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(Chest. 2003;124:644-652.)
© 2003 American College of Chest Physicians

Deactivation of Alveolar Macrophages in Septic Neutropenic ARDS*

Djamel Mokart, MD; Benoit P. Guery, MD, PhD; Reda Bouabdallah, MD; Claude Martin, MD; Jean-Louis Blache, MD; Christine Arnoulet, MD and Jean-Louis Mege, MD, PhD

* From the Departments of Anesthesiology and Intensive Care Unit (Drs. Mokart and Blache), Biology (Dr. Arnoulet), and Hematology (Dr. Bouabdallah), Paoli-Calmette Institute, Marseille, France; the Department of Critical Care and Infectious Diseases (Dr. Guery), CH Dron, Tourcoing, France; the Department of Anesthesiology and Intensive Care Unit (Dr. Martin), Hôpital Nord, Marseille, France; and the Laboratory of Immunology and Hematology (Dr. Mege), Hôpital de la Conception, Marseille, France.

Correspondence to: Djamel Mokart, MD, Department of Anesthesiology and Intensive Care Unit, Paoli-Calmette Institute, 232 Blvd Sainte Marguerite, 13273 Marseille Cedex 9, France; e-mail: mokartd{at}marseille.fnclcc.fr


   Abstract
TOP
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Study objectives: Neutrophils often have been involved in the pathophysiology of ARDS. However, authentic ARDS has been described in patients with severe neutropenia, suggesting the presence of other potential mechanisms that are responsible of this syndrome. Alveolar macrophages (AMs) could be involved in the development of ARDS, and so we decided to study AM activation in neutropenic patients.

Patients: We designed a prospective study and enrolled two subgroups of consecutive patients (group A, 18 patients; group B, 22 patients) with septic ARDS. In the first period, 7 of 18 patients were neutropenic, and in the second period 10 of 22 patients were neutropenic. All neutropenic patients were treated with granulocyte colony-stimulating factor (G-CSF).

Measurements and results: In group A, BAL fluid samples were analyzed for differential and total cell counts, and alveolar activation marker expression (ie, human leukocyte antigen [HLA]-DR locus) was determined. Basal and lipopolysaccharide (LPS)-stimulated production of tumor necrosis factor, interleukin (IL)-1ß, IL-6, and IL-10 was evaluated in group B. In neutropenic patients, the BAL fluid total cell count and the neutrophil absolute count was significantly lower compared to those in nonneutropenic patients (p = 0.029 and p = 0.046, respectively). HLA-DR expression on AMs was significantly decreased (p = 0.016), and the percentage of AMs expressing HLA-DR was also significantly lower (p = 0.041). In neutropenic patients, the mean percentage of AMs expressing HLA-DR was significantly lower in deceased patients compared to survivors (30 ± 7 vs 43 ± 1, respectively; p = 0.047). Basal AMs released cytokines was comparable between the two groups; however, LPS stimulation yielded a deactivation of AMs in neutropenic patients.

Conclusion: These results suggest a deactivation and/or hypoactivation of AMs in septic ARDS patients. This deactivation/hypoactivation could be linked to the use of G-CSF as this molecule has been shown to generate a down-regulation of HLA-DR expression.

Key Words: alveolar macrophage • ARDS • human leukocyte antigen-DR • neutropenia


   Introduction
TOP
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
The syndrome ARDS, which formally was described by Ashbaugh et al1 in 1967, is the result of local or systemic insults leading to diffuse alveolar damage. Various mediators have been shown to be involved in the pathophysiology of ARDS, with a complex interplay between proinflammatory and anti-inflammatory mediators.2 Among the inflammatory cells, neutrophils seem to play a major role. In an endotoxemic sheep model,3 granulocyte depletion has prevented an increase in lung vascular permeability. Moreover, neutrophil influx into the airspace occurs prior to the development of ARDS,4 circulating neutrophils are activated in ARDS,5 the severity of lung injury correlates with neutrophil influx,6 and finally, in some patients, the persistence of the initial neutrophilic inflammatory response is associated with a higher mortality rate.7 8 However, different studies have shown the occurrence of ARDS in severe neutropenic patients who have been exposed to radiation and cytotoxic drugs,9 10 suggesting an alternative mechanism besides neutrophils.

In septic neutropenic patients with infectious pneumonia, BAL is used predominantly to recover alveolar macrophages (AMs).11 12 Activated AMs can release a wide variety of mediators, most of them capable of damaging the lung alveolar-capillary barrier.13 14 15 16 Schwartz et al17 showed in ARDS patients an increased in vivo activation of the nuclear transcriptional regulatory factor nuclear factor {kappa}B in AMs, which may contribute to the increased expression of various cytokines. Consistent with an important role for macrophage in ARDS, in a septic neutropenic guinea pig model of ARDS18 lung injury could be induced with primed AMs. Considering these elements, we can speculate that AMs could play a major role in the pathophysiology of ARDS in neutropenic patients.

To our knowledge, no studies in the literature have focused on the activation state of AMs during ARDS in septic patients with severe neutropenia. Therefore, we decided to study prospectively the characteristics of AMs in septic neutropenic ARDS patients. We studied the AM expression of human leukocyte antigen (HLA)-DR locus in one subgroup of patients. Variations in HLA-DR expression (ie, class II major histocompatibility complex) on the surface of monocytes/macrophages are strongly linked to the activation state of these cells and to the outcomes of patients with sepsis.19 20 To further characterize AM activation, in the second part of our study we tried to evaluate in vitro AM products under basal conditions and after lipopolysaccharide (LPS) exposure.


   Patients and Methods
TOP
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients
The study was divided into the following two time periods. First, we evaluated HLA-DR expression, and these results raised the question of AM activation, which was therefore studied in the second period. For the first part of the study, between March 1997 and June 1998, 18 consecutive patients (group A) were prospectively enrolled into the study. For the second part of the study, between April 1998 and May 1999, 22 consecutive patients (group B) were prospectively enrolled into the study.

All patients had developed septic ARDS and were divided into two groups, neutropenic (ie, absolute neutrophil count, < 500 cells/µL) and nonneutropenic (ie, absolute neutrophil count, > 1,000 cells/µL). We used the definition of ARDS recommended by the American-European Consensus Conference,21 and sepsis was defined according to the criteria of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference.22 The study was conducted after obtaining approval from our institutional ethics committee and informed consent had been obtained from each patient’s next of kin. Standard supportive care as well as therapy with broad-spectrum antibiotics were provided in all patients. All neutropenic patients were treated with granulocyte colony-stimulating factor (G-CSF). All patients underwent fiberoptic bronchoscopy with BAL fluid sampling using standard procedures23 during the first 3 days after the onset of ARDS. BAL fluid samples were obtained from the lingula and middle lobe if these segments were radiographically involved. Otherwise, the BAL fluid sample was obtained from areas of radiographic densities. Before BAL, all patients were ventilated using pressure-controlled mechanical ventilation with positive end-expiratory pressure. When BAL was performed, no patient was receiving inhaled nitric oxide. Patient characteristics are summarized in Tables 1 2 3 .


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  		Table 1.. Characteristics of Group A Patients*

 

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  		Table 2.. Characteristics of Group B Patients*

 

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  		Table 3.. Baseline Population Description*

 
Cytologic Analysis
BAL fluids were immediately analyzed with numeration of total nucleated elements, cytologic examination, and determination of AM surface marker expression. A total cell count was performed by light microscopy using a hemocytometer. After cytocentrifugation (Cytospin 2; Shandon Southern Instruments; Pittsburgh, PA), slides were stained for a differential cell count using the May-Grünwald Giemsa method. Percentages of macrophages, lymphocytes (LPCs), and polymorphonuclear neutrophils (PMNs) were determined by microscopic examination. A minimum of 300 nucleated cells was examined.

Phenotype Analysis
Given the low cellularity of some BAL fluids, a total aliquot was washed once in phosphate-buffered saline solution, and the pellet was diluted in 600 µL phosphate-buffered saline solution containing 30% AB serum without enumeration. A maximum number of cells was therefore examined in each experiment. Immunophenotyping was performed by three-color flow cytometry using direct immunofluorescence with a panel of monoclonal antibodies conjugated to fluorescein isothiocyanate and R-phycoerythrin (PE), combined with the panleukocytic CD45 marker conjugated to PE-cyanin 5.1. The following surface markers were studied: HLA-DR, as an activation marker; and CD16, as it is relatively specific for monocyte-macrophage lineage. Irrelevant fluorescein isothiocyanate and PE/IgG1 coupled to PE-cyanin 5.1/CD45 were used as controls. Table 4 indicates clones and the provenance of the used monoclonal antibodies. Fluorescent cells were analyzed with a flow cytometer (FACScan; Becton Dickinson, Franklin Lakes, NJ) after the lysis of RBCs with a lysing reagent (Becton Dickinson). Macrophages were separated from cell debris, LPCs, and PMNs by gating on light-scatter characteristics and CD45 positivity. The selected population was further controlled by CD14 and CD11c expression. A minimum of 10,000 cells was recorded on forward and side-scatter parameters, and at least 2,000 macrophages were further gated and analyzed on each sample. For each marker, we considered the percentage of positive cells and the mean fluorescence intensity (MFI).


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  		Table 4.. Monoclonal Antibodies Used for Phenotyping of AMs

 
Isolation and Culture of AMs
AMs were obtained from BAL fluid, as previously described,24 and were incubated with supplemented RPMI 1640 medium for 24 h at 37°C. Endotoxin contamination was excluded by testing reagents with an amoebocyte lysate assay (Limulus assay; Whittaker Bioproducts; Fontenay-sous-Bois, France).

Macrophage Activation and Immunoassays for Cytokine Determination
AMs were cultured (5 x 105 cells per assay) in RPMI 1640 medium containing 10% fetal bovine serum and antibiotics in the presence or absence of Escherichia coli LPS (1 µg/mL) for 16 h at 37°C. Cell supernatants were collected and stored at -70°C before the assays were performed. Cytokine measurements were performed with a quantitative sandwich enzyme immunoassay (R&D systems; British Biotechnology; Abington, UK). Supernatants were assayed for tumor necrosis factor (TNF), interleukin (IL)-1ß, IL-6, and IL-10 by enzyme immunoassays (Immunotech; Marseille, France).

Statistical Analysis
Comparisons between two independent groups were analyzed by the Mann-Whitney U test, and a p value of < 0.05 was considered to be significant. Comparisons between two related groups were analyzed by Wilcoxon test, and a p value of < 0.05 was considered to be significant. For dichotomous data, percentages were calculated and compared using the Fisher exact test, and a p value of < 0.05 was considered to be significant.


   Results
TOP
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Decrease in Total Number of WBCs in BAL Fluid
As expected, the total WBC count in BAL fluid was significantly lower in neutropenic patients than in nonneutropenic patients. The absolute count of PMNs in BAL fluid was significantly lower in neutropenic patients than in nonneutropenic patients (Fig 1 ). The percentage of AMs was statistically higher in neutropenic patients compared to that in the other group (group A, 71 ± 7% vs 54 ± 8%, respectively; group B, 69 ± 6% vs 45 ± 8%, respectively; p < 0.05), however, the absolute count was decreased compared to that in nonneutropenic patients (Fig 1) .



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  		Figure 1.. Absolute numbers of total alveolar cells, PMNs, AMs, and LPCs retrieved per milliliter of BAL fluid. Top, A: group A. Bottom, B: group B. * = significant comparisons between neutropenic patients and nonneutropenic patients (p < 0.05). Values given as the mean ± SEM.

 
Lower HLA-DR Expression in Neutropenic Patients and Correlation With Poor Prognosis
The number of AMs expressing HLA-DR was significantly lower in neutropenic patients than in nonneutropenic patients (35 ± 4% vs 66 ± 8%, respectively; p = 0.041), and, similarly, the levels of expression (ie, MFI) were also significantly lower (102 ± 38 vs 265 ± 52, respectively; p = 0.016) [Fig 2 ]. In neutropenic patients, the percentage of AMs expressing HLA-DR was significantly lower in deceased patients compared to survivors (30 ± 7% vs 43 ± 1%, respectively; p = 0.047). We did not observe any change in CD45 or CD16 expression between the two groups (Fig 3 ).



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  		Figure 2.. Surface expression of HLA-DR on AMs is expressed in MFI. % AMs DR + = the percentage of AMs expressing HLA-DR; * = significant comparisons between neutropenic patients and nonneutropenic patients (p < 0.05). Values given as the mean ± SEM.

 


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  		Figure 3.. Surface expression of CD45 and CD16 on AMs is expressed in MFI. Values are given as the mean ± SEM. No statistical difference was observed.

 
Deactivation of AMs in Neutropenic Patients
There was no significant difference between neutropenic and nonneutropenic patients in cytokine production by unstimulated AMs (Table 5 ). LPS stimulated the release of TNF, IL-1ß, IL-6, and IL-10 by AMs in nonneutropenic patients. In neutropenic patients, LPS was unable to stimulate the production of IL-1ß and IL-10, and induced only a moderate increase in IL-6 and TNF production (Table 5) . Consistent with our previous results, the mortality rate was significantly higher in neutropenic patients than in nonneutropenic patients (Table 3) .


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  		Table 5.. Cytokine Production by AMs of Neutropenic and Nonneutropenic Patients With Septic ARDS*

 

   Discussion
TOP
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
In this study, we confirmed that ARDS can develop in an almost total absence of circulating PMNs. In neutropenic ARDS patients, BAL fluid showed a low cellularity and a major "alveolar neutropenia" with a predominance of AMs.11 However, HLA-DR down-regulation as well as decreased LPS-induced cytokine response underlined the hyporeactive state of these AMs.

The role of PMNs has been extensively studied in patients with acute lung injury and ARDS.25 26 27 Conflicting evidence exists from animal studies demonstrating that PMN depletion could protect or not protect patients from ARDS.3 18 However, two studies9 10 reported the occurrence of authentic ARDS in the setting of neutropenia; in both there were either no alveolar PMNs or a very small number. In our study, we showed the occurrence of ARDS in neutropenic patients in whom we also found major alveolar neutropenia (Fig 1) . Sato et al,28 in experimental pneumonia, showed that the absence of neutrophils in the alveoli does not exclude their sequestration in the microvessels of the lung. However, in this study neutropenia was induced very rapidly with intratracheal and IV injection of Streptococcus pneumoniae and was not related to drug-induced toxicity. In our study, given the duration of aplasia before the onset of ARDS and its persistence during ARDS, the possibility of the pulmonary sequestration of PMNs would appear to be very unlikely.

Few studies have stressed the importance of neutrophil-independent mechanisms in ARDS. In nonneutropenic patients, Steinberg et al7 compared the BAL fluid profile of alveolar cells, in which high neutrophil concentration was associated with more severe lung injury and a poor outcome, an increased macrophage count resulted in a better resolution and an improved survival rate in patients with sepsis and ARDS. It is widely known that AMs have an important role in the resolution of inflammation, antibacterial defense, and the repair process following injury,13 29 but different studies have showed that AMs and macrophage secretory products also could contribute to lung injury.30 Phorbol myristate acetate instillation can induce lung injury, depending on the dose, independently of PMN and oxygen radical production.31 32 In our study, the relative number of AMs was increased in neutropenic patients, and it is therefore possible that, in the context of alveolar neutropenia, AMs may be responsible for lung injury. The activation state was the first step to evaluate AM responsibility in ARDS. Variations in HLA-DR expression on the surface of monocytes/macrophages are strongly linked to the activation state of these cells in patients with sepsis as well as other diseases.19 20 33 A study performed by Rosseau et al34 in ARDS patients showed a decrease in the percentage of AMs compared to that in healthy control subjects, and absolute cell counts revealed an expansion of the AM population. Sequential BAL revealed the presence of two subgroups of patients. The first group developed an increased expression of the AM mature phenotype with a significant up-regulation of HLA-DR that was associated with a 75.7% survival rate. The second group exhibited prolonged predominance of the immature phenotype with no HLA-DR up-regulation and a 25% survival rate. In our study, we performed only one BAL within the first 3 days of the onset of ARDS and, therefore, did not show these two patterns of AM phenotype evolution in time. However, our purpose was to compare neutropenic and nonneutropenic patients, and we showed in neutropenic patients that a decrease in the number of AMs expressing HLA-DR was associated with decreased expression per cell. These results suggested either the persistence of AM immaturity in neutropenic patients or a cell deactivation.

As we have reported previously, Rosseau et al34 showed that macrophage immaturity was associated with a higher mortality rate. Allavena et al35 showed a shifting of macrophage CD16 expression during maturation, but in our study we did not find any difference between the two groups in CD16 expression.

The desensitization phenomena already has been described with PMNs in HIV-infected patients.36 37 Similarly, macrophage desensitization already has been characterized in different situations38 39 40 41 but not in patients with ARDS. We therefore decided to further characterize the activation state of AMs in ARDS, and studied basal level and LPS-induced production of various cytokines. The spontaneous production of TNF, IL-1ß, IL-6, and IL-10 was unchanged in neutropenic patients compared to nonneutropenic patients, but LPS-induced secretion was significantly decreased in neutropenic patients. Consistent with our results, Volk et al20 reported that monocyte deactivation can occur and is associated with a much higher mortality in septic patients.

This deactivation may be related to sepsis,19 chemotherapy,42 or neutropenia per se.43 In fact, these patients presented a major inflammatory syndrome (ie, ARDS) associated with a local immunosuppression (eg, alveolar hypocellularity, HLA-DR down-regulation, and alveolar neutropenia). While local immunosuppression is associated with a good prognosis and appears to be an adapted response in nonneutropenic patients with ARDS,44 this situation could be inappropriate in neutropenic patients. In agreement with this hypothesis, in neutropenic patients we found a decreased percentage of AMs expressing HLA-DR in deceased patients compared to survivors. In bone marrow transplant recipients with pneumonitis, Milburn et al45 showed a decreased HLA-DR expression in AMs, which was more prominent in nonsurvivors.

Considering our population and the results that we obtained, we observed that most of the neutropenic patients in group A (6 of 7 patients) received a diagnosis of pneumonia, while 6 of 11 nonneutropenic patients in group A did not have pneumonia. So one concern could be that the results of BAL might be influenced by the results of BAL in pneumonia patients when they have been performed in the area of infection vs a random site of acute lung injury. First, from a methodological standpoint, BAL samples always were obtained from the lingula and middle lobe if these segments were radiographically involved, which was the case in > 90% of our patients. Moreover, a study published by Dehoux et al46 showed that the number of LPS-induced cytokines released from AMs that were recovered from patients with unilateral pneumonia were similar between cells recovered from the involved lung and those recovered from the contralateral lung. Besides the site of BAL, another difference could be related to the origin of the sepsis (ie, extrapulmonary vs pulmonary), and, to our knowledge, only respiratory mechanical differences have been reported.47

All neutropenic patients in our study received G-CSF as a supportive treatment. AM hypoactivation could be increased by G-CSF. Indeed, G-CSF is known to induce anti-inflammatory cytokine secretion48 and could down-regulate HLA-DR expression on monocytes/macrophages.49 Furthermore, G-CSF could promote the development of ARDS due to pulmonary infection in neutropenic patients.50 Moreover, it has been reported that low concentrations of IL-10 and IL-1ra in BAL fluid could worsen the prognosis of nonneutropenic patients with ARDS.44 Hence, the low LPS-stimulated production of cytokines in neutropenic ARDS patients may be deleterious since inflammatory cytokines are involved in antibacterial defenses and anti-inflammatory cytokine release during lung repair following injury. Our results constitute a good line of evidence with which to question the indication of G-CSF in septic neutropenic patients who are at risk or have already developed ARDS.

In this study, we showed the deactivation of AMs in neutropenic patients with septic ARDS. The AM was a good candidate to explain ARDS pathophysiology in the context of systemic and alveolar neutropenia. The results we have shown do not support this hypothesis. This dysfunction could be related to chemotherapy, neutropenia, or sepsis, and it could also be amplified by the use of G-CSF. The use of G-CSF in this situation remains to be evaluated, and the rationale for immunomodulation seems to be, from our data, more toward of stimulation rather than inhibition.


   Footnotes
 
Abbreviations: AM = alveolar macrophage; G-CSF = granulocyte colony-stimulating factor; HLA = human leukocyte antigen; IL = interleukin; LPC = lymphocyte; LPS = lipopolysaccharide; MFI = mean fluorescence intensity; PE = phycoerythrin; PMN = polymorphonuclear neutrophil; TNF = tumor necrosis factor

Received for publication April 3, 2002. Accepted for publication January 7, 2003.


   References
TOP
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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