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High Concentrations of Keratinocyte Growth Factor in Airways of Premature Infants Predicted Absence of Bronchopulmonary Dysplasia

Unité de réanimation néonatale, Centre Hospitalier Intercommunal de Créteil, Créteil; Service de Réanimation néonatale, Hôpital Cochin-Port Royal, Paris; and INSERM U492, Faculté de Médecine de Créteil, Créteil, France

Correspondence and requests for reprints should be addressed to Christophe Delacourt, Service de Pédiatrie, Centre Hospitalier Intercommunal de Créteil, 40 avenue de Verdun, 94000 Créteil, France. E-mail: christophe.delacourt{at}chicreteil.fr

	ABSTRACT

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Premature lungs are highly susceptible to lung injuries, leading to bronchopulmonary dysplasia (BPD). Keratinocyte growth factor (KGF) is produced by the developing lung and may reduce the risk of BPD by preventing injury to the lung epithelium and enhancing its repair. To determine whether KGF concentrations in the airways during the initial phase of hyaline membrane disease are correlated with subsequent development of BPD defined as the need for supplemental oxygen at a postconceptional age of 36 weeks, we obtained tracheal aspirates within 3 hours of birth (Day 0) from 91 intubated neonates with a gestational age of 30 weeks or less. Repeat samples were obtained from 42 neonates within 5 days after birth. KGF in aspirate supernatants was measured by enzyme-linked immunosorbent assay. On Day 0, KGF was detected in all but six neonates. A significant increase in KGF concentration was found from the first to the second samples. The highest KGF concentration within 5 days after birth (KGF_max) was significantly higher in survivors without BPD than in those with BPD. A KGF_max value higher than 110 pg/ml had a positive predictive value of 95% for absence of BPD. KGF may hold promise for the treatment of very premature neonates.

Key Words: lung development • newborn • bronchopulmonary dysplasia

	INTRODUCTION

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Premature neonates with hyaline membrane disease are at risk of developing bronchopulmonary dysplasia (BPD), as a sequel of both the disease and its treatment. Although the pathogenesis of BPD is unclear, it probably involves a response to damage inflicted on the immature lung by mechanical ventilation, oxygen therapy, and airway inflammatory responses (1). In particular, these insults may interfere with normal epithelial cell proliferation and differentiation, which are crucial to normal alveolar development (2). Inadequate repair of injured alveolar epithelium may further contribute to BPD development. Minimizing alveolar epithelial injury and enhancing epithelial repair may, therefore, reduce the risk of BPD. Keratinocyte growth factor (KGF) has been reported to regulate several functions in the alveolar lung epithelia, including proliferation of alveolar epithelial cells (3–6), enhanced synthesis of surfactant (7), and acceleration of wound closure in airway epithelium (8). KGF was also shown in adult rodents to attenuate ventilator- or oxygen-induced lung injury (9, 10). We therefore postulated that high KGF concentrations in the airways of premature infants at the early phase of hyaline membrane disease might protect against subsequent BPD.

	METHODS

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Study Group
Ninety-one neonates with gestational age (GA) of 30 weeks or less were included in the study. They all had clinical and radiologic diagnostic criteria of hyaline membrane disease and were initially intubated. Suspected chorioamnionitis or maternofetal infection led to exclusion from the study. Mean (± SEM) GA was 27.2 ± 0.2 weeks (range 24.3–30 weeks) and mean birth weight was 912 ± 22 g (480–1,480 g). Corticosteroids had been administered to the mother in 65 cases.

A tracheal aspirate was obtained from each neonate within 3 hours of birth (Day 0), before surfactant instillation. Forty-two neonates were resampled before extubation, on Day 3, or on Day 5 when still intubated. Some neonates had three samples taken. In all, 144 samples were collected.

The diagnosis of BPD was based on a need for oxygen supplementation at a postconceptional age (PCA) of 36 weeks (11).

This study was part of a clinical research program (PHRC) that was approved by the local ethics committee. Informed consent was obtained from the parents.

Collection of Tracheal Aspirates
Gentle tracheal aspiration is routinely performed in our unit to maintain airway patency in intubated neonates. These aspirates served as the samples for this study. Suction was preceded by instillation of 0.2 ml of isotonic saline. After three to five ventilator breaths, suctioning was performed through a small catheter. The aspirated material was collected in an Infant Mucus Extractor (Vygon, Ecouen, France), diluted in 0.2-ml isotonic saline, gently vortexed, and centrifuged at 1,200 rpm and 4° C for 10 minutes. The supernatant was recovered and stored at -80° C. This technique is very similar to those described in other studies (12, 13). Although some authors used larger instillate volumes and greater aliquot numbers, the neonates had older GAs and higher birth weights than in our population (14, 15). In our experience, higher instillate volumes were badly tolerated by many premature infants weighing less than 1,000 g. Moreover, because of the small volume of saline instilled into the airways, the dilution factor induced by our technique was believed to be limited and was evaluated in preliminary experiments, using secretory IgA (sIgA) as a dilution marker (enzyme-linked immunosorbent assay [ELISA]; Immun Diagnostik, Bensheim, Germany). sIgA was measured in 60 samples collected within the first 5 days of life from intubated premature infants less than 30 weeks of gestational age. The intersubject coefficient of variation was found to be very low (18.2%), demonstrating considerably smaller variability in dilution than that reported with larger aliquot volumes (15). Given the fact that the small volume of recovered sample did not allow measurement of sIgA in addition to the other parameters for all samples, this limited variability in dilution would permit normalization of the assay results per milliliter of supernatant. To definitely assess this method, we preliminary compare results normalized per milliliter of supernatants to those normalized per sIgA concentration in samples with available sIgA measurement.

KGF Assay
A selective ELISA system (R&D Systems, Abingdon, UK) was used to determine human KGF concentrations in tracheal aspirate supernatants. The minimum detectable dose of KGF in our experiments was less than 10 pg/ml. Intra- and interassay coefficients of variation were 3.3 and 6.1%, respectively. The specificity of the R&D ELISA kit for KGF was evaluated by the manufacturer for more than 70 human factors. These, including factors related to KGF (basic-fibroblast growth factor [basic-FGF], acidic-FGF, FGF-4, FGF-5, FGF-6), were assessed for cross-reactivity with anti-KGF antibody. These factors were prepared at 50 ng/ml in the kit diluent and tested for interference in the assay in a mid-range of recombinant human KGF (rhKGF) standard. No significant cross-reactivity or interference was observed.

In addition, we also tested the tightly KGF-related FGF-10 for possible cross-reactivity and interference with KGF. No significant cross-reactivity was found for several concentrations of FGF-10 (up to 100 ng/ml). We evaluated interactions of 50 ng/ml FGF-10 with several concentrations of rhKGF in the range of those observed in samples from our population (15.6–125 pg/ml, i.e., about three orders less than the FGF-10 concentration). No interaction was observed.

Data Analysis
Because KGF concentrations were not normally distributed, we expressed each concentration as the median, 25th–75th percentiles, and 10th–90th percentiles. Data were normalized by log transformation for statistical analysis. The influence of GA and birth weight on airway KGF concentrations on Day 0 was evaluated by regression analysis, with these two parameters as independent variables and KGF values as the dependent variable. Changes in KGF concentrations over time in serially sampled neonates were assessed by analysis of variance (ANOVA) for repeated measures. ANOVA was used to look for an association between BPD and the airway KGF concentration on Day 0 or the highest KGF concentration within 5 days of birth (KGF_max). p Values smaller than 0.05 were considered statistically significant.

	RESULTS

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One hundred and forty-four samples were collected from 91 neonates. Mean available volume of tracheal aspirate supernatant was 190 ± 12 µl. sIgA could be adequately measured in 66 of these samples (n = 48 infants). In these samples, there was a strong correlation between KGF results expressed as picograms per milliliter of supernatant and those expressed as picogram per nanogram sIgA (r = 0.823; p < 0.0001). This finding allowed us to express KGF data as picograms per milliliter of tracheal aspirate.

KGF Concentrations in Tracheal Aspirates at Birth
Of the 91 neonates sampled within 3 hours after birth, eight died before 36 weeks PCA. Death was related to severe neurologic complications (n = 4), cardiorespiratory complications (n = 3), or enterocolitis (n = 1). Fourteen of the 83 other infants still needed oxygen supplementation at 36 weeks PCA and were consequently diagnosed with BPD.

We were able to assay KGF in 88 of the 91 samples obtained on Day 0. KGF was detected in 82 of these 88 samples. We arbitrarily assigned a value of 1 pg/ml to the neonates with a negative assay. On Day 0, median KGF concentration in the 88 infants was 61.2 pg/ml (22.9–111.4 pg/ml) (25th–75th percentiles). Neither birth weight nor GA significantly influenced KGF concentrations on Day 0, although the 60 neonates born before 28 weeks GA had lower median KGF concentrations than the 28 infants born at 28 weeks GA or later: 54.0 pg/ml (22.5–101.2 pg/ml) versus 85.3 pg/ml (25.2–182.0 pg/ml), respectively. KGF concentrations on Day 0 were not significantly influenced by antenatal corticosteroid exposure.

Postnatal Changes in KGF Concentrations
A second sample was obtained from 42 neonates, with a time interval of 2.6 ± 0.2 days (mean ± SEM) between the first and the second samples. In these neonates, median KGF concentration increased significantly from 52.0 pg/ml (26.0–96.8 pg/ml) in the Day 0 sample to 93.7 pg/ml (53.2–136.8 pg/ml) in the second sample (p < 0.008). GA did not influence this postnatal increase. A third sample was obtained in 14 neonates at 5 days of age. Median KGF was 60.3 pg/ml (39.6–184.0 pg/ml) in these samples, and there was no significant difference from the median for the second samples.

For each infant, we defined the KGF_max value as the maximal KGF concentration determined in tracheal samples collected between birth and Day 5. The median KGF_max was 95.7 pg/ml (50.4–172.9 pg/ml).

KGF Concentrations and BPD Outcome
Fourteen premature infants had BPD, defined by a need for oxygen supplementation at 36 weeks PCA. No significant difference in median KGF concentration on Day 0 was found between the infants with and without subsequent BPD. However, median KGF_max was significantly lower in these 14 infants than in the infants without BPD (p < 0.03, Figure 1) . Furthermore, the highest KGF_max values were observed in the neonates who remained free of BPD (Figure 1). Of particular interest is the outcome of the six children with undetectable KGF on Day 0. Three of these infants developed BPD and two others had a persistent need for oxygen supplementation on Day 28 but not at 36 weeks PCA.

View larger version (20K): [in this window] [in a new window]   Figure 1. KGFmax concentrations (A: pg/ml; B: pg/ng sIgA) measured in tracheal aspirates from premature neonates during the first 5 days after birth. A total of 14 neonates did and 69 did not have BPD at 36 weeks PCA. Eight infants died before 36 weeks PCA and could not be evaluated for BPD. sIgA could be evaluated in only 48 infants. Individual values are shown, as well as box plots for the median and 25th–75th percentiles; error bars span the 10th–90th percentiles. ANOVA was used on log-transformed data; BPD- versus BPD+, p < 0.03; BPD- versus BPD+ or death before 36 weeks PCA, p < 0.02 (p < 0.05 and <0.03 when analysis restricted to samples with sIgA determination, respectively). The broken line represents the cutoff value (KGFmax > 110 pg/ml or >4 pg/ng sIgA) shown on the receiver-operating characteristics curve to discriminate between neonates with and without subsequent BPD.

To confirm that our results were not dependent on the method of expression, we restricted our analysis to the 48 infants with available sIgA measurement. Similar results were obtained (Figure 1B). Children who survived with BPD (n = 8) had significantly lower KGF_max values than infants who survived without BPD (n = 35) (p < 0.05). KGF_max > 4 pg/ng sIgA was the best cutoff associated with the absence of subsequent BPD and yielded a sensitivity of 57%, a specificity of 88%, a positive predictive value of 95%, and a negative predictive value of 32%. When infants who died before 36 weeks PCA (n = 5) were grouped with infants who survived with BPD, results were unchanged: the median KGF_max value of this subgroup was 2.0 pg/ng sIgA (0.8–3.3 pg/ng sIgA), still significantly lower than in infants surviving without BPD (p < 0.03).

	DISCUSSION

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Because KGF is involved both in regulating lung development (17) and in enhancing epithelial repair after injury (8), it may play an important protective role in premature neonates at high risk of chronic lung disease. We measured KGF concentrations in airway secretions of very premature neonates early in the course of hyaline membrane disease and found that high KGF concentrations within the first 5 days after birth were significantly associated with absence of subsequent BPD.

KGF is a member of the FGF family and is also known as FGF-7. It was initially believed to regulate branching morphogenesis during lung development (18), but later studies showed this effect to be mainly related to FGF-10 (19). However, KGF has been shown to control processes later in lung development. In particular, KGF stimulated the synthesis of all surfactant components in developing alveolar type II cells (7). Furthermore, based on reports that KGF enhanced alveolar epithelial cell proliferation both in vitro (5) and in vivo (4, 6), it may also exert a key influence on alveolar development by regulating alveolar epithelial cell proliferation, which occurs at a high rate during alveolar septation (2). However, little is known about KGF expression within the lungs during alveolar development. Our results demonstrate the presence of KGF in human airways during the last trimester of gestation. Indeed, samples obtained immediately after birth could be considered to reflect physiologic concentrations present in airways at a given GA. Detectable concentrations of KGF were found in the airways of nearly all the neonates on Day 0, showing that KGF is spontaneously expressed in the airways during the saccular and alveolar stages of human lung development. A slight, but nonsignificant, increase with GA was found, suggesting that KGF expression may be influenced by maturational processes and may be higher at the end of gestation. An early postnatal increase in KGF concentrations was also observed in our patients, with no influence of GA. However, we do not know to what extent this increase was related to normal birth-related changes or to lung injury in these premature neonates with hyaline membrane disease. For obvious reasons, control samples from healthy neonates could not be obtained. Several stimulatory factors may contribute to the postnatal rise in KGF. Interleukin-1 (IL-1) was demonstrated to be the most effective factor able to stimulate KGF expression in fibroblasts from multiple sources and may therefore play a significant role in this postnatal increase (20). Furthermore, intra-amniotic IL-1 has been shown to accelerate surfactant protein synthesis in fetal rabbits, although no direct effect on fetal alveolar cells could be demonstrated (21). An indirect action through KGF stimulation is an attractive hypothesis, because KGF has been demonstrated to directly enhance synthesis of surfactant (7). However, higher IL-1 concentrations in amniotic fluids were related to a higher risk for BPD (22), and the presence of IL-1 in tracheal lavage of neonates from the first day of life was associated with the development of BPD (23). Thus, high IL-1 and KGF concentrations in neonates clearly do not share the same predictive value for respiratory outcome. It is therefore difficult to support a unique role for IL-1 in the rise in KGF. More complex mechanisms are likely to be involved in this enhancement. Corticosteroids may be implicated, for although they have been shown to reduce KGF production in skin fibroblasts (24), they enhance KGF expression in the lung (17, 25). A rise in endogenous corticosteroids in maturing neonates (26) may therefore account for increased KGF concentrations. It should be underlined, however, that we detected no influence of maternal antenatal corticosteroid treatment.

The main result of our study is the apparent protective effect of high KGF concentration against BPD. Among the 36 neonates who had KGF values above 110 pg/ml during the first 5 days after birth and who were still alive at 36 weeks PCA, only two had BPD. Thus, a high KGF concentration during the first 5 days of life had a high positive predictive value for absence of BPD.

Previous animal models have highlighted the role of KGF in minimizing lung injury and in enhancing lung epithelium repair. In particular, KGF prevented bleomycin-induced lung fibrosis (27), ventilator-induced lung edema (9), Pseudomonas aeruginosa–induced alterations in alveolocapillary barrier permeability (28), and oxygen-induced alveolar epithelium damage (10). Furthermore, KGF accelerated airway epithelial repair following injury (8). All these studies strongly support a protective role for KGF in the neonates included in our study. Early after birth, premature neonates must cope with multiple insults capable of injuring the airway and/or alveolar epithelium, including mechanical ventilation, oxygen supplementation, and airway inflammatory responses. Interference of these early injuries with normal alveolar development, or abnormal repair processes following airway damages are believed to be major factors for BPD development (1, 29). Our study suggests that high KGF concentrations present in airspaces during this critical period after birth may limit the risk for BPD development. Thus, KGF may hold promise for the management of very premature neonates.

	Acknowledgments

 
The authors thank Sandrine Majoux and Annie Chevallier for technical assistance.

Received in original form December 17, 2001; accepted in final form February 14, 2002

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