franz J. Wiedermann, MD, Department of Anesthesiology and Critical Care Medicine, Leopold-Franzens-University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria; e-mail: franz.wiedermann{at}uibk.ac.at


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Discussion
 References
 
Objectives: To determine granulocyte colony-stimulating factor (G-CSF), epithelial neutrophil-activating peptide (ENA)-78, and interleukin (IL)-8 in BAL fluid (BALF), epithelial lining fluid (ELF), and serum for establishing the concentration gradient of G-CSF, ENA-78, and IL-8 between the blood and the alveolar space in ARDS and acute lung injury (ALI); and to evaluate the relationship of G-CSF, IL-8, and ENA-78 to pulmonary neutrophilia and severity of lung injury.

Design: Prospective study.

Setting: An adult trauma/surgical ICU.

Patients: Nineteen patients with ARDS and 10 patients with ALI.

Interventions: None.

Measurements and main results: BAL and blood sampling simultaneously within 12 h and 24 h after onset of ARDS/ALI; G-CSF was detected in BALF in 18 of 19 patients with ARDS, in 7 of 10 patients with ALI, and in all serum samples. G-CSF in BALF and serum was significantly higher in ARDS than in ALI. ENA-78 was detected in BALF in 14 of 19 patients with ARDS, in 8 of 10 patients with ALI, and in serum of all patients. Levels in BALF and serum were not different between ARDS and ALI. IL-8 was detected in all patients; concentrations in BALF in ARDS were significantly higher than in ALI. Concentrations of G-CSF, ENA-78, and IL-8 in ELF were significantly higher than in serum. G-CSF in BALF and serum and IL-8 in BALF correlated positively with pulmonary neutrophilia. G-CSF in serum and IL-8 in BALF correlated negatively with PaO2/fraction of inspired oxygen (FIO2) ratio. However, ENA-78 did not show a correlation with neutrophil count or with PaO2/FIO2 ratio.

Conclusions: G-CSF may be pathophysiologically important for accumulation and activation of neutrophils in ARDS. Local G-CSF production is the likely driving force for neutrophils rather than elevation of circulating levels. In comparison to ENA-78, IL-8 seems to be the predominant neutrophil chemoattractant in the early phase of ARDS.

Key Words: acute lung injury • chemokine • epithelial lining fluid • epithelial neutrophil activating peptide-78 • granulocyte colony-stimulating factor • interleukin-8 • neutrophils


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Discussion
 References
 
ARDS is described as a syndrome of inflammation and increased permeability associated with a constellation of clinical and physiologic abnormalities.1 Common causes include pneumonia, aspiration of gastric contents, sepsis, severe trauma with shock, and multiple transfusions.2 Activated neutrophils are important for microvascular injury and the development of increased permeability and edema seen in ARDS.2 3

Granulocyte colony stimulating factor (G-CSF), a central mediator of the endogenous response to infection and inflammation, is approved for use in the prevention of infection-related complications in patients with nonmyeloid malignancies during antineoplastic therapy associated with high risk of severe neutropenia.4 It has recently been reported that G-CSF can induce acute lung injury (ALI) when introduced directly into the lungs of rats.5 The potential of G-CSF to contribute to the pathogenesis of ARDS is supported by reports of development of ALI in patients treated with G-CSF.6 Azoulay et al7 reviewed clinical case reports and experimental data on human G-CSF–related pulmonary toxicity.

Only in a few studies8 9 has the G-CSF in BAL fluid (BALF) of patients with ARDS been measured. The median concentration of G-CSF was significantly elevated on day 1 of ARDS and decreased progressively to day 14.8 Furthermore, G-CSF in BALF correlated strongly with neutrophil count in BALF.9 G-CSF enhances chemotaxis by expressing neutrophil chemotactic receptors, primes respiratory burst, promotes phagocytosis and antimicrobial activity at sites of infection, and can prolong the life span of neutrophils in vitro by delaying their apoptosis.10 11 BALF from patients with early ARDS delays neutrophil apoptosis in vitro, and this effect is partially mediated by G-CSF.12

The main chemotactic factor for neutrophils in the blood and BALF of patients with ARDS probably is interleukin (IL)-8.13 Higher levels of IL-8 are present in BALF from nonsurvivors than survivors with ARDS, and elevations of IL-8 concentration in BALF predict progression to ARDS in at-risk populations.14 Among other potent neutrophil chemoattractants, epithelial neutrophil activating peptide (ENA)-78 has been measured in BALF of patients with ARDS in a study by Goodman et al,15 who found that IL-8 and ENA-78 were strongly and consistently correlated with neutrophil count in BALF of patients with ARDS. Driving forces for the development of pulmonary neutrophilia, including the question whether neutrophil-attracting and -activating mediator concentrations in ARDS are higher in the alveolar space than in the blood-circulating compartment, is not well established.

In order to extend these observations, we measured G-CSF, ENA-78, and IL-8 in BALF and serum in our patients in the early phase of ARDS and ALI within 12 h and 24 h after onset of ARDS/ALI. Additionally, we determined the concentration of G-CSF, ENA-78, and IL-8 in lung epithelial lining fluid (ELF) by using the urea-dilution method16 for estimating the volume of ELF in the lavaged lung segment. The main aims of the study were as follows: (1) to evaluate levels of G-CSF, ENA-78, and IL-8 in BALF, ELF, and serum for establishing the concentration gradient of G-CSF, ENA-78, and IL-8 between the blood circulating compartment and the alveolar space; (2) to determine the relationship of G-CSF, IL-8, and ENA-78 to neutrophil count in BALF; and (3) to evaluate if there is a difference between ARDS and ALI or a correlation to lung injury expressed as PaO2/fraction of inspired oxygen (FIO2) ratio concerning the measured variables.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Discussion
 References
 
Study Population
This prospective, observational study was carried out on 29 patients (24 men and 5 women; median age, 50 years; range, 19 to 70 years): 19 patients with ARDS and 10 patients with ALI. Diagnosis of ARDS or ALI was made according to criteria of the American-European Consensus Conference on ARDS17 (acute onset of respiratory failure, bilateral infiltrates on chest radiography, pulmonary-artery wedge pressure <= 18 mm Hg or the absence of clinical evidence of left atrial hypertension; ALI was considered to be present if PaO2/FIO2 ratio was <= 300, and ARDS if PaO2/FIO2 ratio was <= 200). ALI/ARDS was observed after major surgery, multiple trauma, head injury, thorax trauma, pancreatitis, pneumonia, or severe sepsis. Exclusion criteria for enrollment of patients were hemofiltration, massive transfusion in the immediately preceding 24 h, medical history of chronic lung disease, and immunosuppressive therapy. All patients were receiving mechanical ventilation and standard intensive care support. Severity of illness was scored during the first 24 h after onset of ALI/ARDS using the simplified acute physiology score II (SAPS II) and sequential organ failure assessment (SOFA). For calculation of the SAPS II and SOFA score, which were single determinations during the first day after onset of ALI/ARDS, the worst values of physiologic and clinical variables observed over 24 h were taken in account as originally described.18 19 BAL (routine protocol for microbiologic culture with 100 mL of 0.9% saline solution sequentially instilled and suctioned in 20-mL portions) was performed in a subsegment of the right middle lobe of lung within 12 h and 24 h after onset of ALI/ARDS. Blood for determination of G-CSF, ENA-78, and IL-8 in serum was obtained from the patients at the same time. The protocol for this study was approved by the Ethics Committee of the Leopold-Franzens-University of Innsbruck.

BALFs and Blood Sampling
Recovered BALF volume was not different between the ARDS and ALI groups (ARDS group, 43 mL [range, 28 to 57 mL]; ALI group, 41.5 mL [range, 30 to 56 mL]; p = 0.5819). After collecting BALF in tubes, the fluid retrieved was filtered through sterile gauze and centrifuged at 300g at 4°C for 10 min to remove mucus and cells. The supernatants were aliquoted into cups and frozen at - 80°C until analysis. Blood sampling was performed with three 4-mL syringes and then ice cooled. Blood was allowed to clot and then centrifuged at 1,000g for 10 min at 4°C. Multiple aliquots of serum were frozen at - 80°C until analysis.

Measurement of G-CSF, ENA-78, and IL-8
Concentrations of G-CSF, ENA-78, and IL-8 in BALF as well as in serum were determined by solid-phase, enzyme-linked immunosorbent assay kits (Quantikine Human G-CSF, Human ENA-78, and Human IL-8 Immunoassay; R&D Systems; Minneapolis, MN); for technical details see: http://www.rndsystems.com.

Calculation of Recovered Pulmonary ELF Volume
The total volume of recovered ELF can be calculated by using the following formula16 :

Concentrations of G-CSF, ENA-78, and IL-8 [X] in the pulmonary ELF were then calculated by the following formula and are shown as picograms per milliliter of ELF:

or

Cell Count in BALF and Cytospin Preparations
After centrifugation of BALF, the cell pellet was resuspended in 2 mL of normal saline solution and the cells were counted in a "Neubauer improved" (Brand; Wertheim, Germany) hemocytometer. Cytocentrifuge preparations were made on a Shandon Cytospin II (Shandon Instruments; Sewickley, PA) using 100-µL aliquots of the above cell suspension. WBC differentiation was made by May-Gruenwald and Giemsa stains. Five hundred cells were counted on each slide.

Statistical Analysis
Data are expressed as median (range). Comparisons of levels of G-CSF and chemokines between ARDS and ALI patients, between ELF and serum concentrations, and nonsurvivors and survivors in the ARDS group were made using the Mann-Whitney U test. The Fisher exact test was used to compare gender distribution and observed mortality between the ARDS and ALI groups. Correlations were determined by Spearman rank correlation; p < 0.05 was considered significant. Analyses were performed using the StatView software package (SAS Institute; Cary, NC).

Results
The ARDS and ALI groups were comparable in age, clinical conditions responsible for lung injury, and clinical scoring with SAPS II and SOFA (Table 1 ). Most of the patients had a combination of risk factors for the development of ALI/ARDS. The mortality of patients with ARDS was higher than the mortality of patients with ALI (36.8% vs 10%, statistically not significant due to small sample size; Table 1 ). In the ARDS group, SAPS II was significantly higher in patients who died (nonsurvivors, 55 [range, 35 to 66]; survivors, 36.5 [range, 27 to 57]; p = 0.0225).


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  		Table 1.. Demographic Data and Clinical Characteristics of Patients With ARDS and ALI*

 
G-CSF was detected in BALF in 18 of 19 patients with ARDS, and in 7 of 10 patients with ALI (detection limit, 40 pg/mL), and in all serum samples. Concentrations of G-CSF in BALF (ARDS, 690 pg/mL [range, 0 to 4,990 pg/mL]; ALI, 117.5 pg/mL [range, 0 to 878 pg/mL]; p = 0.0459) and serum (ARDS, 287 pg/mL [range, 41 to 6,270 pg/mL]; ALI, 65.5 pg/mL [range, 43 to 258 pg/mL]; p = 0.0261) were significantly higher in patients with ARDS than with ALI (Fig 1 ). G-CSF in BALF and serum of all patients correlated positively with neutrophil count in BALF (r = 0.507, p = 0.0073 and r = 0.587, p = 0.0019, respectively) [Fig 2 ]. There was a negative correlation of G-CSF in serum with PaO2/FIO2 ratio (r = - 0.511, p = 0.0068) [Fig 3 ]. As G-CSF levels in BALF are diluted into BALF and do not reflect actual concentrations in lung airways, calculations were normalized for ELF to allow for comparisons with levels in the lung blood-circulating compartment. Concentrations of G-CSF in ELF of all patients were significantly higher than in serum (ELF, 4,466 pg/mL [range, 0 to 64,157 pg/mL]; serum, 114 pg/mL [range, 41 to 6,270 pg/mL]; p = < 0.0001) [Fig 4 ].



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  		Figure 1.. G-CSF, ENA-78, and IL-8 in BALF and serum of patients with ARDS and ALI. Results are expressed in box plots: 10th, 25th, 50th (median), 75th, and 90th percentiles. Concentrations of G-CSF in BALF and serum, and IL-8 in BALF were statistically significantly higher in ARDS than ALI patients. Statistics are by Mann-Whitney U test; *p < 0.05.

 


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  		Figure 2.. G-CSF in BALF (top, a) and serum (middle, b), and IL-8 in BALF (bottom, c) of all ARDS/ALI patients correlated positively with neutrophil count in BALF. Statistics are by Spearman rank correlation; log10 scale for G-CSF, IL-8 concentrations, and neutrophil count in BALF.

 


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  		Figure 3.. G-CSF in serum (top, a) and IL-8 in BALF (bottom, b) of all ARDS/ALI patients correlated negatively with PaO2/FIO2 ratio. Statistics are by Spearman rank correlation; log10 scale for G-CSF in serum and IL-8 in BALF.

 


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  		Figure 4.. Concentrations of G-CSF and ENA-78 in ELF of all ARDS/ALI patients were significantly higher than in serum. Results are expressed in box plots: 10th, 25th, 50th (median), 75th, and 90th percentiles. Statistics are by Mann-Whitney U test; *p < 0.0001, **p < 0.01.

 
ENA-78 could be detected in BALF in 14 of 19 patients with ARDS (306 pg/mL; range, 0 to 9,276 pg/mL; detection limit, 30 pg/mL), and in 8 of 10 patients with ALI (189 pg/mL; range, 0 to 6,498 pg/mL), and in serum of all patients (ARDS, 438 pg/mL [range, 204 to 4,038 pg/mL]; ALI, 657 pg/mL [range, 42 to 2,700 pg/mL]) [Fig 1 ]. Levels in BALF and serum were not statistically different between ARDS and ALI. There was neither a correlation with neutrophil count nor with PaO2/FIO2 ratio. Concentrations of ENA-78 in ELF of all patients were significantly higher than in serum (ELF, 4,011 pg/mL [range, 0 to 217,683 pg/mL]; serum, 444 pg/mL [range, 42 to 4,038 pg/mL], p = 0.0096) [Fig 4 ].

IL-8 was detected in all patients in BALF, and serum concentrations in BALF of patients with ARDS were significantly higher than in patients with ALI (ARDS, 3,899 pg/mL [range, 288 to 15,294 pg/mL]; ALI, 1,219 pg/mL [range, 86 to 2,586 pg/mL]; p = 0.0193) [Fig 1 ]. IL-8 in BALF of all patients correlated with neutrophil count in BALF (r = 0.608, p = 0.0013) [Fig 2 ] and showed a negative correlation with PaO2/FIO2 ratio (r = - 0.504, p = 0.0076) [Fig 3 ]. Concentrations of IL-8 in ELF of all patients were significantly higher than in serum (ELF, 29,726 pg/mL [range, 738 to 240,422 pg/mL]; serum, 58 pg/mL [range, 31 to 1,142 pg/mL]; p < 0.0001).

Concentrations of G-CSF in BALF correlated with levels of IL-8 in BALF (r = 0.53, p = 0.005); however, there was no correlation between G-CSF and ENA-78 or between ENA-78 and IL-8 in BALF. Concentrations of G-CSF in BALF showed a weak correlation with levels of G-CSF in serum (r = 0.43, p = 0.023); there was no correlation of ENA-78 or IL-8 in BALF concentration of these chemokines in serum.

Levels of G-CSF in BALF and ENA-78 in serum were not different between nonsurvivors and survivors in the ARDS group. However, concentrations of ENA-78 in BALF (nonsurvivors, 468 pg/mL [range, 306 to 9,276 pg/mL]; survivors, 63.5 pg/mL [range, 0 to 960 pg/mL]; p = 0.0088) and IL-8 in serum (nonsurvivors, 171 pg/mL [range, 31 to 1,142 pg/mL]; survivors, 39.5 pg/mL [range, 33 to 390 pg/mL]; p = 0.0346) were significantly higher in patients with ARDS who died. Levels of G-CSF in serum (nonsurvivors, 775 pg/mL [range, 43 to 6,270 pg/mL]; survivors, 196.5 pg/mL [range, 41 to 2,500 pg/mL]; p = 0.2719) and IL-8 in BALF (nonsurvivors, 4,975 pg/mL [range, 470 to 14,706 pg/mL]; survivors, 2,149 pg/mL [range, 288 to 15,294 pg/mL]; p = 0.2367) tended to be higher in patients with ARDS who died.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Discussion
References
 
Administration of G-CSF results in improvement of host defense paired with anti-inflammatory effects. There is evidence from animal and clinical studies that administration of G-CSF may also be beneficial in nonneutropenic infections.20 Such observations clearly demonstrate the potential of G-CSF to affect polymorphonuclear leukocyte (PMN)-dependent pathophysiology. Since G-CSF improves the functional activity of developing and mature PMNs, a major concern using G-CSF in patients with pneumonia and ARDS has been that activated PMNs recruited to the lungs, further stimulated by G-CSF, could aggravate lung injury. There was no harmful effect of G-CSF on endotoxin-induced lung injury in sheep, guinea pigs, and pigs.21 22 23 Other studies24 25 showed that G-CSF potentiates endotoxin-induced lung injury. Results of the present investigation demonstrate high concentrations of endogenous G-CSF in ELF of the lung in the early phase of ARDS and ALI; G-CSF levels in BALF and serum are significantly higher in ARDS than in ALI, they correlate with pulmonary neutrophilia, and G-CSF in serum correlates with severity of lung injury expressed as PaO2/FIO2 ratio. This study further supports a prominent role of IL-8 for recruitment of neutrophils into the lung in the early phase of ARDS; since concentrations of IL-8 in BALF of patients with ARDS are significantly higher than in ALI, they correlate with pulmonary neutrophils and PaO2/FIO2 ratio and are clearly higher in ELF than in serum. However, levels of ENA-78 in BALF and serum were not different between ARDS and ALI and show no correlation with pulmonary neutrophilia or PaO2/FIO2 ratio, suggesting that ENA-78 may not be so important.

G-CSF serum levels were determined in many settings of infection and inflammation and suggested the relevance of this factor for steady-state blood cell formation and in pathologic situations. In > 85% of healthy volunteers, G-CSF serum levels were < 40 pg/mL, and no significant modulation was found during the course of a day. In ICU patients with septic shock, G-CSF serum levels reached 20,000 pg/mL; in trauma patients with diagnosed sepsis, an increase in G-CSF serum levels was followed by a significant decrease after recovery.26

Previous studies8 12 of G-CSF levels in BALF from patients with ARDS on day 1 showed that they were on average 10-fold higher than those in BALF from healthy volunteers and decreased progressively to day 14; the concentrations of G-CSF in BALF paralleled the antiapoptotic effect of BALF of patients with ARDS on neutrophils. Aggarwal et al9 demonstrated that levels of G-CSF and IL-8, but not GM-CSF, in BALF correlated strongly with BALF neutrophil counts; levels of G-CSF were significantly higher in nonsurvivors than survivors. The results of the present study confirm the relationship of G-CSF in BALF and pulmonary neutrophilia. Levels of G-CSF in BALF and serum were significantly higher in ARDS than in ALI, suggesting a pathophysiologic role of G-CSF in the development of lung injury in these patients. The comparison of the concentrations of G-CSF between ELF and serum extends previous data by indicating a high local production of G-CSF in the lung. Transcriptional activation of G-CSF is triggered by lipopolysaccharides and pro-inflammatory cytokines like tumor necrosis factor-{alpha} and interleukin-1ß,27 which are key inflammatory mediators in ARDS. Monocytes and macrophages seem to represent the major G-CSF–producing cell type. In addition, a considerable synthesis of G-CSF has been reported in endothelial cells, fibroblasts, and T lymphocytes.26 Production of G-CSF messenger RNA by bronchial epithelial cells was dramatically increased in a rat model of hemorrhagic shock that also demonstrated lung injury.28 The potential of G-CSF to contribute to the pathogenesis of ARDS is further supported by reports of the development of ALI in patients treated systemically with G-CSF,6 29 and by results from animal studies.5 24 25 30 However, G-CSF treatment was safe and well tolerated when administered to patients with multilobar pneumonia31 or patients with systemic inflammatory response syndrome and sepsis in a surgical ICU.32 Clarification of when and how G-CSF may be beneficial or deleterious awaits further study. The present study demonstrates for the first time that in ARDS, pulmonary ELF levels of G-CSF are higher than serum levels, thus forming a concentration gradient between alveoli and blood vessels that may contribute to the tissue accumulation of PMNs.

The {alpha}-chemokines IL-8 and ENA-78 have been found in BALF of patients at risk for and with established ARDS. Correlations between IL-8 and total neutrophil count in BALF at the onset of ARDS are poor in several studies.14 Goodman et al15 found that IL-8 and ENA-78 were the cytokines most strongly and consistently correlated with neutrophil count in BALF of patients with ARDS. We found a strong correlation of IL-8 with neutrophils in BALF in ALI/ARDS patients; however, no correlation of ENA-78 with neutrophil count in BALF measured 12 to 24 h after the onset of ALI/ARDS. In contrast to our study, Goodman et al15 started their investigation on day 3 after onset of ARDS, which might explain the differing results. Furthermore, Donnelly et al33 reported in an abstract that there was a clear relationship between high levels of IL-8 (but not ENA-78) in BALF (most of which were performed within 2 h of the trauma incident) in patients at risk for ARDS and subsequent ARDS development. However, in established ARDS, both IL-8 and ENA-78 levels were significantly elevated in BALF in comparison to control subjects receiving mechanical ventilation. IL-8 and ENA-78 have been identified as products of lipopolysaccharide-stimulated alveolar macrophages.14 34 The hypothesis of local production of IL-8 and ENA-78 in the lungs is supported by our observation that levels of both chemokines are much more higher in ELF than in serum. An in vitro study34 demonstrated that IL-8 is the predominant C-X-C chemokine and dominant neutrophil chemoattractant accumulating in 24-h supernatants of lipopolysaccharide-stimulated human alveolar macrophages. Significant associations with the severity of ARDS or alveolar neutrophilia of IL-8 but not ENA-78 despite elevated BALF and ELF levels confirm that in early ARDS IL-8 may be the more important of the two chemokines. However, ENA-78 was significantly higher in nonsurvivors than in survivors in BALF of patients with ARDS, indicating its possible role in the further development of lung injury. The pathophysiologic importance of IL-8 in BALF in the development of ARDS is underlined by the present findings that levels of IL-8 in BALF were higher in patients with ARDS than in ALI, and the negative correlation of IL-8 in BALF with the severity of lung injury expressed as PaO2/FIO2 ratio. The concentration gradient of IL-8 between the circulatory (serum) and alveolar (ELF) compartment suggest a direct role of IL-8 in the attraction of PMNs into lung alveoli.

The preponderance of male subjects in the study population can be explained by the setting of a trauma/surgical ICU. Data indicate a significantly smaller number of female patients requiring surgical intensive care as well as a significantly lower incidence of severe sepsis in female intensive care patients.35 The admission rate to a level I trauma center is higher for male (71.4%) than for female (28.6%) patients, and the incidence of posttraumatic sepsis and multiple organ dysfunction syndrome is significantly increased in severely injured male patients in comparison to female patients.36 A study37 on the incidence and mortality of ALI/ARDS in three Australian states revealed a male/female ratio of 70:30. Although the percentage of male patients was higher in the ARDS group than in the ALI group (89.5% vs 70%, statistically not significant; Table 1 ), so far there is no evidence that the inflammatory response in the development of ARDS is sex specific.

We conclude that G-CSF may play a pathophysiologically important role in the accumulation and activation of neutrophils in ARDS. Local G-CSF production is the likely driving force for neutrophils, rather than elevation of circulating levels of G-CSF such as in therapeutic parenteral administration. If the concentration gradient of G-CSF between parenchymal tissue and blood circulating compartment directs neutrophil locomotion toward the lung, disruption of this gradient by exogenous elevation of circulating G-CSF may attenuate neutrophil accumulation. Theoretically, as G-CSF tissue levels are elevated early during the development of ALI and ARDS, systemic G-CSF therapy would be required early on in the clinical course such as achieved with prophylactic administration. In comparison to ENA-78, IL-8 seems to be the predominant neutrophil chemoattractant in the early phase of ARDS.


   Acknowledgements
 
We thank Dr. Peter Niedermueller for technical assistance and Dr. Rajam Csordas for editorial assistance and critical reading.


   Footnotes
 
Abbreviations: ALI = acute lung injury; BALF = BAL fluid; ELF = epithelial lining fluid; ENA-78 = epithelial neutrophil activating peptide-78; FIO2 = fraction of inspired oxygen; G-CSF = granulocyte colony-stimulating factor; IL = interleukin; PMN = polymorphonuclear leukocyte; SAPS II = simplified acute physiology score II; SOFA = sequential organ failure assessment

Supported by a Swarovski-University of Innsbruck grant to Dr. Wiedermann.

Received for publication January 31, 2003. Accepted for publication June 10, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Discussion
 References
 

  1. Wyncoll, DLA, Evans, TW (1999) Acute respiratory distress syndrome. Lancet 354,497-501[CrossRef][ISI][Medline]
  2. Ware, LB, Matthay, MA The acute respiratory distress syndrome. N Engl J Med 2000;342,1334-1349[Free Full Text]
  3. Tate, RM, Repine, JE Neutrophils and the adult respiratory distress syndrome. Am Rev Respir Dis 1983;128,552-559[ISI][Medline]
  4. Louie, SG, Jung, B Clinical effects of biologic response modifiers. Am J Hosp Pharm 1993;50(suppl 3),S10-S18
  5. Hierholzer, C, Kelly, E, Lyons, V, et al G-CSF instillation into rat lungs mediates neutrophil recruitment, pulmonary edema, and hypoxia. J Leukocyte Biol 1998;63,169-174[Abstract]
  6. Takahashi, Y, Kobayashi, Y, Chikayama, S, et al Effect of granulocyte colony-stimulating factor on the onset of the adult respiratory distress syndrome. Acta Haematol 1999;101,124-129[CrossRef][ISI][Medline]
  7. Azoulay, E, Attalah, H, Harf, A, et al Granulocyte colony-stimulating factor or neutrophil-induced pulmonary toxicity: myth or reality? Chest 2001;120,1695-1701[Free Full Text]
  8. Matute-Bello, G, Liles, WC, Radell, F, II, et al Modulation of neutrophil apoptosis by granulocyte colony-stimulating factor and granulocyte/macrophage colony-stimulating factor during the course of acute respiratory distress syndrome. Crit Care Med 2000;28,1-7[CrossRef][ISI][Medline]
  9. Aggarwal, A, Baker, CS, Evans, TW, et al G-CSF and IL-8 but not GM-CSF correlate with severity of pulmonary neutrophilia in acute respiratory distress syndrome. Eur Respir J 2000;15,895-901[Abstract]
  10. Root, RK, Dale, DC Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor: comparisons and potential for use in the treatment of infections in nonneutropenic patients. J Infect Dis 1999;179(suppl 2),S342-S352
  11. Cox, G, Gauldie, J, Jordana, M Bronchial epithelial cell derived cytokines (G-CSF and GM-CSF) promote the survival of peripheral blood neutrophils in vitro. Am J Respir Cell Mol Biol 1992;7,507-513
  12. Matute-Bello, G, Liles, WS, Radella, F, II, et al Neutrophil apoptosis in the acute respiratory distress syndrome. Am J Respir Crit Care Med 1997;156,1969-1977[Abstract/Free Full Text]
  13. Kunkel, SL, Standiford, TJ, Kasahara, K, et al Interleukin-8 (IL-8): the major neutrophil chemotactic factor in the lung. Exp Lung Res 1991;17,17-23[ISI][Medline]
  14. Martin, TR Lung cytokines and ARDS: Roger S Mitchell Lecture. Chest 1999;116(1 Suppl),2S-8S
  15. Goodman, RB, Strieter, RM, Martin, DP, et al Inflammatory cytokines in patients with persistence of the acute respiratory distress syndrome. Am J Respir Crit Care Med 1996;154,602-611[Abstract]
  16. Rennard, SI, Basset, G, Lecossier, D, et al Estimation of volume of epithelial lining fluid recovered by lavage using urea as a marker of dilution. J Appl Physiol 1986;60,532-538[Abstract/Free Full Text]
  17. Bernard, GR, Artigas, A, Brigham, KL, et al The American-European consensus conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994;149,818-824[Abstract]
  18. Le Gall, JR, Lemeshow, S, Saulnier, F A new simplified acute physiology score (SAPS II) based on a European/North American multicenter study. JAMA 1993;270,2957-2963[Abstract]
  19. Vincent, JL, Moreno, R, Takala, J, et al The SOFA (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. Intensive Care Med 1996;22,707-710[ISI][Medline]
  20. Wiedermann, FJ, Mittermayr, M, Hoffmann, G, et al Recombinant granulocyte colony-stimulating factor (G-CSF) in infectious diseases: still a debate. Wien Klin Wochenschr 2001;113,90-96[ISI][Medline]
  21. Koizumi, T, Kubo, K, Koyama, S, et al Neutrophils pretreated with granulocyte colony-stimulating factor (G-CSF) are not related to the severity of endotoxin-induced lung injury. Exp Lung Res 1997;23,393-404[ISI][Medline]
  22. Kanazawa, M, Ishizaka, A, Hasegawa, N, et al Granulocyte colony-stimulating factor does not enhance endotoxin-induced acute lung injury in guinea pigs. Am Rev Respir Dis 1992;145,1030-1035[ISI][Medline]
  23. Fink, MP, O'Sullivan, BP, Menconi, MJ, et al Effect of granulocyte colony-stimulating factor on systemic and pulmonary responses to endotoxin in pigs. J Trauma 1993;34,571-578[ISI][Medline]
  24. King, J, Deboisblanc, BP, Mason, CM, et al Effect of granulocyte colony-stimulating factor on acute lung injury in the rat. Am J Respir Crit Care Med 1995;151,302-309[Abstract]
  25. Terashima, T, Kanazawa, M, Sayama, K, et al Granulocyte colony-stimulating factor exacerbates acute lung injury induced by intratracheal endotoxin in guinea pigs. Am J Respir Crit Care Med 1994;149,1295-1303[Abstract]
  26. Hareng, L, Hartung, T Induction and regulation of endogenous granulocyte colony-stimulating factor formation. Biol Chem 2002;383,1501-1517[CrossRef][ISI][Medline]
  27. Vellenga, E, Rambaldi, A, Ernst, TJ, et al Independent regulation of M-CSF and G-CSF gene expression in human monocytes. Blood 1988;71,1529-1532[Abstract/Free Full Text]
  28. Hierholzer, C, Kelly, E, Tsukada, K, et al Hemorrhagic shock induces G-CSF expression in bronchial epithelium. Am J Physiol 1997;273,L1058-L1064
  29. Schilero, GJ, Oropello, J, Benjamin, E Impairment in gas exchange after granulocyte colony stimulating factor (G-CSF) in a patient with the adult respiratory distress syndrome. Chest 1995;107,276-278[Abstract/Free Full Text]
  30. Azoulay, E, Attalah, H, Yang, K, et al Exacerbation by granulocyte colony-stimulating factor of prior acute lung injury: implication of neutrophils. Crit Care Med 2002;30,2115-2122[CrossRef][ISI][Medline]
  31. Nelson, S, Heyder, AM, Stone, J, et al A randomized controlled trial of filgrastim for the treatment of hospitalized patients with multilobar pneumonia. J Infect Dis 2000;182,970-973[CrossRef][ISI][Medline]
  32. Gross-Weege, W, Weiss, M, Schneider, M, et al Safety of a low-dosage filgrastim (rhG-CSF) treatment in non-neutropenic surgical intensive care patients with inflammatory process. Intensive Care Med 1997;23,16-22[CrossRef][ISI][Medline]
  33. Donnelly, SC, Strieter, RM, Kunkel, SL, et al Chemotactic cytokines in the established adult respiratory distress syndrome and at-risk patients [abstract]. Chest 1994;105,98S-99S
  34. Goodman, RB, Strieter, RM, Frevert, CW, et al Quantitative comparison of C-X-C chemokines produced by endotoxin-stimulated human alveolar macrophages. Am J Physiol 1998;275,L87-L95
  35. Wichman, MW, Inthorn, D, Andress, HJ, et al Incidence and mortality of severe sepsis in surgical intensive care patients: the influence of patient gender on disease process and outcome. Intensive Care Med 2000;26,167-172[CrossRef][ISI][Medline]
  36. Oberholzer, A, Keel, M, Zellweger, R, et al Incidence of septic complications and multiple organ failure in severely injured patients is sex specific. J Trauma 2000;48,932-937[ISI][Medline]
  37. Bersten, AD, Edibam, C, Hunt, T, et al Incidence and mortality of acute lung injury and the acute respiratory distress syndrome in three Australian states. Am J Respir Crit Care Med 2002;165,443-448[Abstract/Free Full Text]



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