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ABSTRACT |
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INTRODUCTION
METHODS
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The phagocytic capability afforded by neutrophil influx into the lungs is essential to ward off invading bacteria. The objective of this study was to evaluate the effect of prior neutrophil recruitment induced by alveolar instillation of endotoxin (LPS, 200 µg/kg) 16 h before a pulmonary infection caused by instillation of live Pseudomonas aeruginosa ([PYO]: 1.5 × 108 colony-forming units [cfu]/kg) in rats. A first series of experiments showed that lipopolysaccharide (LPS) instillation induced recruitment of alveolar neutrophils that were capable, ex vivo, of elastase exocytosis, reactive oxygen species secretion, and PYO killing. In a second set of experiments, LPS followed by PYO was compared with PYO alone (n = 11 surviving rats in each group). Parameters were studied 24 h after the bacterial challenge. As compared with PYO alone, pretreatment with LPS followed by PYO was associated with decreased mortality (0% versus 54%, p < 0.05), decreased protein leakage into bronchoalveolar lavage (BAL) fluid (1.8 ± 0.4 versus 13.5 ± 2.2 mg/ml, p < 0.001), and improved bacterial clearance from BAL (4.0 ± 1.4 × 102 versus 1.2 ± 0.5 × 104 cfu/ml, p < 0.05) and from pulmonary parenchyma (8.5 ± 6.4 × 105 versus 1.9 ± 0.8 × 107 cfu/ml, p < 0.05). We conclude that prior alveolar endotoxin instillation induces local recruitment of functionally active neutrophils, and that this is associated with resistance to subsequent experimental pneumonia.
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Endotoxin instillation into the air spaces is known to induce marked polymorphonuclear neutrophil (PMN) recruitment contrasting with very mild injury in rats (1). The phagocytic capability afforded by neutrophil influx into the lungs is essential to ward off invading bacteria. It is therefore conceivable that endotoxin instillation into the rat air spaces may protect against subsequent experimental bacterial pneumonia. However, alveolar PMN influx preceding bacterial challenge may be beneficial only if the incoming cells retain their bactericidal activity. There have been reports of impairment of ex vivo alveolar PMN functions during acute respiratory distress syndrome (ARDS) (4, 5). However, this does not necessarily mean that the in vivo defense mechanisms of the lungs were also impaired.
The objective of this study was to determine whether alveolar PMN recruitment induced by endotoxin instillation into the air spaces alters bacterial clearance after a subsequent alveolar challenge with live Pseudomonas aeruginosa (PYO). Also, ex vivo functions of endotoxin-recruited PMNs relevant to antibacterial defense were evaluated.
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INTRODUCTION
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Pseudomonas aeruginosa Inoculum Preparation
A nonmucoid PYO strain (serotype 11) was used in all studies. These bacteria were maintained in peptone broth containing 25% glycerol. Before each experiment, the strain was propagated on tryptone soy agar plates for 24 h at 37° C. One colony was then transferred to tryptone soy broth for another 24-h period at 37° C. On the day of the experiment, the bacteria were centrifuged at 3,000 × g for 15 min, and the bacterial pellet was washed twice with saline. PYO solution was finally resuspended in saline at a concentration of 2 to 4 × 109 bacteria/ml. Routine antibiotic susceptibility testing was performed to check that the characteristics of the PYO strain did not change from one experiment to the next.
Models of Rat Acute Lung Injury
Sprague-Dawley male rats weighing about 250 g were used (Charles River France, Saint-Aubin-lès-Elbeuf, France). The rats were housed in air-filtered, temperature-controlled units with food and water freely accessible.
Alveolar instillations of PYO inoculum and lipopolysaccharide (LPS) (Escherichia coli endotoxin 055:B5 LPS; Sigma Chemical, Poole, Dorset, UK) were performed as previously described (1, 3, 6). Briefly, the rats were anesthetized using halothane, and the trachea was exposed. Subsequently, either 0.5 ml/kg weight of a PYO inoculum (strain 011, 2 to 4 × 109 bacteria/ml) in sterile physiological saline (PYO rats) or 0.5 ml/kg weight of LPS (200 µg/kg) in sterile physiological saline was instilled into the trachea via a 25-gauge needle (LPS rats).
Experimental Conditions
These conditions are summarized in Figure 1. Preliminary experiments showed that PMN influx into the air spaces reached the steady state from the fourth hour to the thirtieth hour after endotoxin challenge (3). Bacterial infection was therefore induced at the sixteenth hour, during the plateau phase of PMN recruitment, after the initial recruitment wave (first 4 h) and before the beginning of PMN clearance from the air spaces.
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Experiment 1 (LPS-16-h group). Sixteen hours after LPS instillation, bronchoalveolar lavage (BAL) was performed to allow differential cell counts and alveolar PMN isolation. Alveolar neutrophil functions (elastase exocytosis, reactive oxygen species secretion, and bactericidal activity) were studied ex vivo.
Experiment 2 (LPS-40-h group). BAL with differential cell counts was performed 40 h after LPS instillation.
Experiment 3 (PYO group). BAL with differential cell counts was done 24 h after the bacterial (PYO) challenge. Total protein concentration was measured in BAL fluid, and alveolar PMNs were isolated. BAL fluid and lung homogenate samples were cultured. Alveolar neutrophil functions (elastase exocytosis, reactive oxygen species secretion, and bactericidal activity) were studied ex vivo.
Experiment 4 (LPS-PYO group). PYO infection was induced 16 h after LPS instillation, and BAL (total protein concentration and differential cell counts) was done 24 h after the bacterial challenge. Alveolar PMNs were isolated from BAL fluid. BAL fluid and lung homogenate samples were cultured. Alveolar neutrophil functions (elastase exocytosis, reactive oxygen species secretion) were studied ex vivo.
Experiment 5 (casein). Casein 1% was used to induce alveolar recruitment of PMNs. BAL was done 16 h after casein instillation to allow PMN isolation and ex vivo determination of alveolar neutrophil bactericidal activity. Alveolar neutrophils rather than vascular or peritoneal neutrophils recruited by casein were studied because recent studies have suggested that migration processes and basement membrane composition may affect neutrophil activation (7, 8).
BAL and Differential Cell Count
Rats were exsanguinated, and BAL was carried out by flushing the
lungs nine times with 2.5 ml of 37° C, sterile, pyrogen-free, physiological saline via the tracheal cannula. The first fraction was discarded.
The next eight 2.5-ml fractions were recovered and pooled. The total
number of cells was counted using a standard hemocytometer. Cytospin preparations were made using a Shandon 3 cytocentrifuge (Shandon, Paris, France). The cells were fixed, and stained with May-Grünwald Giemsa. Differential counts on 200 cells were made using standard
morphologic criteria. The BAL fluid was then centrifuged at 300 × g
for 7 min. The supernatant was collected and stored at 
80° C, and
the pellet was suspended in Hanks' balanced salt solution (HBSS).
Total Protein Concentration
Total protein concentration in BAL fluid was determined using the Bradford protein assay with a standard curve for albumin.
Isolation and Purification of Alveolar Neutrophils
Two-step discontinuous Percoll gradients with different densities (1.062 and 1.077 g/ml, respectively) were used to isolate the alveolar neutrophils, as previously described (3). BAL cells were layered onto the gradient and centrifuged at 400 × g for 15 min. Thrombocytes and mononuclear cells banded at the surface of the upper layer, PMNs at the interface between the two density concentrations, and erythrocytes at the bottom. PMNs were separated and washed in HBSS without Ca2+ or Mg2+. Their concentration was adjusted to 106 cells/ml in RPMI. The purity of isolated PMNs was verified using May-Grünwald-Giemsa-stained cytocentrifuged preparations. This procedure allowed us to obtain a greater than 95% pure cell preparation devoid of erythrocyte contamination. Viability, as checked using the trypan blue exclusion method, was greater than 98%.
Chemiluminescence Determination of Oxygen Radical Production by PMNs
Chemiluminescence (CL) assays of isolated alveolar PMNs were performed in polystyrene CL vials at 37° C in a LKB-Wallac 1251 luminometer (Wallac Co., Turku, Finland) connected to a microcomputer. CL reaction mixtures for isolated PMNs were composed of 10 5 cells and
10
4 M luminol in RPMI. After 5 min of incubation, the reaction was started by delivery of the appropriate stimulus (106 M N-formyl-methionyl-leucyl-phenylalanine [FMLP] or 107 M phorbol 12-myristate 13-acetate [PMA]). Unstimulated control conditions were run in
parallel (steady state condition). All experimental conditions were
run in duplicate. CL was continuously recorded for 30 min. Results
obtained under FMLP- and PMA-stimulated conditions were expressed as a ratio compared with unstimulated control conditions.
Proteinase (Elastase) Exocytosis
As rat leukocyte elastase is very similar to its human counterpart, supernatants and cell lysates were assayed using a specific neutrophil elastase substrate, methoxysuccinyl-ala-ala-pro-val paranitroanalide (MEOSAAPVNA 0.2 mM; Sigma), as described elsewhere (3). FMLP-stimulated elastase exocytosis, expressed as a percentage of total elastase content, was computed as the elastase activity released into the supernatant divided by the total elastase activity (the sum of elastase activities obtained from supernatants and PMN lysates).
Bactericidal Activity
The bactericidal activity of alveolar neutrophils against PYO was measured in a rotating plate, as previously described (4). PYO was cultured overnight in trypticase soy broth, washed two times, and resuspended in HBSS to an optical density of 0.2 at 540 nM. Alveolar neutrophils were suspended in a concentration of 10 6 cells/ml in HBSS containing 5% rat serum, and the bacteria were added to yield a final cell/bacteria ratio of approximately 1:1. The tubes were rotated in a 37° C incubator for 90 min, and aliquots were taken after 15, 30, 60, and 90 min for quantitative culture using the pour-plate method. Bactericidal activity of alveolar neutrophils from BAL fluids collected 16 h after intratracheal instillation of LPS or casein 1% was tested.
Bacteriologic Culture of Lung and BAL Fluid
After BAL, the lungs were exposed aseptically, removed, weighed, and homogenized. Samples of BAL fluid and lung homogenate were obtained aseptically for culturing. The concentration of bacteria was quantified by placing successive 10-fold dilutions of the suspension on tryptone soy agar plates and scoring visible colonies after 24 h of incubation at 37° C. Results were expressed as colony-forming units (cfu) per gram of tissue or milliliter of BAL fluid.
Statistical Analysis
All data were expressed as mean ± SEM. One-way analysis of variance (ANOVA) and Fisher's least-significant difference test were used to detect statistically significant differences between the study groups. The differences were considered significant when p was less than 0.05.
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RESULTS |
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Effects of PYO and LPS-PYO Alveolar Instillation on Severity of Acute Lung Injury (Experiments 1, 3, and 4)
The severity of the PYO model was demonstrated by the 54% mortality rate at 24 h. LPS alveolar instillation alone induced no mortality. All PYO rats that survived for as long as 24 h were tachypneic, whereas LPS rats were eupneic. Interestingly, LPS-PYO rats also exhibited no mortality. Thus, previous LPS instillation prevented death from PYO infection.
To further assess the severity of the models, protein leakage into the alveolar spaces was measured (Figure 2). LPS instillation before PYO infection was found to have a protective effect on alveolar space protein leakage.
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Bacteriologic Cultures of Lungs and BAL Fluid in the PYO and LPS-PYO Models (Experiments 3 and 4)
Cultures of lung homogenates and BAL fluids showed significantly higher numbers of cfu in the PYO model than in the LPS-PYO model (Figure 3). Thus, clearance of PYO was increased in lungs previously exposed to LPS.
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BAL Fluid Cells (Experiments 1, 2, 3, and 4)
No significant differences were observed in BAL cell counts (total cells and PMNs) determined 24 h after PYO, 16 h after LPS, or 24 h after PYO preceded by LPS (Figure 4). In contrast, in the absence of bacterial challenge neutrophil counts were significantly decreased, as demonstrated by the results of Experiment 2 involving BAL 40 h after endotoxin instillation. Thus, the bacterial challenge prolonged the plateau phase of the air-space neutrophil count curve.
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Alveolar PMN Functions
Alveolar PMN functions 16 h after LPS instillation (Experiment 1) were evaluated to assess whether recruited PMNs were capable of responding ex vivo to a bacterialike challenge. Also, alveolar PMN functions in the LPS-PYO experiment (Experiment 4) and in the LPS-alone experiment (Experiment 3) were studied to determine whether repeated stimulation (LPS then PYO) versus a single stimulation (PYO) modified ex vivo PMN responses to FMLP and PMA.
Reactive oxygen species (ROS) (Experiments 1, 3, and 4). There were no significant differences in ROS secretion in response to FMLP exposure in the three experimental conditions (Figure 5).
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By contrast, ROS secretion in response to PMA was significantly lower in PYO rats than in LPS-16-h and LPS-PYO rats.
Elastase exocytosis (Experiments 1, 3, and 4). There were no significant differences in the percentage of elastase exocytosis in response to FMLP between the three experimental conditions (LPS-16-h, 18 ± 4%; PYO-24-h, 20 ± 4%; LPS-PYO, 12 ± 5%; n = 6 in each group).
Bactericidal activity (Experiments 1 and 5). We compared the bactericidal activity of alveolar neutrophils 16 h after intratracheal instillation of LPS (Experiment 1) or casein 1% (Experiment 5) to determine whether alveolar neutrophil functions were modified by an endotoxin-priming effect (Figure 6). The rate of in vitro PYO killing was similar with both agents.
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DISCUSSION |
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Because neutrophil influx into the lungs is an essential component of the body's defense mechanisms against airborne bacteria such as PYO (9, 10), treatments capable of enhancing pulmonary neutrophil recruitment such as granulocyte colony-stimulating factor may be beneficial in patients with pneumonia (11). On the other hand, enhancing PMN influx into the alveoli may conceivably be deleterious. We previously developed a model of acute lung injury in rats consisting of alveolar instillation of endotoxin; unexpectedly, this produced only mild interstitial edema, although there was marked neutrophil influx into the alveoli (3). Thus, alveolar PMN recruitment per se does not imply severe alveolar capillary wall injury, as previously suggested (12).
We hypothesized that endotoxin instillation in rats would protect against subsequent bacterial infection by PYO. We used PYO to induce pneumonia since nosocomial pneumonia is often due to this bacteria, especially during ARDS (13). Because alveolar neutrophils recruited before a bacterial challenge may afford effective protection only if their bactericidal activity is intact, we assessed alveolar neutrophil functions.
Our most salient findings are that alveolar instillation of endotoxin before a challenge with live PYO was associated with a dramatic decrease in mortality (to zero), a decrease in protein leakage into the air spaces, and enhanced bacterial clearance from the lungs, as compared with PYO instillation alone. These beneficial results are in accordance with the major role of neutrophils in PYO clearance (10). Our results clearly demonstrate that the recruited alveolar PMNs retained their ability to generate reactive oxygen species and to release elastase (colocalized with defensins) (14) in response to FMLP, a bacterial wall-like peptide, as previously described (3). The weak response to FMLP in terms of ROS secretion was similar to that of human alveolar PMNs reported by Chollet-Martin and colleagues (15). Despite this weak response, the bactericidal activity of alveolar PMNs against PYO was preserved in vivo and ex vivo. Although a study by Martin and colleagues (4) showed that alveolar PMNs exhibited decreased bactericidal activity as compared with vascular PMNs in patients with ARDS, we found that the bactericidal activity of alveolar PMNs recruited before a bacterial challenge was sufficient to enhance bacterial clearance.
It would be interesting to know if endotoxin instillation also improves the pulmonary clearance of bacteria that are equipped with other virulence factors. Indeed, it has been demonstrated that different bacterial species are killed at different rates within the lung (16). Furthermore, Doerschuk and colleagues (17, 18) have performed experiments which have demonstrated that CD18-dependent and CD18-independent neutrophil emigration mechanisms could be involved in bacterial pneumonia. Thus, PYO and E. coli endotoxin involve a CD18-dependent emigration; by contrast Streptococcus pneumoniae involves a CD18-independent pathway (17, 18). Nevertheless, emigrated air-space neutrophils consistently expressed greater levels of CD18 than intravascular and interstitial neutrophils (17). Thus, the activation state of emigrated neutrophils seems to be quite similar whatever the recruitment mechanism was.
On the other hand, modified function may be a characteristic of alveolar PMNs related to migration across the alveolar-capillary barrier. It has been demonstrated that migration per se can enhance neutrophil functions (7). Thus, these changes in alveolar PMN functions could be partially independent of the mechanism of recruitment and of the severity of acute lung injury. Arguing for this hypothesis is our previous finding that protease secretion by PMNs was apparently independent from respiratory failure in ventilated patients with or without ARDS (19). Similarly, both protease secretion and reactive oxygen species secretion by PMNs were independent from the degree of respiratory failure in two experimental models of acute lung injury under unstimulated conditions (3). Consistent with these findings, in the present study alveolar neutrophil functions were quite similar after instillation of endotoxin, bacteria, or the combination of the two, or even after a noninfectious instillation such as casein. It must be stressed that these PMN functions were investigated at the early phase of injury, probably characterized by similar pro-inflammatory air-space changes in all models, regardless of the mechanism of PMN recruitment. Modifications in alveolar PMN functions at the later phase of injury resolution characterized by anti- inflammatory air-space changes remain to be evaluated. Moreover, Jones and colleagues (20) recently suggested that neutrophil migration and activation may show differences according to whether the neutrophils migrate to the upper or to the lower airways.
The beneficial effect of prior endotoxin challenge observed in our study is apparently at variance with a study by Walmrath and colleagues (2) involving in vivo "priming" by alveolar endotoxin instillation. An intravascular endotoxin challenge delivered after "priming" of the lungs for 3 h by bronchoalveolar LPS deposition was responsible for dramatic increases in pulmonary arterial pressure, weight, and shunt flow, denoting a deleterious effect. The absence of such an effect in our study may be ascribable to the 16-h lag between the initial insult and the bacterial challenge and/or to the difference in the route used for the bacterial challenge, namely, alveolar versus intravascular.
Although the most likely explanation for the beneficial effect of endotoxin instillation is influx of functionally active PMNs into the air spaces, a number of other hypotheses deserve discussion.
First, alveolar macrophage functions may have been enhanced. However, Jacobs and colleagues (21) demonstrated reduced phagocytosis of E. coli by alveolar macrophages during endoxinemia. Furthermore, alveolar macrophages do not seem to play a central role in PYO clearance (10). Interestingly, downregulation of alveolar oxidant generation by alveolar macrophages upon PMA stimulation was obtained by Jenkins and colleagues (22) during PYO bacteremia in pigs, a result consistent with our finding that ROS secretion by alveolar neutrophils in response to PMA was decreased in PYO rats as compared with LPS rats (this study and [3]).
Second, LPS instillation may have directly or indirectly induced functional modifications in noninflammatory cells. Endothelial cells can respond to LPS challenge in the presence of LPS-binding protein and soluble CD14, and can therefore contribute to the inflammatory response (23). We have also previously reported that fluid clearance by epithelial cells was stimulated in vivo by endotoxin instillation, and we suggested that this mechanism was involved in limitation of alveolar flooding (1). Moreover, endotoxin may induce heat shock proteins or antioxidants in lung cells, two effects that would be beneficial in the event of a bacterial challenge (24, 25). Interestingly, Ribeiro and colleagues (26) recently demonstrated that heat shock protein induction was associated with a protective effect against a subsequent insult consisting of vascular endotoxin administration 18 h later. Furthermore, in another study LPS instillation induced expression of interleukin (IL)-6 and leukemia inhibitory factor (LIF), two cytokines involved in the anti-inflammatory response (27).
Third, LPS instillation may modify acellular components of epithelial lining fluid. The role of acellular lung lining material was pointed out many years ago (16), and Martin and colleagues (28) recently found soluble CD14 and LPS-binding protein in the epithelial lining fluid of patients with ARDS.
In our study, the bacterial challenge prolonged the neutrophil count plateau that started 4 h after the endotoxin instillation. At least two factors may explain this finding. First, the bacterial challenge may have induced further recruitment of PMNs into the air spaces. However, White and colleagues (29) have reported that LPS instillation failed to produce alveolar PMN recruitment in rats with previously induced peritonitis. Other studies also found that vascular PMN migration was inhibited after the onset of sepsis (30) and suggested that this inhibition may be due in part to anti-inflammatory cytokines such as IL-6 and LIF that limit the magnitude and duration of neutrophil accumulation in the lung (27). Second, the bacterial challenge may have blocked PMN clearance by inhibiting apoptosis; in vitro studies found that neutrophil survival was longer in the presence of inflammatory mediators or bacterial products (33). Our data do not allow a determination of the exact cause of the prolongation in the neutrophil count plateau. A reasonable hypothesis is that the powerful initial wave of neutrophil migration into the alveoli subsides rapidly when the initial injurious process resolves but persists and is accompanied with increased recruited PMN survival when the initial injury is perpetuated or when bacterial infection occurs.
In summary, we found that endotoxin instillation in rats resulting per se in very mild lung injury improved significantly the bacterial clearance of the lungs subsequently instilled with PYO, associated with a decrease in mortality. Sixteen hours after endotoxin-induced injury, alveolar PMN responses in terms of reactive oxygen species secretion, proteinase exocytosis, and bactericidal activity ex vivo to subsequent bacterialike challenges were preserved. Thus, recruited alveolar PMNs may have been at least partly responsible for the protective effect of endotoxin instillation against subsequent PYO infection. The fact that alveolar neutrophil functions were preserved in our study apparently argues against the hypothesis that impairment of alveolar neutrophil functions may contribute to the increased incidence of nosocomial pneumonia during ARDS; it also suggests that alveolar neutrophils may contribute to the absence of early onset of ventilator-associated pneumonia during ARDS when neutrophil influx is maximal (13).
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. Daniel Jean, Unité de Physiologie Respiratoire, INSERM U 296, Faculté de Médecine, 8 rue du Général Sarrail, 94010 Créteil, France.
(Received in original form September 29, 1997 and in revised form January 21, 1998).
Acknowledgments: The writers thank Dr. Laurent Brochard for his stimulating comments and Liliane Leclercq for her technical assistance.
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References |
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