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Am J Physiol Endocrinol Metab 292: E308-E313, 2007. First published September 5, 2006; doi:10.1152/ajpendo.00251.2006
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Epithelial lining fluid free IGF-I-to-PAPP-A ratio is associated with bronchopulmonary dysplasia in preterm infants

Ettore Capoluongo,1,2 Franco Ameglio,1 Paola Lulli,1 Angelo Minucci,1 Concetta Santonocito,1 Paola Concolino,1 Enrico Di Stasio,1 Simona Boccacci,3 Valentina Vendettuoli,3 Giuseppe Giuratrabocchetta,3 Angela De Cunto,3 Milena Tana,3 Costantino Romagnoli,3 Cecilia Zuppi,1 and Giovanni Vento3

1Institute of Biochemistry and Clinical Biochemistry and 2International Scientific Institute "Paolo VI" Catholic University of the Sacred Heart and 3Division of Neonatology, Department of Pediatrics, Catholic University of the Sacred Heart, Rome, Italy

Submitted 25 May 2006 ; accepted in final form 28 August 2006


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Preterm newborns developing retinopathy of prematurity (ROP) and bronchopulmonary dysplasia (BPD) show persistently low levels of insulin-like growth factor-I (IGF-I) in sera. They also present higher free IGF-I concentrations in epithelial lining fluids (ELFs) and lung tissues. Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase that dissociates three binding proteins from the active form of IGF-I, namely free IGF-I. The present study analyzes the ELF concentrations of free IGF-I, PAPP-A, and their ratios in preterm newborns developing or not BPD, defined as O2 dependence at 36 wk postmenstrual age. Bronchoalveolar lavage fluids of 41 infants (34 without and 7 with BPD) were analyzed on the 2nd and 4th day after birth. Infants developing BPD showed increased ELF free IGF-I and decreased PAPP-A concentrations on both days 2 and 4 compared with newborns without BPD. A nonsignificant trend between these 2 days was observed for free IGF-I (increasing) and PAPP-A (decreasing). On the same days, the free IGF-I-to-PAPP-A ratio was always significantly higher in patients developing BPD. These differences were more significant than those of IGF-I or PAPP-A when individually evaluated. A multivariate analysis confirmed the significance for free IGF-I on day 4, whereas the ratio was confirmed on both days 2 and 4. The same ratio was significantly correlated with some indexes of disease severity, such as hours of oxygen administration, days of hospitalization, and ROP severity scores. Finally, the ratio between ELF free IGF-I and PAPP-A appears to be a useful marker for lung injury of premature newborns.

insulin-like growth factor I; pregnancy-associated plasma protein-A

BRONCHOPULMONARY DYSPLASIA (BPD), evaluated as oxygen dependence at the 36th wk postconception in very-low-birth-weight infants, is a major health concern because of its morbidity and high mortality (22, 30, 32). The pathogenesis of BPD is still unclear, although several risk factors have been described (2, 8, 9, 22, 30–32). Recently, pulmonary inflammation (6, 8, 31) and several proinflammatory and anti-inflammatory/fibrogenic cytokines in epithelial lining fluid (ELF) have been indicated as possible triggers of pulmonary fibrosis (4, 6, 8, 22, 30–32), one of the main characteristics of BPD (6, 9, 22, 30–32).

In adult lung fibrosis, an increased level of insulin-like growth factor-I (IGF-I) has been described in lung fibroblasts (19). IGF-I has been shown to be a strong profibrogenic mediator, acting as a potent mitogen (24) and stimulator of collagen synthesis (19, 24). Liver principally produces serum IGF-I (7, 14) as a result of growth hormone induction. In addition, a number of different cells (such as fibroblasts and endothelial cells) may also release IGF-I (14, 27). Lung macrophages are the cells responsible for the IGF-I synthesis and release in adult patients with idiopathic pulmonary fibrosis (27) and other fibrotic lung diseases (20), including interstitial lung disease in children (20, 24).

IGF-I is present, as inactive form, in all tissues, including the lung. It is mostly coupled with one of six IGF-binding proteins (IGFBPs-1 to -6), but it also exists (~10%) in an unbound, active form, named free IGF-I (7). As a powerful inducer of T-helper-2 (TH-2) polarization, free IGF-I modulates the cytokine network (20, 24). TH-2 lymphocytes release an abundance of transforming growth factor-beta1, a strong pro-fibroticmediator (20), that in turn induces IGF-I production in lung fibroblasts (7). In a recent paper, we observed that preterm neonates that developed BPD presented higher ELF free IGF-I values than neonates without BPD (5).

The free IGF-I availability depends on pregnancy-associated plasma protein A (PAPP-A). The latter is a 200-kDa metalloproteinase capable of inducing the dissociation of free IGF-I from three of the binding proteins (IGFBP-2, -4, and -5). In addition to the placenta, PAPP-A is expressed in a wide variety of reproductive and nonreproductive organs and fetal tissues, and many cells are able to produce PAPP-A, such as fibroblasts, endothelial cells, and smooth muscle cells (3, 10, 16, 25).

Elevated PAPP-A serum levels have been reported in patients with acute coronary syndrome, indicating that it may be considered as a novel heart biomarker (13, 23). In this particular model, PAPP-A and IGF-I are inversely correlated (13, 22). Some hormones and cytokines may modulate PAPP-A gene expression (11, 12), whereas interferon-{gamma} treatment strongly inhibits its synthesis (29). Hypoxic/oxidative/inflammatory stresses are capable of enhancing PAPP-A’s bioactivity (13, 14). In addition, experimental damage induces an increase in local PAPP-A expression and IGF-I bioactivity (14, 15) with immunomodulatory and anti-inflammatory actions (13). These data suggest that PAPP-A is involved in the physiological repair and replicative programs through its product: free IGF-I (13, 14).

Because no information of PAPP-A levels concerning ELF or serum of premature neonates (especially in relation with BPD development) was available in the literature, we planned to perform the present study to evaluate: 1) the presence and quantification of PAPP-A in ELFs of premature newborns, 2) a possible association of this molecule or its free IGF-I-to-PAPP-A ratio to BPD, 3) possible correlations of free IGF-I, PAPP-A, or their ratio with several variables linked to the clinical outcome, and 4) the reciprocal relationship between free IGF-I and PAPP-A levels in ELFs.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients’ enrollment. This study was carried out in the Neonatal Intensive Care Unit of the Catholic University of Rome between July 2004 and December 2005 and included babies whose characteristics are reported in Table 1. Eligibility requirements included gestational age ≤30 wk, delivery in our hospital, endotracheal intubation at birth, and ongoing intensive care. Newborns with major congenital malformations, prenatal infection [positive blood or bronchoalveolar lavage fluid (BALF) cultures at birth] with severe asphyxia (Apgar score <5 at 1 and 5 min), or babies treated with early (1st wk of life) dexamethasone therapy were all excluded from this study. Infants enrolled in this study but who died before the BPD diagnosis were also excluded from the final analysis. A total of 11 subjects were excluded for the presence of at least one of the previous exclusion criteria.


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  		Table 1. Baseline patients’ characteristics and clinical and respiratory variables describing patients’ course on day 2 (total n = 41) and day 4 (total n = 26)

 
All newborns received surfactant therapy (200 mg/kg Curosurf) during the first 6 h of life. Mechanical ventilation was performed with BabyLog 8000 plus (Draeger, Lubeck, Germany) in high-frequency oscillatory ventilation modality, as previously described (30, 32). A second dose of 100 mg/kg of Curosurf was used if mean airway pressure (MAP) was >10 cmH2O, without significant differences between the two groups. The goals of respiratory management were to maintain blood gas values with pH 7.30–7.45, PaCO2 45–55 mmHg (5.9–7.2 kPa), and PaO2 50–70 mmHg (6.6–9.3 kPa) with oxygen saturation 88–94%.

The policy of weaning of ventilatory support during the recovery stage of the illness consisted of the reduction of MAP and FIO2. Extubation was attempted when the neonate’s condition remained stable for at least 6 h while receiving minimal ventilation: FIO2 <0.25, MAP <6 cmH2O, and amplitude <30%. All the babies were extubated on nasal continuous positive airway pressure of 4–6 cmH2O (nasal prongs Argyle; Sherwood Medical, St. Louis, MO). All infants also received antibiotic prophylaxis with the purpose of preventing pulmonary colonization and/or infections during the study period (5 days of life). No hemotransfusions were administered during the first 4 days of the infants’ life.

The study protocol and consent forms were approved by the Ethics Committee of the Department of Pediatrics, following the indication of the Helsinki Declaration.

BALF collection. BALF samples were collected on day 2 (within the first 48 h after birth), and on day 4, as previously described (5, 32). BALF samples were centrifuged at 800 g for 5 min at 4°C and were then divided into two aliquots, both stored at –80°C until analyzed. To normalize the dilution bias resulting from BALF collection practice, a measurement of urea BALF and serum concentrations was performed in duplicate by means of a colorimetric assay (Urea Nitrogen suitable on Olympus AU2700). The serum-to-BALF urea ratio was used as a multiplying coefficient so as to transform BALF into ELF concentrations for the different molecules (28).

Culture-positive BALF specimens, or those with visible blood staining, were excluded from final analysis.

Free IGF-I assay. Free IGF-I in ELFs was measured in triplicate by means of the RIA method (Diagnostic Systems Laboratories; see Ref. 5). The detection limit of this method was 0.03 ng/ml.

Ultra sensitive PAPP-A assay. PAPP-A levels in the ELFs were measured by means of a commercially available high-sensitive kit (Ultra-sensitive PAPP-A ELISA, Diagnostic Systems Laboratories). The detection limit of the method is 0.06 µIU/ml (17).

Statistical analysis. Quantitative data with Gaussian distribution were expressed as means and SD. Comparisons were made by Student’s t-test. Quantitative nonparametric data or ratios or scores were expressed as medians and ranges. Comparisons were obtained by using the Mann-Whitney variance analysis test.

Correlations were calculated by Spearman’s rank correlation test. Comparisons of qualitative data were performed by chi-square or contingency tables. Bonferroni’s correction for multiple correlations was also applied.

Multivariate analysis. SPSS version 6.0 for Microsoft Windows 95/98 was used for statistical analysis. All tests for statistical significance were two sided. Multiple Logistic Regression was performed by selecting significant correlating variables at univariate analysis to determine whether free IGF-I-to-PAPP-A ratio values were independent predictors of the incidence of BPD. The effect on the relationship between free IGF-I, PAPP-A, or their ratio and BPD development was analyzed including several possible confounding variables by means of the multivariate logistic model. This model applies the stepwise logistic regression ("SPSS backward LR method"). The limit for significance has been fixed to P < 0.05.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patients’ characteristics. Table 1 reports the patients’ description subdivided into the following two groups: BPD positive and BPD negative. Only diagnosis of clinical chorioamnionitis was made (premature rupture of membranes ≥12 h and ≥2 of the following: maternal fever, uterus tenderness and pain, maternal or fetal tachycardia, increased number of blood leukocytes), because placental pathology was not available in our patients. Ten of 34 (29.0%) in the BPD-negative group and 3 out of 7 (43.0%) in the BPD-positive group (P = 0.65) received a second dose (100 mg/kg) of Curosurf.

Only one variable exhibited a significant difference between the two groups (Apgar 1 min, on day 2).

A correlation matrix of quantitative variables showed that gestational age was highly correlated with birth weight (r = 0.73, P < 0.001) and continuous positive airway pressure (CPAP; r = –0.70, P < 0.001), and was significantly different for the type of delivery options (P = 0.006). The number of subjects evaluated was 41 on day 2, whereas on day 4 it was 26. In fact, 15 patients were extubated between days 2 and 4. It is clear that a greater number of extubated patients belonged to the group showing a less severe disease, that is BPD negative, whereas BPD-positive patients underwent a prolonged intubation treatment.

The behavior of the main and secondary clinical and respiratory outcomes in the two different groups is also reported in Table 1.

As expected, on day 2, the hours of mechanical ventilations and of oxygen administration, the number of hemotransfusions observed during the entire period of hospitalization, severe intraventricular hemorrhage (IVH), days of hospitalization, and retinopathy of prematurity (ROP) stages were all associated with BPD outcome, showing an increase in BPD-positive subjects. On day 4, significant differences appeared only within hours of oxygen administration and days of hospitalization, notwithstanding a reduction of the patients’ number. Anyhow, the trends were similar. Significant associations were also observed with birth weight, number of hemotransfusions, ROP frequencies, and intraventricular hemorrhage development (data not shown).

Free IGF-I and PAPP-A measurements. Table 2 reports the medians and ranges of ELF free IGF-I concentrations stratified for the two groups. On day 2, significant increases were observed for free IGF-I in patients developing BPD. Even though PAPP-A levels were decreased, the significance was not reached. Instead, on day 4, both free IGF-I and PAPP-A levels showed significant changes between the two groups, manifesting opposite behaviors, that is, an increase of free IGF-I and decrease of PAPP-A ELF concentrations. In fact, a correlation between free IGF-I and PAPP-A levels, calculated on the overall logarithmic data, combining days 2 and 4, gave r = –0.25 (P = 0.04), improving from day 2 (r = –0.20, P = 0.08) to day 4 (r = –0.44, P = 0.02).


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  		Table 2. Epithelial lining fluid levels of free IGF-I, PAPP-A, and free IGF-I-to-PAPP-A ratios (expressed as ng/ml and corrected for urea ratio BALF/serum)

 
To establish whether or not the results observed could be influenced by confounding variables (those reported in Table 1), a multivariate logistic regression analysis was performed, correcting for the latter. The data showed that, on day 2, only a nonsignificant trend could be confirmed, whereas on day 4 a significant difference was found for free IGF-I and only a trend for PAPP-A.

Because PAPP-A and IGF-I are reciprocally influenced at physiological levels, we tried to analyze the behavior of the ratio between free IGF-I and PAPP-A concentrations. To avoid very low values, we multiplied free IGF-I values by 10,000. As shown in Table 2, the ratio was always significant for all classification types both on days 2 and 4. Moreover, as already observed for IGF-I, the ratio increased between days 2 and 4, particularly regarding the BPD-positive patients (ratio = 3.25).

The multivariate logistic regression analysis showed that the ratio was not influenced by the baseline variables sex, gestational age, birth weight, maternal infection, and antenatal steroids and confirmed the significance both on days 2 and 4.

Table 3 completes the analysis of the data obtained in this study. In consideration of the fact that these findings have not been previously reported, a correlation matrix between the ELF values of free IGF-I and PAPP-A levels (after urea corrections) and their ratios vs. 12 clinical variables previously considered in Table 1 was carried out. The correlation P values are presented without correction for multiple comparisons to highlight any possible correlations.


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  		Table 3. Correlation coefficients and significances between free IGF-I, PAPP-A (corrected for urea), or their ratios with several severity indexes of BPD (no. of observations = 41 on day 2 + 26 on day 4 = 67)

 
Interestingly, only the hours of oxygen administration and the number of hemotransfusions were significantly correlated with free IGF-I, PAPP-A, and their ratio. Notably, the ratio of significance was higher than those of the individual molecules. In only one case (namely hours of mechanical ventilation) was there a significance of the single free IGF-I, whereas a significance of the single PAPP-A molecule was observed in three cases (CPAP, gestational age, and birth weight). The ratio was often correlated with the clinical variables implicated in disease severity (reported on Table 1) and never with the baseline variables (those reported in Table 1). In fact, no significant ratio differences were found between males and females (P = 0.51), weight appropriateness for gestational age (P = 0.68), type of delivery (P = 0.19), premature rupture of membranes (P = 0.33), maternal infections (P = 0.28), and antenatal steroid administration (P = 0.85).


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
BPD, ROP, and necrotizing enterocolitis represent some of the main diseases associated with prematurity. They are also associated with each other, suggesting a possible common pathogenetic mechanism localized in three different areas (4, 18). It has recently been hypothesized that, at least for what concerns ROP and necrotizing enterocolitis, a serum IGF-I reduction (common in prematurity) may be involved, particularly in the case of ROP when this decrease was persistent after birth and an imbalance between IGF-I and vascular endothelial growth factor serum concentrations was also present (18).

In contrast with the low serum IGF-I levels associated to ROP and necrotizing enterocolitis, there are two previous studies exhibiting higher IGF-I concentrations in tissues and ELF of premature infants affected by BPD (5, 8). In a previous study, our group analyzed the free IGF-I levels instead of total IGF-I molecule. This choice was because of the fact that free IGF-I is considered to be the active molecular form generated by cleavage of the total form from some binding proteins (7). This process is mediated by a metzincin metalloproteinase named PAPP-A, especially active in IGFBP-2, -4, and -5 cleavage (26).

An analysis of IGF-I and PAPP-A concentrations has been previously performed in some fields, such as pregnancy and embryo development (where low IGF-I is associated with high PAPP-A serum levels) and acute coronary syndrome (where low IGF-I levels are concomitant with high PAPP-A values; see Ref. 13). In both of these models, there is an inverse correlation between free IGF and PAPP-A values. No data regarding the PAPP-A levels determined in BALF samples of premature infants are available in literature. On the basis of the previous findings, one could hypothesize that higher ELF IGF-I levels of preterm newborns developing BPD should be associated with lower ELF PAPP-A concentrations when compared with data belonging to infants not developing BPD.

Because the methodology employed to obtain BALF samples cannot be completely standardized, we used the urea method (28) to correct this bias and transformed the data obtained from the BALF in ELF values.

The new data obtained confirm the previously published findings (5) regarding the association of BPD and high free IGF-I levels and give new information regarding the reduced PAPP-A levels found in ELF of subjects developing BPD. Furthermore, the ratio between the two molecules shows a more significant association with the disease than the same molecules do when individually considered.

To assess whether or not these results were independent of other baseline variables regarding the infants (sex, gestational age, birth weight, maternal infection, and antenatal steroids), a logistic multivariate analysis was performed, where the results confirmed the free IGF-I/BPD association only on day 4, probably because of the fact that the mechanisms of the disease are more pronounced, as also suggested by the molecular concentration trends observed between days 2 and 4 (increase of free IGF-I and decrease of PAPP-A values). The ratio was instead significantly associated with BPD on both days.

Because it is known that serum free IGF-I values increase with the gestational age and are lower in infants developing ROP/BPD (18), the data support the idea that the free IGF-I molecules, determined in the BALF, may derive from a local production, and this finding is in agreement with the literature data showing that these molecules may be produced by the alveolar macrophages/monocytes (5, 8, 13). A limit of this study is the fact that the methods used cannot identify the IGF-I- and PAPP-A-producing cells.

As expected, the BPD outcome was correlated to some of a series of other variables, suggested as possible severity indexes and listed on Table 1. Table 1 also reports the association between BPD and ROP. All of these variables were analyzed for possible correlations with the two molecules determined and their ratios. Only the PAPP-A values were significantly correlated with gestational age and birth weight, and thus the multiparametric analysis could not significantly confirm its association with BPD. The ratio between free IGF-I and PAPP-A levels showed the greater number of significant correlations with the severity indexes (6/8, mechanical ventilation, oxygen administration, hemotransfusions, IVH stage, hospitalization, and ROP stage), whereas PAPP-A levels had only five significant correlations (oxygen administration, CPAP, hemotransfusions, hospitalization, and IVH stage) and only three were those found with free IGF-I (mechanical ventilation, oxygen administration, and hemotransfusions). Only oxygen administration and the number of hemotransfusions were significantly correlated with both free IGF-I and PAPP-A molecules and their ratio. The biological and clinical implications of a red blood cell transfusion given to premature infants in terms of IGF-I load have recently been underlined (21). Of course, ELF IGF-I levels measured in our patients during the first 4 days of life are not dependent on hemotransfusions, since these were only administered after this period. In our study, the higher number of hemotransfusion given during hospitalization in the BPD group is a marker of severity of neonatal disease. In addition, hemotransfusions administered during the observation period were not different between the two groups.

The P values of Table 3 are presented without correction for multiple comparisons. They were reported so as to indicate any possible correlation. Obviously, the Bonferroni’s correction reduced the significances to P < 0.0001. Appropriate prospective studies should be planned to confirm the weaker correlations.

Considered altogether, these data may further suggest an involvement of these IGF system molecules in the lung injury development and their possible use as markers of BPD.

From a point of view of the IGF-I involvement in the pathogenesis of the disease, the latter is known to enhance the TH-2 immune response, stimulating the release of profibrotic cytokines (fibroblast growth factor, vascular endothelial growth factor, transforming growth factor-beta1), which in turn are able to enhance fibrotic processes. In our previous studies (31, 33), we reported the fact that severe BPD was characterized by the presence of high levels of transforming growth factor-beta1, platelet-derived growth factor-BB, and vascular endothelial growth factor in ELFs. In particular, the highest levels of transforming growth factor-beta1 were found in severe forms of BPD and were associated with poor pulmonary mechanics (31).

Previous studies showed that IGF-I was increased in adults affected by idiopathic lung fibrosis, and lungs of preterm newborns affected with BPD were highly positive for IGF-I molecules (19, 24, 27). The data reported in this study are in agreement with the idea that free IGF-I is increased at lung levels (ELF values) in affected infants, further confirmed by decreased PAPP-A levels, which are always inversely correlated in the different models studied (1, 10). It has already been reported that tumor necrosis factor-{alpha} is able to reduce IGF-I and induce the release of PAPP-A molecules (1, 10).

As a feedback mechanism, it is reasonable to speculate that PAPP-A levels (causing an increase in IGF-I hydrolysis) should be reduced in lungs affected by BPD, where the IGF-I levels are elevated, to avoid production of more free IGF-I molecules that may enhance the fibrotic processes. On the contrary, PAPP-A levels should be high in patients with acute coronary syndrome to obtain an increase of the low serum concentrations of free IGF-I, a molecule considered useful in terms of cell survival.

Despite the need for further studies concerning the interactions between IGF-I and PAPP-A, so as to fully understand their regulatory mechanisms, the present work suggests that the ratio between ELF free IGF-I and PAPP-A value may be taken in consideration as a new useful marker correlating with lung injury and several severity indexes in preterm newborns, also in relation to the fact that BPD is a significant problem and markers for this disease may help predict its development, clarify the mechanisms involved, and serve as the basis for interventions. (2)


   FOOTNOTES
 

Address for reprint requests and other correspondence: E. Capoluongo, Laboratory of Molecular Biology, Dept. of Biochemistry and Clinical Biochemistry, Catholic University, Largo F. Vito 1, 00168, Rome, Italy (e-mail: ecapoluongo{at}rm.unicatt.it)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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