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Pneumonia and systemic infection are common in premature infants. The antimicrobial peptides human 
-defensin 1 and 2 (hBD-1 and hBD-2) and the cathelicidin LL-37/hCAP-18 are effector molecules of the innate respiratory immune system. It is unknown
whether these host defense substances are produced in the respiratory tract of newborns. Concentrations of these peptides were
determined in tracheal aspirates of mechanically ventilated newborn infants. All three antimicrobial peptides could be detected in
airway lining fluid with equivalent levels in term and preterm newborns. Concentrations of antimicrobial peptides correlated with
each other and with levels of interleukin-8 and tumor necrosis factor-
in the bronchoalveolar lavage fluid. Pulmonary or systemic
infections were associated with significantly increased concentrations of LL-37, hBD-1, and hBD-2. Western blotting detected mature peptides in the lavage fluid. In conclusion, mucosal antimicrobial peptides are present in lung secretions of premature and
mature newborns. The molecules are upregulated in response to
infection and inflammation and probably represent effector molecules of the respiratory defense system.
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Keywords: antimicrobial peptide; cathelicidin; defensin; innate immunity; pneumonia
Infectious complications of the respiratory tract are common in
preterm newborns. Host defense reactions of the lung against microbial infection include several mechanisms (1). Antimicrobial peptides are effector molecules of the innate immune system of the airways (2). Two families of antimicrobial peptides
are expressed in the epithelium of the human adult lung, including the human -defensins-1 (hBD-1) and-2 (hBD-2) (3-5)
and the cathelicidin LL-37/hCAP-18 (6). Antimicrobial peptides contribute to innate immunity by direct microbiocidal
activity. In addition, defensins and LL-37/hCAP-18 have multiple other functions, such as the activation of inflammatory
cells and the regulation of adaptive immunity (7-9). Studies of
murine homologs of human antimicrobial peptides indicated
that expression of defensins correlates positively with gestational age (10-12). It is unknown whether human newborns secrete antimicrobial peptides into the airway lumen or whether
preterm infants have lower concentrations of antimicrobial
peptides in their airway surface fluid. It was the aim of this
study to analyze the levels of human mucosal antimicrobial
peptides in tracheal aspirates of term and preterm newborns
with and without respiratory infections. We found that antimicrobial peptides are present in the airway secretions of newborns. No association between concentration and gestational
age was found. Respiratory and systemic infections resulted in
increased concentrations of antimicrobial peptides.
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Patient Characteristics and Sampling Procedures
All mechanically ventilated newborn infants in our neonatal intensive care unit were enrolled during a 12-month study period (October 1999 to September 2000) if informed consent was given by the parents. All procedures were approved by the Institutional Review Board of the University of Munich (Munich, Germany). The characteristics of patients are summarized in Table 1. Bronchoalveolar lavage fluid (BALF) was sampled once a day for the duration of the mechanical ventilation, using a standardized procedure. A suction catheter was inserted through the endotracheal tube, 0.5-1 ml of normal saline was flushed into the trachea, and BALF was recovered by applying suction to the catheter.
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Measurement of Concentrations of Antimicrobial Peptides
To determine the concentrations of hBD-1, hBD-2, and LL-37/hCAP-18, we used an antigen capture assay. Three microliters of each sample was dotted onto a nitrocellulose membrane and immunolabeling was performed with polyclonal rabbit antibodies to hBD-1, hBD-2, and LL-37/hCAP-18 (all three diluted 1:500), followed by a monoclonal peroxidase-conjugated anti-rabbit antibody from goat (Sigma, Munich, Germany). Antisera against hBD-1, hBD-2, and LL-37 were obtained by injecting 100 µg of peptide coupled to keyhole limpet hemocyanin into two rabbits for each peptide (Research Genetics, Huntsville, AL) and purified by protein A column chromatography. Recombinant hBD-2 (41-amino acid form, MW 4,327.8) and hBD-1 (44-amino acid form, MW 4,767.0) were generated or purified as described previously (6, 13). LL-37/hCAP-18 (C-terminal 37 amino acids) was synthesized chemically (IPF Pharmaceuticals, Hanover, Germany). After washes, bound antibodies were visualized with a chemiluminescent substrate (enhanced chemiluminescence [ECL] Western blotting detection kit; Amersham, Arlington Heights, IL) and exposure to X-ray films. Signal intensity was quantified with a Bio-Rad (Munich, Germany) densitometer. Standards of known peptide concentrations were used to calculate the concentrations in the biologic samples (recombinant hBD-1, hBD-2, and synthetic LL-37). Measurements were repeated twice and the average values were used for further analysis. Concentrations of antimicrobial peptides are shown as relative values to display the results of all three peptides in one convenient format. Further, we wanted to avoid demonstrating a methodological certainty that in general cannot be achieved for measurements of substances in tracheal suctions. For the calculation of the actual concentrations in the BALF, exchange factors are given in the legends to Figures 1-3. For detection of antimicrobial peptides in Western blots, BALF was extracted in acetonitrile (final concentration, 60%) and trifluoroacetic acid (final concentration, 1%) overnight at room temperature. After centrifugation and lyophilization, the material was subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. After resuspension in distilled water and determination of the total protein content, 20 µg of protein were boiled in Laemmli loading buffer containing 2-mercaptoethanol and loaded onto a 15% Tris-Tricine running gel. After electrophoretic separation, the proteins were blotted onto nitrocellulose and immunoreactive bands were visualized as described above for the dot-blot assay.
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Measurement of Inflammatory Mediators
The concentrations of interleukin-8 (IL-8) and tumor necrosis factor-
(TNF-) were measured in an enzyme-linked immunosorbent assay
(ELISA) as described earlier (14). Numbers of leukocytes and platelets and the levels of c-reactive protein (CRP) were determined according to routine procedures.
Statistical Analysis
All data were tested for normal distribution with the Kolmogorov-
Smirnov test. A two-tailed Spearman rank order correlation was applied to calculate the correlation coefficients. Groups were compared
by the Mann-Whitney rank sum test. Values are displayed as means ± the standard deviation. p 
0.05 was considered statistically significant.
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Antimicrobial Peptides Are Present in Airway Secretions of Newborns
It is unknown whether antimicrobial peptides are present in the airways of newborns. Concentrations of antimicrobial peptides in BALF of newborns were determined by an antigen capture dot-blot assay. This assay was validated earlier to measure the amounts of peptides in human body fluids and reached a sensitivity of 5 ng/ml (15). On the basis of earlier results, we did not extract the patient material; instead, we directly applied the BALF to the assay. We first addressed the question of whether mucosal antimicrobial peptides are found in airways of premature or mature newborns. hBD-1, hBD-2, and LL-37 were detectable in the airway secretions of newborn infants and were found in equivalent concentrations in groups of different gestational age (Figure 1).
Concentrations of Antimicrobial Peptides in the Airway Fluid of Newborn Infants Are Increased during Pulmonary or Systemic Infection
Next, we explored whether the concentrations of mucosal antimicrobial peptides correlate with disease status or with levels of inflammatory mediators in BALF or serum. Patients were
assigned to the following groups based on the results of laboratory investigations: group A
no infection: no growth in
bacterial cultures of pulmonary secretions during the study
period and no other signs of pulmonary infection or systemic
inflammation (CRP < 5 mg/L, normal blood cell count and
differential cell count); group Bsystemic infection, no pulmonary infection: sterile pulmonary culture but possessing an
increase in systemic inflammatory parameters (CRP > 5 mg/L, or more than 30,000 or less than 5,000 leukocytes per µl); and group Cpulmonary infection: cultures of BALF yielding
pulmonary pathogens with or without an increase in systemic
inflammatory parameters. Concentrations of hBD-1, hBD-2,
and LL-37 in BALF were significantly increased in children
with pulmonary or systemic infections (Figure 2). In addition,
we measured concentrations of IL-8 and TNF- in these samples and found several positive correlations between these
mediators, both with each other and with the antimicrobial
peptides (Figure 3 and Table 2).
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Western Blot Analysis
Last, we analyzed antimicrobial peptides in Western blots of extracted BALF and found immunopositive bands representing the size of mature peptides (Figure 4).
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Infectious diseases are common in newborn infants and correlate with prematurity. It was the aim of our study to analyze whether mucosal antimicrobial peptides are present in the airways of newborns and whether their levels correlate with local or systemic infection. We determined concentrations of hBD-1, hBD-2, and LL-37 in BALF of mechanically ventilated newborns. Our results show that newborns indeed present antimicrobial peptides in their lung secretions and that premature infants have equivalent levels of these peptides in their airway fluid. These results were surprising because murine homologs of antimicrobial peptides are expressed at low levels during gestation (10-12). On the basis of our data, functional levels and molecular forms of antimicrobial peptides are found in respiratory secretions of newborns and likely contribute to local immunity. Regarding the presence of the three peptides investigated in the present study, the situation seems to be similar to the adult respiratory tract. Pulmonary infections in preterm newborn infants seem not to be associated with decreased levels of hBD-1, hBD-2, or LL-37.
Antimicrobial peptides play an important role in innate and
adaptive immunity; however, their role in host defense of newborns has been unclear. Several molecules of the -defensin
family (hBD-1-4) (3-5, 13, 16-18) and the only human cathelicidin LL-37/hCAP-18 (6, 19) are synthesized in respiratory epithelial cells and secreted into the airway lumen. The expression of some of these molecules is upregulated in response to
infection. In the present study, we show that increased concentrations of antimicrobial peptides in tracheal aspirates are
associated with local or systemic infections. Remarkably, systemic infections with no signs of pulmonary infection resulted
in increased peptide levels in tracheal secretions. This phenomenon is likely mediated by a systemic inflammatory response. In tissue culture experiments, hBD-2 and LL-37 were increased at the peptide or transcript level after stimulation with IL-1, IL-6, or TNF- (20-22). hBD-1 seemed not to be
inducible in these experiments. In the present study, we show
that levels of all three antimicrobial peptides correlate with
disease status and inflammatory parameters in newborns. It is
likely that hBD-2 and LL-37 are regulated at the transcriptional level. Complex regulatory mechanisms in the intact organism, posttranscriptional regulation, increased secretion, or
inhibited cleavage of the secreted peptide could explain the
increase in hBD-1 peptide described here. In addition, accumulation of peptides in abundant airway secretions during infection might contribute to this phenomenon.
In summary, our results show that antimicrobial peptides are present in the respiratory tract of term and preterm newborns. Their direct antimicrobial activity and role as regulatory molecules likely contribute to local and systemic mechanisms of defense and inflammation.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Robert Bals, M.D., Ph.D., Department of Internal Medicine, Pulmonology, Hospital of the University of Marburg, Baldingerstrasse, 35033 Marburg, Germany. E-mail: bals{at}mailer.uni-marburg.de
(Received in original form October 5, 2001 and accepted in revised form December 30, 2001).
Acknowledgments: Supported by grants from the Sanitätsrat, Dr. A. Huebner und Gemahlin Stiftung and from the Deutsche Gesellschaft für pädiatrische Infektiologie (Schaller-Bals) and from the Deutsche Forschungsgemeinschaft (Ba 1,641/3-1; Bals).
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D. M. E. Bowdish, D. J. Davidson, D. P. Speert, and R. E. W. Hancock The Human Cationic Peptide LL-37 Induces Activation of the Extracellular Signal-Regulated Kinase and p38 Kinase Pathways in Primary Human Monocytes J. Immunol., March 15, 2004; 172(6): 3758 - 3765. [Abstract] [Full Text] [PDF]
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 R. Bals and P.S. Hiemstra Innate immunity in the lung: how epithelial cells fight against respiratory pathogens Eur. Respir. J., February 1, 2004; 23(2): 327 - 333. [Abstract] [Full Text] [PDF]
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D. J. Davidson, A. J. Currie, G. S. D. Reid, D. M. E. Bowdish, K. L. MacDonald, R. C. Ma, R. E. W. Hancock, and D. P. Speert The Cationic Antimicrobial Peptide LL-37 Modulates Dendritic Cell Differentiation and Dendritic Cell-Induced T Cell Polarization J. Immunol., January 15, 2004; 172(2): 1146 - 1156. [Abstract] [Full Text] [PDF]
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G. S. Tjabringa, J. Aarbiou, D. K. Ninaber, J. W. Drijfhout, O. E. Sorensen, N. Borregaard, K. F. Rabe, and P. S. Hiemstra The Antimicrobial Peptide LL-37 Activates Innate Immunity at the Airway Epithelial Surface by Transactivation of the Epidermal Growth Factor Receptor J. Immunol., December 15, 2003; 171(12): 6690 - 6696. [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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