PEDIATRICS Vol. 110 No. 4 October 2002, pp. 768-771
Early Postnatal Dexamethasone Decreases Hepatocyte Growth Factor in Tracheal Aspirate Fluid From Premature Infants
From the Hospital for Children and Adolescents, Helsinki University Central Hospital, Helsinki, Finland
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ABSTRACT |
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Objective. To evaluate in preterm infants the effect of dexamethasone on hepatocyte growth factor (HGF), an epithelial cell mitogen, and on vascular endothelial growth factor (VEGF), an endothelial cell mitogen, in tracheal aspirate fluid (TAF).
Methods. Thirty preterm infants (birth weight: 1000–1500 g) with respiratory distress syndrome were randomized to receive dexamethasone or to serve as control subjects. Dexamethasone was started at the age of 12 to 24 hours at a dose of 0.5 mg/kg/d for 2 days and 0.25 mg/kg/d for the subsequent 2 days. HGF and VEGF levels were examined from TAF samples during the first postnatal week. For eliminating the effect of dilution, the concentration of the secretory component of immunoglobulin A was determined. Student t test, 1-way analysis of variance, 
2, and simple regression analysis were used for statistical analysis.
Results. Mean HGF concentrations were similar in the dexamethasone and control groups on days 1 to 2, but the dexamethasone group had a lower mean HGF concentration on days 3 to 4 and 5 to 7. In contrast, no differences existed in mean VEGF levels between the dexamethasone and control groups.
Conclusions. In preterm infants who received early postnatal dexamethasone, reduced levels of HGF were seen in tracheal aspirates. This reduction may participate in the suppressive effects of dexamethasone on lung development.
Key Words: bronchopulmonary dysplasia • hepatocyte growth factor • respiratory distress syndrome • vascular endothelial growth factor
Abbreviations: BPD, bronchopulmonary dysplasia • HGF, hepatocyte growth factor • VEGF, vascular endothelial growth factor • RDS, respiratory distress syndrome • TAF, tracheal aspirate fluid • IgA-SC, secretory component of immunoglobulin A • TBS, 20 mM of Tris/500 mM of NaCl • TTBS, 0.05% Tween 20 in TBS
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INTRODUCTION |
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In preterm infants, lung injury resulting from mechanical ventilation, in addition to the toxic effects of oxygen and inflammation, has been associated with development of bronchopulmonary dysplasia (BPD).1–3 With new therapeutical possibilities, BPD today affects the most immature preterm infants,4 and its pathogenesis has been suggested to be caused more by an arrest of normal lung development than from volutrauma or inflammation.5
Hepatocyte growth factor (HGF), also known as scatter factor, is an epithelial cell mitogen and mitogen that stimulates growth, maturation, and maintenance of tissue homeostasis in the fetal and neonatal lung.6–9 In experimental animals, HGF is thought to act as a pulmotrophic factor responsible for airway and alveolar regeneration after acute lung injury.10 Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen that regulates endothelial cell differentiation, angiogenesis, and maintenance and repair of existing vessels.11–13 Mice deficient in VEGF, even in the heterozygous state, show abnormal angiogenesis and die in utero, indicating a crucial role for VEGF in vascular development.14 The aim of the study was to evaluate, in preterm infants with respiratory distress, the effect of dexamethasone on tracheal lavage concentrations of HGF, an epithelial cell growth factor, and of VEGF, an endothelial cell growth factor.
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METHODS |
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Study Patients
The study was conducted between August 1997 and July 1999 at the Hospital for Children and Adolescents, University of Helsinki (Helsinki, Finland). The study protocol was approved by the institutional review boards, and informed consent was obtained from the parents. The aim of the clinical study was to evaluate the effect of early postnatal dexamethasone on severity of respiratory distress syndrome (RDS) and development of BPD in preterm infants. However, in multiple trials at the time, several adverse effects on early dexamethasone treatment became evident, and the effect on reducing the risk of BPD became controversial.15 Therefore, the clinical trial was discontinued at the time when 30 preterm infants had been enrolled.
This open-label study comprised 30 preterm infants (gestational age: 29.2 ± 1.1 weeks; birth weight: 1241 ± 154 g [mean ± standard error of the mean (SEM)]) who were randomized to receive dexamethasone (DEX group, n=15) or to serve as control subjects (CONTROL group, n=15). The randomization was performed blinded with sealed envelopes, and the pediatricians involved with the clinical work were not informed whether dexamethasone was given or not. Inclusion criteria were birth weight 1000 to 1500 g and RDS that required mechanical ventilation and surfactant treatment. Dexamethasone, given as a 4-day course, was started at the age of 12 to 24 hours at a dose of 0.5 mg/kg/d for 2 days and 0.25 mg/kg/d for the subsequent 2 days.
The clinical characteristics of patient groups are presented in Table 1. Antenatal glucocorticoid treatment (1–5 courses of betamethasone given as 2 doses of 12 mg with a 12-hour interval) was used to reduce the frequency of RDS. Surfactant treatment was given as Curosurf (Chiesi Farmaceutici SPA, Parma, Italy) 100 mg/kg; the first dose of surfactant was given at the age of 1 to 24 hours. Indomethacin was given as 3 doses (0.2 mg/kg + 0.1 mg/kg + 0.1 mg/kg at 12-hour intervals) for patent ductus arteriosus requiring treatment. All patients received ampicillin 200 mg/kg and netilmicin 6 mg/kg from the first day of life.
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Tracheal Aspirate Sample Collection
During the first postnatal week, 41 samples were collected from 15 infants in the DEX group, and 49 samples were collected from 15 infants in the CONTROL group. In the first sampling period (days 1–2), all 15 infants remained intubated in both groups (13 samples in both groups). In the second sampling period (days 3–4), 12 infants (18 samples) in the DEX group and 13 infants (20 samples) in the control group remained intubated. In the third sampling period (days 5–7), 4 infants (10 samples) in the DEX group and 7 infants (16 samples) in the control group remained intubated. Sample collection was started after the first dose of dexamethasone was given. Samples were collected once daily from each infant by standardized routine tracheal lavage until extubation. One milliliter of sterile isotonic saline was instilled into the endotracheal tube, the infant was manually ventilated for 3 breaths, and the trachea was suctioned twice, each time for 5 seconds. For analysis of tracheal aspirates, secretions were collected into a trap and transferred into tubes containing 500 IU of aprotinin (Trasylol, Bayer, Leverkusen, Germany) and 5 mg of deferoxamine (Desferal, Ciba, Basel, Switzerland). The samples were stored at -20°C until analysis.
Analysis of HGF, VEGF, and Secretory Component of Immunoglobulin A in Tracheal Aspirate Fluid
HGF was analyzed by the Quantikine Human HGF Immunoassay, and VEGF was analyzed by the Quantikine Human VEGF Immunoassay (both from R&D Systems, Oxon, UK). For eliminating the effect of dilution of tracheal aspirate fluid (TAF) samples, the concentration of the secretory component of immunoglobulin A (IgA-SC) was determined by direct enzyme-linked immunosorbent assay, after which HGF/IgA-SC and VEGF/IgA-SC ratios were calculated. IgA-SC isolated from human colostrum served as the standard. Microtiter plates (Nunc, Roskilde, Denmark) were coated overnight at 4°C with 100 µL aliquots of 1:2000-diluted anti-human secretory component (Dako, Glostrup, Denmark) in 50 mM of Nabicarbonate (pH 9.5). After the plates were washed with 200 µL of 20 mM of Tris/500 mM of NaCl (TBS, pH 7.5), they were blocked for unspecific protein binding by incubation with 200 µL of 2% bovine serum albumin in TBS and washed with 0.05% Tween 20 in TBS (TTBS). TAF samples were diluted to between 1:10 and 1:500 in diluting buffer (1% bovine serum albumin in TTBS), and 100-µL aliquots were added to the wells. After incubation overnight at room temperature, the plates were washed 3 times with TTBS; 100 µL of peroxidase-conjugated rabbit anti-human SC (Dako), diluted 1:400 in diluting buffer, was added, and the plates were incubated for 4 hours at room temperature. After being washed with TTBS, the plates were developed with 100 µL of substrate solution containing 8 mg of orthophenylenediamine (Dako) and 5 µL of 30% H2O2 in 12 mL of water. After 30 minutes at room temperature, the optical densities of the plates were read at 450 nm.
Statistical Analysis
Infant data are given as mean ± standard deviation, and results are given as mean ± SEM. Comparisons between unpaired items were performed with Student t test, and comparisons between groups were performed with the 1-way analysis of variance. The Bonferroni correction served for post hoc comparisons. The 2 served for categorical variables, and simple regression analysis served for continuous variables. Logarithmic transformation of the data were performed when appropriate. P < .05 was considered significant. All calculations were done with StatView 5.0 (Abacus Concepts Inc, Berkeley, CA).
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RESULTS |
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Patient Population
In the DEX group, less BPD was observed (1 of 15 vs 7 of 15 in CONTROL group; P=.01), but no differences existed between the DEX and CONTROL groups in regard to other clinical parameters (all P > .05, Table 1). Because TAF samples were not available every day from every patient, the mean value on postnatal days 1 to 2, 3 to 4, and 5 to 7 were used for analysis. IgA-SC was measured, and data were corrected for dilution by adjustment with IgA-SC before analysis.
HGF
No differences existed in mean HGF concentrations between DEX and CONTROL groups on days 1 to 2 (62.3 ± 8.2 vs 110.1 ± 32.4, pg/IgA-SC unit, respectively; P=.16). The DEX group had a lower mean HGF concentration than the CONTROL group on days 3 to 4 (40.8 ± 4.7 vs 96.2 ± 20.4 pg/IgA-SC unit, respectively; P=.0022) and on days 5 to 7 (46.6 ± 11.4 vs 123.1 ± 49.4 pg/IgA-SC unit, respectively; P = .030; Fig 1A).
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Infants who had received antenatal betamethasone had a tendency toward a lower mean HGF on days 1 to 2 than did those who were given no betamethasone (68.5 ± 10.7 vs 144.3 ± 65.0 pg/IgA-SC unit, respectively; P=.064). No associations were seen between mean HGF on days 1 to 2 and other prenatal parameters (all P > .05, Table 1). Moreover, no associations existed between mean HGF on days 3 to 4 or days 5 to 7 and postnatal parameters (all P > .05, Table 1).
VEGF
No differences existed between the DEX and CONTROL groups in mean VEGF levels on days 1 to 2 (18.4 ± 7.5 vs 14.8 ± 5.0 pg/IgA-SC unit, respectively; P=.70), on days 3 to 4 (35.4 ± 5.6 vs 38.7 ± 10.7 pg/IgA-SC unit, respectively; P=.77), or on days 5 to 7 (48.8 ± 9.0 vs 37.9 ± 9.0 pg/IgA-SC unit, respectively; P=.45; Fig 1B).
No associations were seen between mean VEGF on days 1 to 2 and prenatal parameters or parameters at birth (all P > .05; Table 1). A correlation was found between mean VEGF on days 3 to 4 and the initial arterial-alveolar ratio (R=0.46, P=.011). Negative correlations existed between mean VEGF on days 3 to 4 and number of surfactant doses (R = -0.50, P=.0014) and between mean VEGF on days 5 to 7 and duration of mechanical ventilation (R=-0.42, P=.036). No other associations were found between mean VEGF on days 3 to 4 or 5 to 7 and other postnatal parameters (all P > .05, Table 1).
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DISCUSSION |
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We discovered lower HGF in TAF from preterm infants who received dexamethasone. Moreover, a tendency toward lower HGF was detected in infants who received antenatal betamethasone. Our finding is in line with previous in vitro studies in which corticosteroids suppress HGF gene expression and secretion in embryonic lung fibroblasts,16 and dexamethasone inhibits growth factor–induced HGF mRNA expression and HGF secretion in human skin fibroblasts.17 In fetal organ cultures, HGF elicits mitogenic action in alveolar type 2 cells and bronchiolar epithelial cells,8 and added HGF stimulates epithelial branching of the lung.9 In experimental animals after acute lung injury, expression of HGF mRNA and HGF activity both increase,18 and HGF concentration in lung lavage fluid rises, which is associated with both bronchial and alveolar epithelial cell proliferation.19 In such animals, intravenous injection of human recombinant HGF stimulates DNA synthesis of airway and alveolar epithelial cells and prevents progression of the injury.10 These data suggest that HGF participates in alveolar development, and after acute lung injury, it mediates airway and alveolar regeneration in lung repair.
Antenatal maternal glucocorticoids increase lung compliance, volume, and alveolar surfactant and reduce the incidence of RDS after preterm delivery.20 Early postnatal dexamethasone treatment has been shown to reduce the severity of RDS in preterm infants and shorten the requirement for mechanical ventilation, and it may also reduce subsequent development of BPD.21–25 Postnatal dexamethasone has adverse effects on infant growth, and it increases the risk for hypertension, hyperglycemia, and intestinal perforation.21–23,25 In embryonic rat lung cultures, dexamethasone treatment results in impaired growth, distorted branching, dilated proximal tubules, and suppressed proliferation of epithelial cells of the distal tubules.22 In rats, postnatal dexamethasone treatment impairs septation26,27 and accelerates alveolar thinning, resulting in emphysematous lungs.28 Also, antenatal dexamethasone treatment may suppress alveolarization in rats.29 Moreover, in preterm lambs, maternally given betamethasone results in larger, thinner, and fewer alveoli.30 Glucocorticoids inhibit inflammatory cytokines of which interleukin-1 and interleukin-6 have been shown to induce HGF expression in vitro.31,32 One possible explanation for reduced pulmonary HGF in infants who receive dexamethasone may be related to its anti-inflammatory effects.
The development of BPD today has been suggested to be caused by an arrest of normal lung development.5 We show here evidence that glucocorticoids reduce levels of HGF, an epithelial cell mitogen, in TAF in human preterm infants during the early postnatal period. BPD today is a disease of the most immature preterm infants,4 and it is probable that glucocorticoids affect HGF in an analogous way also in more immature infants. Therefore, we suggest that dexamethasone—through its effect on pulmonary HGF—may have adverse influence on pulmonary development and on repair of acute injury in the preterm lung.
No differences existed between the DEX and CONTROL groups for VEGF levels in TAF. Previously, dexamethasone treatment has been shown to be associated with increased VEGF in TAF in human preterm infants,33 but we detected no such association. In vitro, corticosteroids downregulate VEGF expression in human pulmonary fibroblasts and pulmonary vascular smooth muscle cells,34 and dexamethasone blocks the hypoxia-induced increase in VEGF mRNA in pulmonary artery smooth muscle cells.35 In contrast, in vivo, dexamethasone treatment increases VEGF mRNA expression in developing mouse lung.36 In newborn rabbits, during their recovery from experimental lung injury, repair of the microvascular endothelium correlates with increased expression of VEGF in alveolar epithelial cells37; in these animals, hyperoxic lung injury reduces pulmonary expression of VEGF mRNA and protein, a process that may contribute to impaired microvascular repair of the injury.38 In this study, infants with more severe RDS, defined as low initial arterial-alveolar ratio, high number of surfactant doses, and long duration of mechanical ventilation, had lower VEGF. This is in accordance with our previous data showing an association between lower VEGF in TAF during the early postnatal period and more severe RDS, as well as development of BPD.39
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CONCLUSION |
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In tracheal aspirates during the early postnatal period in human preterm infants, reduced levels of HGF but not of VEGF were evident in infants who received early postnatal dexamethasone therapy. The reduced tracheal levels of HGF may indicate a suppressive effect of dexamethasone on lung development.
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ACKNOWLEDGMENTS |
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This study was supported by Finska Läkaresällskapet, the Duodecim Research Fund, the Helsinki University Central Hospital Research Fund, and the Foundation for Pediatric Research.
We thank the personnel of the neonatal intensive care unit and the neonatal nursery of the Hospital for Children and Adolescents for kind cooperation, Marjatta Vallas for excellent technical assistance, and Prof Ch. Speer and Dr B Götze-Speer (Kinderklinik, Tübingen, Germany) for generous help with IgA-SC standardization.
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FOOTNOTES |
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Received for publication Nov 14, 2001; Accepted Apr 10, 2002.
Reprint requests to (P.L. c/o S.A.) Hospital for Children and Adolescents, Stenbäckinkatu 11, 00029 HUS, Helsinki, Finland. E-mail: patrik.lassus{at}helsinki.fi
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