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INTRODUCTION
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Chronic endobronchial infection frequently caused by gram-negative organisms and an increased, neutrophil-dominated inflammation are characteristics of cystic fibrosis (CF). The present study examines endotoxin levels in bronchoalveolar lavage fluids of CF versus non-CF (N) control children, and correlates these with the inflammatory markers interleukin-8 and neutrophils. Fifty-five patients with CF and 56 patients without CF between the ages of 0.04 to 13.25 years were included. Infection, defined as a bacterial count above 50,000 cfu/ml, was present in 27 CF and 25 N patients. Endotoxin levels were not different between patients with and without CF (infected: 74.9 ± 12.1 EU/ml versus 51.4 ± 12.5 EU/ml, p = 0.16; noninfected: 5.9 ± 4.8 EU/ml versus 11.1 ± 4.3 EU/ml, p = 0.28). Endotoxin activity correlated to the number of gram-negative organisms in CF and N patients, and endotoxin activity per bacterial colony forming unit did not differ with various gram-negative species. Both interleukin-8 and neutrophils were positively correlated with endotoxin, but this slope was shifted toward higher levels of inflammation in CF patients. We conclude that it is unlikely that higher levels of endotoxin in the absence of viable bacteria explain the increased inflammatory response in CF.
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Keywords: cystic fibrosis; inflammation; endotoxin; bronchoscopy
Tenacious mucus and recurrent bacterial infections characterize cystic fibrosis (CF). In young patients, frequently isolated pathogens include viruses, Haemophilus influenzae and Staphylococcus aureus, but infection with Pseudomonas aeruginosa and other gram-negative organisms may start early, and infections with these organisms persist in most patients. The chronic infection results in ongoing inflammation and progression of obstructive lung disease and bronchiectasis.
Gram-negative bacteria have a bilayered outer membrane
composed of an inner phospholipid and an outer lipopolysaccharide (LPS) portion. LPS actually describes the protein-free
form of endotoxin, but these terms are frequently used synonymously. Endotoxin contains a lipid A portion, which is responsible for the proinflammatory effects, and a polysaccharide portion responsible for the antigenic property. Endotoxin
is a strong stimulator for cells of monocytic origin to secrete
proinflammatory cytokines and is linked to the symptoms of
sepsis associated with gram-negative bacteremia. Inhalation of
endotoxin results in a dose-dependent inflammatory response in the lung with increases in proinflammatory cytokines such
as interleukin 1
, tumor necrosis factor, and interleukin-8 (IL-8), accompanied by neutrophil recruitment in healthy adults (1) and asthmatics (2). Endotoxin activity and anti-LPS antibodies have been shown to be present in the sputum of patients
with CF chronically infected with P. aeruginosa (3, 4). In vitro studies have shown that P. aeruginosa endotoxin may contribute to the pathogenesis of CF by causing mucus hypersecretion and production of IL-8 in tracheal epithelial cells (5-7).
The in vivo endotoxin activity from P. aeruginosa or other
gram-negative organisms in sputum or bronchoalveolar lavage
fluid (BALF) from young children has not been reported.
Inflammation is an important factor in the early pathogenesis of CF. Studies examining sputum and BALF have shown increased levels of inflammatory mediators in airway secretions of patients with CF. We have shown that inflammatory mediators, when normalized to the number of bacteria, are increased in children with CF compared with children without CF with respiratory problems (8). IL-8 levels and numbers of polymorphonuclear cells (PMN) in BALF samples correlated with bacterial density in both patient groups, but inflammation was shifted to a higher level in CF subjects. This increase in inflammatory mediators was also present in some patients in whom no active infection could be found by culture of BALF. The cause of this apparently excessive PMN response in CF is not clear. The altered rheology of CF airway secretions causes altered mucociliary clearance, which may contribute to trapping of bacterial products in the airway. It is conceivable that endotoxin is retained in CF airways after eradication or reduction of live bacteria and causes an ongoing proinflammatory stimulus.
In the present study, we determined the degree of endotoxin activity and the amounts of inflammatory mediators in BALF of these patients to assess whether higher endotoxin activity in BALF of patients with CF could explain the increase in inflammation. The relationships among endotoxin activity, inflammatory markers (IL-8 and PMN), and bacterial pathogens were assessed.
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Study Subjects
All infants and children who underwent clinically indicated bronchoscopies between January 1995 and April 1999 were eligible for participation in this study if they were not on inhaled or systemic steroids or high-dose ibuprofen during the 2 months preceding the bronchoscopy. The majority of these subjects were those included in our previous study (8), but additional patients were subsequently included, and patients with CF older than 4 years of age were also included. One of the subjects was currently on rhDNase. Patients in whom viral infection was detected in BALF were excluded from the data analysis. Informed consent was obtained from all parents, and informed assent was obtained from patients older than 6 years. The study was approved by the University of North Carolina Committee on the Protection of the Rights of Human Subjects.
Bronchoscopy and Lavage
Bronchoscopies were performed according to clinical routine procedure as we described previously (8). An aliquot of BALF for the research project was taken in a sterile manner, a cell count obtained,
and stored in sterile tubes at 
70° until assay for IL-8 and endotoxin.
The remainder of the BALF was sent to the hospital laboratory for
cytology and cultures, as ordered by the physician responsible for the patient.
Microbiology
BALF specimens were cultured for gram-positive and gram-negative bacteria on horse blood, calcium nutrient agar, and MacConkey agar. Mannitol-salt agar was used for recovery of S. aureus (9) and PC agar for recovery of Burkholderia cepacia (10) in patients with CF. Cultures and stains for viruses (including cytomegalovirus, respiratory syncytial virus, influenza A and B, parainfluenza 1-3, and adenovirus), fungi, and mycobacteria were performed for all patients with CF and for control patients when these infections were clinically suspected. "Oropharyngeal flora" in BALF specimens was defined according to standard protocol for the UNC Hospitals Clinical Microbiology Laboratory, as described in our previous report (8).
Cell Count and Cytokine Levels
Processing of the samples for cytology and IL-8 measurements in the cell free supernatant was previously described (8).
Endotoxin activity was determined with the Limulus Amebocyte Lysate (LAL) assay (Bio Whittaker, Walkersville, MD). Escherichia coli endotoxin supplied by the manufacturer was used for the standard curve for a concentration of 0.1-1.0 EU/ml, (SD 0.001-0.086). BALF samples were diluted 1:100 in endotoxin-free water before testing.
Statistical Analysis
Data were reported as mean ± standard error of the mean unless otherwise stated. Endotoxin, IL-8, PMN, and bacterial colony forming units (cfu) were log transformed before linear regression analyses. Endotoxin values of 0 were assigned the lowest measurable value for the assay before log transformation. Comparisons between subjects with CF and those without CF were done by two-tailed t test. Linear regressions were computed using the method of least squares, and slopes and elevations were compared by t test. Statistical significance was defined as p < 0.05. Statistical computations were performed on a personal computer using the statistical software package Prism 2 (GraphPad, San Diego, CA).
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Patient Characteristics
Sixty-two CF and 63 non-CF (N) patients were initially recruited into the study. Seven CF and seven N patients had viral infections and were excluded from further analyses. Age of included subjects was 3.7 ± 0.48 years (range 0.1-13.25 years) for CF and 2.1 ± 0.31 years (range 0.04-8.83 years) for N subjects. CF patients were significantly older than N (p = 0.006).
Many patients had received antibiotics before bronchoscopy, and the percentage without antibiotics for at least 3 weeks was higher in N (52.4%) than in CF (21.8%). Generally, antibiotics were stopped 48 hours before the procedure, but this was not the case in 10 CF and 4 N study subjects. Details of antibiotic use are shown in Table 1.
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Culture Results
Bacterial infection was defined as presence of pathogenic bacteria at a concentration greater than 50,000 cfu/ml BALF (11). By this definition, 28 CF and 25 N patients had bacterial infection. The organisms most frequently isolated were S. aureus, P. aeruginosa, and H. influenzae in the CF population and Moraxella catarrhalis and H. influenzae in the N group. As endotoxin is a cell wall component of gram-negative bacteria, BALF specimens were divided into those with gram-negative, mixed (gram-negative and gram-positive), and gram-positive infections. Among CF patients, 11 patients had only gram-negative, 3 only gram-positive, and 14 mixed infections. In the N group, there were 14 only gram-negative, 5 only gram-positive, and 6 mixed infections.
Endotoxin Activity
Endotoxin activity was significantly higher in infected versus uninfected patients, in both CF and N patients. There was no statistical difference between CF and N in either infected (74.9 ± 12.1 EU/ml versus 51.4 ± 12.5 EU/ml, p = 0.16) or uninfected patients (5.9 ± 4.8 EU/ml versus 11.1 ± 4.3 EU/ml, p = 0.28). Infected samples with gram-negative organisms had significantly higher levels of endotoxin than those without gram-negative organisms (EU/ml in gram-negative and mixed BALF versus gram-positive only: p = 0.004 for CF and p = 0.04 for N). There was no difference in endotoxin activity between CF and N samples with gram-negative and mixed versus gram-positive infections (Table 2). CF patients with gram-negative infections were older than N with such organisms (p = 0.049). For all other infections, age did not differ between CF and N. Endotoxin activity did not differ in patients who had recently received antibiotics (either < 2 days or < 14 days) and those without recent antibiotic therapy in any group.
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The correlation between endotoxin activity and bacterial cfu was determined in BALF samples in which gram-negative organisms were present at a bacterial density higher than 50,000 cfu/ml. In 13 CF and 6 N samples, bacteria were only partially quantified as being above 1 × 106, and these were not included in the regression analyses. There was a positive correlation between endotoxin activity and density of gram-negative bacteria in the remaining 12 CF and 14 N BALF samples. These regression curves were not significantly different in slope or Y-intercept between CF and N (Figure 1).
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Endotoxin Activity with Specific Pathogens
To determine whether endotoxin activity may be related to the type of bacterial organisms, the ratio of endotoxin activity to bacterial cfu was calculated in BAL specimens showing infection with a single gram-negative organism. There was no significant difference in BALF endotoxin activity normalized to bacterial count among the different organisms (Figure 2).
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Endotoxin and Markers of Inflammation
As previously reported, both IL-8 and PMN were higher in CF versus N patients (8). There was a positive correlation of IL-8 to endotoxin in both CF and N patients. These lines had similar slopes (p = 0.9), but the line had a significantly higher elevation in the CF group (Figure 3). This finding was also true when samples with undetectable endotoxin activity were excluded from analysis (data not shown). Figures 3 and 4 contain more data points than Figure 1 because BALF with gram-positive pathogens and with semiquantified bacterial cfu were also included. CF patients infected with only P. aeruginosa did not have higher IL-8/endotoxin activity than CF patients with gram-negative organisms other than P. aeruginosa, but both had higher activity than N patients with gram-negative infections (data not shown).
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The same analyses were performed for number of PMN per milliliter versus endotoxin, which also showed a positive correlation. Slopes were parallel (CF 0.32 ± 0.07, N 0.26 ± 0.11, p = 0.8), but the elevation was again significantly higher in CF versus N patients (p < 0.0001). Exclusion of samples with endotoxin values of 0 did not alter the correlation with PMN in either patient group.
Because the mean age of CF patients in this study was higher than that of N and because older CF patients may have a higher bacterial burden, the effect of age on inflammation was analyzed. Endotoxin levels did not increase with age in either CF or N patients. Regression of age versus the ratio of inflammatory markers (PMN or IL-8) over endotoxin units did not show a positive correlation for either patient group but was shifted toward higher inflammation in CF patients.
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In a previous study, we showed that inflammatory mediators normalized to viable bacterial numbers are higher in the BALF of young CF patients compared with N control patients. As patients underwent clinically indicated bronchoscopies, which were frequently done to investigate possible pulmonary infection in CF patients or recurrent pneumonia in N patients, many patients had received antibiotics before bronchoscopy. It is conceivable that at the time of bronchoscopy viable bacteria had been eradicated, but bacterial cell wall components such as endotoxin were still present in the airways, causing an ongoing stimulus for an inflammatory response. The present study investigated the possibility that retained endotoxin of nonviable gram-negative bacteria could be responsible for increased inflammation in CF. The results showed that endotoxin levels were not higher in the CF than in the N group, in either infected or uninfected patients (Table 2). This was also true for patients who had been on antibiotics within the 2 weeks before bronchoscopy, which occurred more frequently in the CF group than in the N group.
If possible, antibiotics were stopped 48 hours before the procedure to avoid inhibition of bacterial growth in vitro, but this was not the case in 14 of 111 patients in this study. The percentage of patients who had received recent antibiotics and subsequently had no culture-proven infection was higher in the CF group, but endotoxin activity was not higher in these compared with either infected CF or N patients. These findings would argue against the possibility that the higher inflammatory response per bacterial colony forming unit in the CF group was caused by endotoxin in the absence of infection.
Activation of the LAL assay by cell wall glucans from yeast is a potential cause of false positive endotoxin reactions (12). Risk factors for colonization with fungal organisms include use of antibiotics, which was more frequent in the CF patients. But if such an incorrect measurement of endotoxin activity was an explanation for higher inflammation in CF, it would have resulted in higher endotoxin levels in these patients.
Endotoxin is known to cause an inflammatory reaction in the airway, including activation of PMN and IL-8 secretion. In the present study, there was a positive correlation between endotoxin activity and IL-8 concentration in both CF and N patients. The slope of this regression line was similar in both groups but was shifted toward higher IL-8 levels in CF patients. This observation is consistent with our previous results of increased inflammation per bacterial cfu, and confirms the finding of a relative increase in PMN-mediated inflammation in the airways of young patients with CF.
In most BALF samples, quantitative bacterial cultures were performed, and we examined the correlation between endotoxin activity and density of gram-negative bacteria. There was a positive correlation of endotoxin activity with bacterial cfu in both CF and N patients, with many CF patients having a higher bacterial density of gram-negative organisms than N patients.
Several studies have examined the correlation of endotoxin with bacterial density by plate counts in nonclinical and clinical specimens. Two recent studies examined the sensitivity and specificity of endotoxin measurements for determination of nosocomial pneumonia in BALF of ventilated patients (13, 14). Both reported a strong correlation of endotoxin activity measured by LAL assay and numbers of gram-negative bacteria. In these studies, a cutoff value of 4 EU/ml or greater (13) or 5 EU/ml or greater (14) resulted in a clinically significant sensitivity and specificity for diagnosis of gram-negative pneumonia. These values were obtained in adult patients in whom a different technique and larger fluid volumes are used for BAL. The cutoff values for endotoxin activity determined in their studies can therefore not be compared with our pediatric samples. There was no significant difference in endotoxin activity between patients who had received prior antibiotic treatment and those who had not, in either of the aforementioned studies.
Nys and colleagues also examined the relationship of endotoxin activity and bacterial density for different bacterial species in vivo (14). This comparison revealed that levels of endotoxin were higher when infection was caused by enterobacteria as compared with P. aeruginosa or H. influenzae, but there was no significant difference between endotoxin levels in BALF with P. aeruginosa versus H. influenzae. In the present study, we had a limited number of samples without mixed infections, and only one patient was infected with E. coli. Comparison of BALF endotoxin in samples with different gram-negative species did not reveal a significant difference in endotoxin activity per bacterial cfu in either CF or N (Figure 2). Among CF patients, presence of P. aeruginosa was not associated with an increase in endotoxin activity per bacterial cfu.
The LAL test measures total concentration of endotoxin activity, but the inflammatory potential may differ among endotoxin from various bacteria, as shown by in vitro studies. One such study compared the potential of LPS purified from two different E. coli strains and P. aeruginosa to stimulate IL-8 release from respiratory epithelial cultures (15). They reported higher chemotactic activity with P. aeruginosa endotoxin than with either strain of E. coli. Two other studies examined the inflammatory response of monocytic cells to purified endotoxin from different gram-negative bacterial species found in CF (16, 17). They both reported that cytokine release varied with LPS isolated from different organisms. Response to P. aeruginosa LPS appeared to be lower than to E. coli or Burkholderia cepacia LPS. It has also been demonstrated that the in vitro inflammatory potential of purified LPS depends on variation of the lipid A structure within the same bacterial species and that enteric bacteria synthesize different forms of lipid A in response to changes in environmental conditions (18). Thus, it is possible that P. aeruginosa may release a structurally different LPS during in vitro than in vivo growth and that this may add to the virulence in CF secretions (7, 19). This could potentially contribute to the higher concentration of inflammatory mediators seen in CF airways. However, we did not previously see an elevated inflammatory response in CF patients with P. aeruginosa compared with other pathogens (8). In the present report, BALF samples with P. aeruginosa did not appear to have higher IL-8 levels per endotoxin unit than those with gram-negative organisms other than P. aeruginosa.
In summary, we show that endotoxin levels in BALF did not differ between CF and N patients, despite an increased inflammatory response in CF. Our data thus argue against an increase in inflammation in CF airway secretions secondary to persistence of endotoxin after eradication of viable bacteria. The present results are consistent with our previous findings that CF patients beyond early infancy have higher levels of BALF inflammation than N control patients, after accounting for quantity of bacteria. Further studies at the in vivo and in vitro levels are needed to elucidate the mechanism underlying this increased inflammation.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Marianne S. Muhlebach, M.D., 635 Burnett-Womack CB 7220, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7220. E-mail: Marianne_Muhlebach{at}med.unc.edu
(Received in original form July 23, 2001 and accepted in revised form December 14, 2001).
Acknowledgments: Supported by grant MUHLEB00D0 of the Cystic Fibrosis Foundation (M.M.).
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 C. M. Greene, T. P. Carroll, S. G. J. Smith, C. C. Taggart, J. Devaney, S. Griffin, S. J. O'Neill, and N. G. McElvaney TLR-Induced Inflammation in Cystic Fibrosis and Non-Cystic Fibrosis Airway Epithelial Cells J. Immunol., February 1, 2005; 174(3): 1638 - 1646. [Abstract] [Full Text] [PDF]
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A. Linden, M. Laan, and G. P. Anderson Neutrophils, interleukin-17A and lung disease Eur. Respir. J., January 1, 2005; 25(1): 159 - 172. [Abstract] [Full Text] [PDF]
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K. Paul, E. Rietschel, M. Ballmann, M. Griese, D. Worlitzsch, J. Shute, C. Chen, T. Schink, G. Doring, S. van Koningsbruggen, et al. Effect of Treatment with Dornase Alpha on Airway Inflammation in Patients with Cystic Fibrosis Am. J. Respir. Crit. Care Med., March 15, 2004; 169(6): 719 - 725. [Abstract] [Full Text] [PDF]
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M. N. Becker, M. S. Sauer, M. S. Muhlebach, A. J. Hirsh, Q. Wu, M. W. Verghese, and S. H. Randell Cytokine Secretion by Cystic Fibrosis Airway Epithelial Cells Am. J. Respir. Crit. Care Med., March 1, 2004; 169(5): 645 - 653. [Abstract] [Full Text] [PDF]
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M. Gilljam, Y. Moltyaner, G. P. Downey, R. Devlin, P. Durie, A. M. Cantin, J. Zielenski, and D. E. Tullis Airway Inflammation and Infection in Congenital Bilateral Absence of the Vas Deferens Am. J. Respir. Crit. Care Med., January 15, 2004; 169(2): 174 - 179. [Abstract] [Full Text] [PDF]
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S. Huang, T. Dudez, I. Scerri, M. A. Thomas, B. N. G. Giepmans, S. Suter, and M. Chanson Defective Activation of c-Src in Cystic Fibrosis Airway Epithelial Cells Results in Loss of Tumor Necrosis Factor-alpha -induced Gap Junction Regulation J. Biol. Chem., February 28, 2003; 278(10): 8326 - 8332. [Abstract] [Full Text] [PDF]
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M. J. Tobin Pediatrics, Surfactant, and Cystic Fibrosis in AJRCCM 2002 Am. J. Respir. Crit. Care Med., February 1, 2003; 167(3): 333 - 344. [Full Text] [PDF]
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 O. Tabary, C. Muselet, S. Escotte, F. Antonicelli, D. Hubert, D. Dusser, and J. Jacquot Interleukin-10 Inhibits Elevated Chemokine Interleukin-8 and Regulated on Activation Normal T Cell Expressed and Secreted Production in Cystic Fibrosis Bronchial Epithelial Cells by Targeting the IkB Kinase {alpha}/{beta} Complex Am. J. Pathol., January 1, 2003; 162(1): 293 - 302. [Abstract] [Full Text] [PDF]
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N. Aldallal, E. E. McNaughton, L. J. Manzel, A. M. Richards, J. Zabner, T. W. Ferkol, and D. C. Look Inflammatory Response in Airway Epithelial Cells Isolated from Patients with Cystic Fibrosis Am. J. Respir. Crit. Care Med., November 1, 2002; 166(9): 1248 - 1256. [Abstract] [Full Text] [PDF]
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M. Berger Lung Inflammation Early in Cystic Fibrosis . Bugs Are Indicted, But the Defense Is Guilty Am. J. Respir. Crit. Care Med., April 1, 2002; 165(7): 857 - 858. [Full Text] [PDF]
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