PEDIATRICS Vol. 117 No. 4 April 2006, pp. 1226-1234 (doi:10.1542/peds.2005-0870)
High Concentrations of Plasminogen Activator Inhibitor-1 in Lungs of Preterm Infants With Respiratory Distress Syndrome
a Departments of Pediatrics
b Surgery
c Haartman Institute, University of Helsinki, Helsinki, Finland
d Department of Pediatrics, Helsinki University Central Hospital, Jorvi Hospital, Espoo, Finland
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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BACKGROUND. Among preterm infants, respiratory distress syndrome (RDS) is characterized by the presence of intraalveolar fibrin deposition. Fibrin monomers inhibit surfactant function effectively. However, little is known about potential disturbances of intraalveolar fibrinolysis in RDS. We studied levels of major plasminogen activator inhibitor-1 (PAI-1), tissue-type plasminogen activator (tPA), and urokinase-type plasminogen activator (uPA) in lungs of preterm infants with RDS.
METHODS. The antigen levels of PAI-1, tPA, and uPA were measured in 262 samples of tracheal aspirate fluid collected from 37 intubated preterm infants during the first 2 postnatal weeks. To examine the expression of PAI-1, tPA, and uPA in lung tissue, immunohistochemical analyses were performed on autopsy specimens from 7 preterm infants with RDS and 6 newborn infants without pulmonary pathologic conditions.
RESULTS. For infants with an immature surfactant profile, as indicated by lecithin/sphingomyelin ratios in tracheal aspirate fluid of <10, PAI-1 levels and ratios of PAI-1 to uPA and tPA were significantly higher during postnatal days 1 to 2, compared with infants with lecithin/sphingomyelin ratios of 
10. Moreover, infants who subsequently developed bronchopulmonary dysplasia (BPD) (n = 15) had higher PAI-1 levels on days 3 to 4 and days 7 to 8 than did those who survived without BPD. For preterm infants with RDS, immunohistochemical analyses demonstrated increased expression of PAI-1, tPA, and uPA predominantly in alveolar epithelium.
CONCLUSIONS. High concentrations of PAI-1 and an increased ratio of PAI-1 to uPA, with a concurrently less-increased ratio of PAI-1 to tPA, are associated with the severity of RDS among preterm infants during the first postnatal days. Pulmonary inhibition of fibrinolysis is a pathophysiologic feature of RDS and may play a role in the development of BPD.
Key Words: respiratory distress syndrome • preterm • respiratory distress syndrome
Abbreviations: RDS—respiratory distress syndrome • BPD—bronchopulmonary dysplasia • tPA—tissue-type plasminogen activator • uPA—urokinase-type plasminogen activator • PAI—plasminogen activator inhibitor • TAF—tracheal aspirate fluid • SC—secretory component of IgA • ELISA—enzyme-linked immunosorbent assay
RESPIRATORY DISTRESS SYNDROME (RDS) is characterized by the presence of intraalveolar hyaline membranes, which are composed principally of fibrin.1 Fibrin monomers inhibit surfactant function effectively2 and may stimulate macrophage adhesion.3 Fibrin and products of fibrin degradation may further injure vascular endothelium and affect neutrophil/macrophage chemotaxis.3–5 Earlier studies suggested that fibrin and its disordered turnover contribute significantly to the immediate respiratory and circulatory complications of RDS and may participate in inflammatory injury and fibrotic repair during the resolution of RDS and the subsequent development of bronchopulmonary dysplasia (BPD).5–7
For preterm infants with RDS, however, data on intraalveolar pathophysiologic features of the main plasminogen activators and inhibitors, ie, tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), and plasminogen activator inhibitor (PAI)-1 and -2, during the first days of life are few and conflicting.6,7 During acute RDS, inhibition of fibrinolysis in tracheal aspirate fluid (TAF) has been observed consistently,6–9 but the factors responsible have not been thoroughly identified. Compared with neonates intubated for nonpulmonary reasons, increased or decreased levels of PAI-1 have been described, and the quantitatively predominant activator has reported to be either tPA or uPA.6,7
Specific pathophysiologic roles for individual fibrinolytic regulators, beyond effects on plasminogen activation, are emerging. PAI-1-deficient mice show relative protection against pulmonary injury,10–12 whereas mice deficient in fibrinogen do not.12 Therefore, in chronic lung injury PAI-1 may have a specific role that is not mediated entirely through decreased removal of fibrin from the intraalveolar space.12
The aim of this study was to characterize the postnatal chronology of intraalveolar fibrinolysis among preterm infants with RDS and to evaluate whether a relationship exists between this fibrinolysis and the severity of RDS and the development of BPD. We therefore measured PAI-1, tPA, and uPA levels in TAF samples from preterm infants with RDS and studied the expression of PAI-1, tPA, and uPA in autopsy pulmonary specimens.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Patients
All studies were performed with the approval of the ethics committee of the Hospital for Children and Adolescents, University Central Hospital (Helsinki, Finland). Preterm infants (n = 37; gestational age: <30 weeks) with respiratory distress who were admitted to the NICU of the Hospital for Children and Adolescents, University of Helsinki, were enrolled between May 1997 and March 2002. All were intubated at birth because of failure to establish spontaneous breathing. Infants with major anomalies were excluded.
All infants received ampicillin (200 mg/kg per day) and netilmicin (6 mg/kg per day) from the first day of life. For 9 infants, ampicillin was changed to vancomycin (15 mg/kg per day) during the first postnatal week because of clinical signs of septic infection; for 2 of them, the diagnosis was verified with positive blood culture results. Treatment with indomethacin for patent ductus arteriosus was given as 4 doses of 0.1 mg/kg at 12-hour intervals. BPD was defined as a need for supplemental oxygen at the age of 36 gestational weeks, in association with chest radiographic findings typical of BPD.13 One infant (gestational age: 24.7 weeks) died as a result of severe cystic leukoencephalomalacia at 40 days of age. Patient characteristics according to the development of BPD are given in Table 1.
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Autopsied Subjects
Autopsy lung specimens from 7 preterm infants with RDS and 6 newborn infants without pulmonary pathologic conditions who died between November 1992 and October 1998 in the University Central Hospital (Helsinki, Finland) were studied. The 7 preterm infants who died as a result of RDS (age at death: 1–2 days; gestational age: 23.9–29.7 weeks; birth weight: 500–1520 g) had received mechanical ventilation, and the autopsies showed hyaline membranes. Prenatal glucocorticoid treatment was given to the mothers of 5 of the studied preterm infants, as 12 mg of betamethasone twice, with a 12-hour interval. Treatment with surfactant was given to 6 of the 7 infants, and the number of surfactant doses varied from 2 to 6. In addition to RDS, significant pathologic findings for the studied infants were intraventricular hemorrhage (n = 2), subdural hemorrhage (n = 1), and hypertrophic cardiomyopathy (n = 2). For none of the preterm infants was there any clinical or microbiologic evidence of pulmonary infection. The 6 newborn infants without pulmonary pathologic conditions had died as a result of acute asphyxia (n = 4) or fetofetal transfusion (n = 2) within 1 day after delivery (gestational age: 22.4–37.0 weeks; birth weight: 510–2900 g). None of the infants presented with any lung anomalies or pneumonia at the time of death. Autopsies were performed within 2 days after death. The lung samples were fixed in 10% neutral buffered formalin, embedded in paraffin, and stored at room temperature. Sections (4 µm) were stained with hematoxylin and eosin. After evaluation of the whole sample, 1 representative tissue block for each case was selected for immunohistochemical studies.
Sampling of TAF
TAF samples were collected once daily through standardized, routine, tracheal lavage, as described previously.14 The tubes were stored at –20°C until analysis.
Lecithin/Sphingomyelin Ratio and Phosphatidyl Glycerol
To determine surfactant maturity, TAF samples were collected from 21 patients within 3 hours after birth, before treatment with surfactant. The samples were analyzed for lecithin/sphingomyelin ratio and phosphatidyl glycerol level with thin layer chromatography, as part of our clinical routine.
Quantitative Assays for PAI-1, tPA, and uPA
PAI-1 and tPA antigen concentrations in TAF were measured with enzyme-linked immunosorbent assay (ELISA) kits (TintElize PAI-1 and TintElize tPA; Biopool AB, Umeå, Sweden), according to the instructions of the manufacturer. The PAI-1 assay measures active, latent, and complexed forms of PAI-1. The tPA assay measures 1-chain, 2-chain, and complexed forms of tPA. uPA antigen concentrations in TAF were measured with an ELISA kit (Assaypro, Brooklyn, NY), according to the instructions of the manufacturer. The uPA assay measures 1-chain, 2-chain, and complexed forms of uPA.
Secretory Component of IgA
To eliminate the effect of dilution, the concentrations of PAI-1, tPA, and uPA in TAF were related to concentrations of the secretory component of IgA (SC), as the reference protein, with direct ELISA, as described previously.15,16 The concentration of SC in lung secretions has been shown to be independent of capillary leak and not affected by gestational age or postnatal age during the first month of life.15
Immunohistochemical Analyses
Immunohistochemical analyses were performed with the automated Ventana Discovery immunohistochemistry slide stainer (Ventana Medical Systems, Tucson, AZ). For PAI-1, tPA, and uPA staining, the Ventana red alkaline phosphatase kit was used. Four-micrometer sections were used. Pronase (0.1%, for 10 minutes at 37°C) was used as pretreatment for uPA immunohistochemical analyses. Tissue sections were incubated with primary antibodies for 32 minutes. Monoclonal antibodies against PAI-1 (20 µg/mL), tPA (12 µg/mL), and uPA (15 µg/mL) (catalogue numbers 3785, 373, and 3689 respectively; American Diagnostica, Stamford, CT) were used. Sections stained with neurofilament protein-specific antibody (dilution: 1:25; Dako, Glostrup, Denmark) served as negative controls. After staining, the slides were rinsed and dehydrated before mounting with Eukitt mounting medium (O. Kindler, Freiburg, Germany). To confirm the presence of PAI-1, uPA, and tPA in macrophages, consecutive sections were immunostained with an antibody against the specific macrophage marker CD68 (dilution: 1:800; Dako).
Statistical Analyses
Patient data are given as mean ± SD and results as medians and ranges. Comparisons between unpaired data were performed with the Mann-Whitney U test. Spearman rank correlation served for continuous variables. P values of <.05 were considered statistically significant. All calculations were performed with StatView 5.0.1 (Abacus Concepts, Berkeley, CA).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Patients and Samples
From the 37 infants, a total of 262 TAF samples were collected, of which 185 were obtained during the first postnatal week. Of the infants, 15 subsequently developed BPD. Those infants tended to have lower gestational ages than those who survived without BPD (P = .16) and their birth weights were significantly lower (P = .02), as shown in Table 1.
PAI-1, tPA, and uPA in TAF Samples
The concentration of PAI-1 was highest during days 1 to 2 and decreased sharply during days 3 to 4, to a constant low level on days 5 to 14 (Fig 1A). Similarly to PAI-1, the concentration of tPA was highest during the first 2 postnatal days and declined during the first week (Fig 1B). In contrast, the levels of uPA in TAF were relatively stable during the study period of the first 2 postnatal weeks (Fig 1C). During the first 2 postnatal days, the concentration of tPA in TAF was >5-fold higher, compared with uPA (Fig 1, B and C). A positive correlation existed between the levels of PAI-1 and tPA in TAF during days 1 to 4 (days 1–2: 
= 0.50; P < .005; days 3–4: = 0.36; P < .05), whereas PAI-1 and uPA showed no significant correlation. During days 1 to 4, a strong positive correlation existed between the levels of uPA and tPA (days 1–2: = 0.59; P < .005; days 3–4: = 0.67; P < .005).
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The levels of PAI-1, tPA, and uPA were not associated with perinatal factors such as proteinuric preeclampsia, maternal treatment with betamethasone, mode of delivery, Apgar score, or umbilical artery pH or base excess (data not shown). However, for infants who were born to mothers with chorioamnionitis or premature rupture of membranes, we detected significantly lower levels of PAI-1 and uPA during days 3 to 8 (PAI-1: median: 0.13 ng/SC unit; range: 0.01–0.64 ng/SC unit; vs median: 0.40 ng/SC unit; range: 0.06–1.68 ng/SC unit; P < .05; uPA: median: 0.06 ng/SC unit; range: 0.01–0.23 ng/SC unit; vs median: 0.14 ng/SC unit; range: 0.04–0.98 ng/SC unit; P < .05) but not during the first 2 postnatal days (data not shown). No association existed between the levels of tPA and chorioamnionitis or premature rupture of membranes (data not shown).
PAI-1, tPA, and uPA levels showed no correlation with gestational age or birth weight during the study period. However, PAI-1 levels were associated strongly with an immature surfactant profile; during days 1 to 4, PAI-1 levels were significantly higher for infants with lecithin/sphingomyelin ratios of <10 (n = 14) than for those with lecithin/sphingomyelin ratios of 10 (n = 7) (Fig 2A). A similar but weaker association existed between lecithin/sphingomyelin ratios and tPA levels (Fig 2B). In contrast, the levels of uPA tended to be higher among infants with lecithin/sphingomyelin ratios of 10, although the detected difference was not statistically significant (Fig 2C). Furthermore, in comparison with infants with lecithin/sphingomyelin ratios of 10, the infants with lecithin/sphingomyelin ratios of <10 showed a significantly higher ratio of PAI-1 to uPA and, to a lesser extent, a higher ratio of PAI-1 to tPA during the first 2 postnatal days (Fig 2, D and E). The patient characteristics according to lecithin/sphingomyelin ratio are given in Table 2. Similarly to the low lecithin/sphingomyelin ratio, the absence of phosphatidyl glycerol in TAF was associated with significantly higher levels of PAI-1 and with significantly higher ratios of PAI-1 to uPA and to tPA during the first 2 postnatal days (all P < .05). During days 3 to 8, a positive correlation existed between PAI-1 levels and the number of surfactant doses needed ( = 0.46; P = .006). In addition, during days 3 to 8, PAI-1 levels tended to show a positive correlation with the duration of mechanical ventilation ( = 0.32; P = .06). The levels of PAI-1were significantly higher during days 3 to 4 and days 7 to 8 among infants who subsequently developed BPD (n = 15) than among those who survived without BPD (n = 21) (Fig 2F). tPA levels, uPA levels, and the ratios of PAI-1 to uPA or tPA were not associated with the development of BPD (data not shown). PAI-1, tPA, and uPA levels showed no association with treatment with indomethacin or dexamethasone (age at start of treatment: mean ± SD: 20 ± 11 days; range: 8–42 days), infection, or the presence of intraventricular hemorrhage (n = 11) (data not shown).
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P < .005.
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PAI-1, tPA, and uPA Immunohistochemical Analyses of Lung Sections
For preterm infants who died as a result of RDS, strong positive staining for PAI-1 was detected in type II- like pneumocytes of alveolar epithelium and in hyaline membranes (Fig 3A). In addition, PAI-1 was found in alveolar macrophages (Fig 3A) that were positive for CD68 (data not shown), in bronchial and bronchiolar epithelium, and in vascular endothelium and smooth muscle (Fig 3A). Similarly to PAI-1, positive staining for tPA and uPA was found in type II-like pneumocytes, hyaline membranes, alveolar macrophages, bronchial and bronchiolar epithelium, and vascular endothelium and smooth muscle (Fig 3, B and C). For newborn infants without pulmonary pathologic conditions, positive staining for PAI-1, tPA, and uPA was detected predominantly in bronchial and bronchiolar epithelium but also in vascular endothelium and smooth muscle, whereas alveolar epithelium exhibited negative results or showed only faint positive staining (Fig 3, D–F).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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In this study, we showed high concentrations of pulmonary PAI-1 and a high ratio of PAI-1 to uPA during the early postnatal days for preterm infants with RDS. PAI-1 levels were associated strongly with the severity of RDS, as indicated by significantly higher PAI-1 levels in TAF of preterm infants who had an immature surfactant profile and who needed more doses of surfactant. After the first few postnatal days, the levels of PAI-1 decreased sharply and then stayed at a constant low level during the first 2 postnatal weeks. Similarly to PAI-1, the levels of tPA were highest early in the postnatal period, and they were significantly higher during the first postnatal days for infants with an immature surfactant profile; in contrast, the levels of uPA tended to be lower for these infants. In this study, functional tests of plasminogen activator components were not possible, because tissue sections were paraffin embedded and TAF samples had been collected for several years and stored at –20°C. However, increased antigen ratios of PAI-1 to plasminogen activators and increased PAI-1 staining in the tissues of preterm infants who died as a result of RDS implicate insufficient fibrinolysis for preterm infants with RDS.
High levels of expression of tPA during the first postnatal days may reflect an attempt of the body to degrade fibrin in hyaline membranes. tPA is known to be more efficient in fibrinolysis than uPA because of its activation through specific binding to fibrin. Excess expression of PAI-1, which is at least partly responding to tPA activity, and low levels of uPA expression imply decreased fibrinolytic potential among preterm infants with RDS. In contrast, among preterm infants with less severe respiratory distress, expression of tPA and PAI-1 was low, probably because of the lack of fibrin. Expression of uPA was higher, however, which suggests sufficient fibrinolytic activity. The findings are consistent with earlier studies showing the presence of fibrin in hyaline membranes and impaired fibrinolysis within the alveolar compartment in early RDS among preterm infants and in adult RDS.1,6–9,17–19
For preterm infants who had died as a result of acute RDS at the age of 1 to 2 days, immunohistochemical analyses showed marked positive staining for PAI-1, uPA, and tPA in type II-like pneumocytes of alveolar epithelium; positive staining was also found in alveolar macrophages, in bronchial and bronchiolar epithelium, and in vascular endothelium and smooth muscle. This is in accordance with earlier studies performed in vitro and in experimental animals that showed expression of PAI-1 and plasminogen activators in resident lung cells.10,20–22 To the best of our knowledge, however, this is the first observation regarding the localization of PAI-1 and plasminogen activators among human subjects with early lung injury. In alveolar macrophages, positive staining for tPA may be related to increased synthesis of tPA by macrophages or, alternatively, may reflect high levels of surface expression of tPA-binding annexin II by this cell type.23 However, positive staining for PAI-1 in macrophages probably reflects truly enhanced synthesis of PAI-1 in these cells, because hypoxia in other settings is known to stimulate pulmonary macrophages to synthesize PAI-1.24
The major plasminogen activator in TAF of preterm infants with respiratory distress seemed to be tPA; during the first postnatal week, the levels of tPA were 2- to 10-fold higher than those of uPA. This is in accordance with an earlier study showing 5- to 10-fold molar excess of tPA over uPA during the first 1 day of life in TAF samples from preterm infants with RDS.6 In contrast, uPA is the major plasminogen activator in bronchoalveolar lavage fluid from adult patients with acute RDS.17,18
We detected significantly higher levels of pulmonary PAI-1 among preterm infants who subsequently developed BPD than among those who survived without BPD. Whether the higher levels of PAI-1 reflect more severe RDS among these infants during the first postnatal days or whether PAI-1 plays a pathophysiologic role in the development of BPD remains unresolved. However, the latter possibility is supported by recent data in a rat model of experimental BPD that showed that oxygen exposure resulted in progressive upregulation of mRNA for PAI-1.25 The inflammatory pathways and the coagulation/fibrinolysis cascades are interconnected through multiple mechanisms. The expression of PAI-1, uPA, and tPA by resident lung cells is influenced by inflammatory mediators such as interleukin-1 and tumor necrosis factor-
.20,21,26,27 In addition, recent evidence from studies with transgenic animals indicates that disordered intraalveolar fibrin turnover plays an important role in the development of lung fibrosis after inflammatory lung injury.10,11 Mice genetically deficient in PAI-1 that were exposed to hyperoxia were protected from intraalveolar fibrin deposition and were more resistant to the lethal effects of hyperoxia.10 After bleomycin-induced lung injury, pulmonary fibrosis was increased in mice overexpressing PAI-1, whereas PAI-1-deficient mice developed less fibrosis, compared with wild-type mice.11 The linkage between impaired intraalveolar fibrin turnover and the development of lung fibrosis is also supported by studies showing reduced postbleomycin lung fibrosis in animals treated with aerosolized uPA.28,29
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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High levels of pulmonary PAI-1 and an increased ratio of PAI-1 to uPA, with a concurrently less-increased ratio of PAI-1 to tPA, during the first postnatal days are associated with the severity of acute lung injury among preterm infants with respiratory distress. Additional studies are needed to evaluate the potential role of disordered intraalveolar fibrinolysis in the development of BPD among preterm infants.
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ACKNOWLEDGMENTS |
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The study was supported by grants from the Foundation for Pediatric Research, Finska Läkaresällskapet, the Sigrid Jusélius Foundation, and the Helsinki University Central Hospital Research Fund.
We thank the personnel of the NICU of the Hospital for Children and Adolescents for their kind cooperation and Marjatta Vallas and Irina Suomalainen for excellent technical assistance.
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FOOTNOTES |
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Accepted Aug 31, 2005.
Address correspondence to Katariina Cederqvist, MD, Hospital for Children and Adolescents, Research Laboratory, Biomedicum Helsinki, PO Box 700, FIN-00029 HUS, Helsinki, Finland. E-mail: katariina.cederqvist{at}helsinki.fi
The authors have indicated they have no financial relationships relevant to this article to disclose.
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