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PEDIATRICS Vol. 108 No. 3 September 2001, pp. 686-692
,,
From the * Hospital for Children and Adolescents, Helsinki
University Central Hospital; Objectives. Matrix metalloproteinases
(MMPs) are a family endoproteinases that act in degradation of
extracellular matrix and basement membranes. The development of
bronchopulmonary dysplasia (BPD) is characterized by early pulmonary
inflammation, increased microvascular permeability, and subsequently by
disordered repair. The aims of our study were to characterize the
presence and molecular weight forms of MMP-2, -8, and -9 and their
specific inhibitor, tissue inhibitor of metalloproteinases (TIMP)-2, in
lungs of preterm infants during the early postnatal period and to
determine whether levels of these MMPs and TIMP-2 in tracheal aspirate
fluid (TAF) are associated with acute or chronic lung morbidity of the
preterm infant.
Methods. TAF samples were collected from 16 intubated
preterm infants (gestational age 27.0 ± 2.0 weeks; birth weight
875 ± 246 g) during their first 5 postnatal days. The
presence and molecular weight forms of MMPs and TIMP-2 were identified
by Western immunoblotting, and their levels were evaluated by
densitometric scanning.
Results. MMP-8 in TAF was higher in infants who needed
treatment with surfactant (25.4 ± 6.3 vs 10.6 ± 1.5 arbitrary unit/secretory component of immunoglobulin A [AU/SC]) and
in whom BPD developed (N = 6; 27.6 ± 5.2 vs
15.1 ± 5.0 AU/SC). TIMP-2 levels were lower in infants with
initial arterial to alveolar oxygen tension ratios <0.22 (2.7 ± 1.1 vs 16.8 ± 7.4 AU/SC) and in infants needing mechanical ventilation for >1 week (5.2 ± 2.1 vs 22.8 ± 11.7 AU/SC).
Conclusions. In preterm infants, an imbalance between
pulmonary MMP-8 and TIMP-2 participates in the acute inflammatory
process in respiratory distress syndrome and may contribute to the
development of chronic lung injury.
Department of Research Institute of
Dentistry, Biomedicum, University of Helsinki; § Department of Clinical
Veterinary Sciences, Faculty of Veterinary Medicine, University of
Helsinki; and Department of Obstetrics and Gynecology, Helsinki
University Central Hospital, Helsinki, Finland.
ABSTRACT
Top
Abstract
Methods
Results
Discussion
References
Matrix metalloproteinases (MMPs) are a family of
structurally and functionally related but genetically distinct
proteinases that act in the remodeling and destruction of extracellular
matrix and basement membranes; in concert, MMPs can degrade almost all extracellular matrix and basement membrane constituents.1 MMPs are secreted in latent proenzyme form and activated in
extracellular space and on the cell surfaces by oxidants and serine
proteinases and by autocatalytic cleavage.2 Additionally,
MMPs can activate and potentiate each others'
activation.3 The major local inhibitors of MMPs are tissue
inhibitors of metalloproteinases (TIMPs). These specific inhibitors of
MMPs form high-affinity complexes with active forms of MMPs in a 1:1
stoichiometric ratio.4 MMPs are regulated by a delicate
balance between their inducers, activators, and specific proteinase
inhibitors; an imbalance among these is believed to generate
parenchymal destruction in a variety of pulmonary inflammatory
diseases, including acute respiratory distress syndrome (RDS),
pulmonary fibrosis, bronchiectasis, and asthma.5-9 MMP-8
(neutrophil-derived collagenase or collagenase-2), which degrades
preferentially interstitial collagen type I, has been implicated in
chronic bronchiectasis and cystic fibrosis.7,10 MMP-2 and
MMP-9, also called type IV collagenases or gelatinases A and B, degrade
basement membrane structures; MMP-9 is released by activated
neutrophils.11 Elevated MMP-9 levels have recently been
reported in bronchoalveolar lavage fluid from patients with acute
RDS.5,12 In a rat model of acute hyperoxic lung injury,
increased MMP-2 and MMP-9 expression was observed in lung interstitium
and alveolar epithelium, suggesting that these enzymes may contribute
to the pathogenesis of lung damage.13
In preterm infants with RDS, the development of bronchopulmonary
dysplasia (BPD) is characterized by early lung inflammation associated
with an increased pulmonary microvascular permeability and subsequently
by parenchymal remodeling and fibrosis.14,15 Within the
first few days of life in preterm infants who subsequently develop BPD,
lung lavage studies have shown higher numbers of neutrophils, excess
levels of the leukocyte proteases, and proinflammatory cytokines.14-17 Immunohistochemical analysis of lung
tissue, obtained postmortem from infants who died of acute RDS, has
shown loss of endothelial basement membrane and interstitial
glycosaminoglycans, a process that begins within hours of
birth.18 Tracheal aspirate fluid (TAF) from preterm
infants with RDS has recently been reported to show elevated MMP-9
levels.19
The aim of this study was to identify and characterize the presence,
molecular weight forms, and degree of activation of MMP-2, MMP-8, and
MMP-9 and their specific inhibitor TIMP-2 in the human preterm lung. We
also wanted to determine whether these MMPs and TIMP-2 in TAF during
the first postnatal days are associated with acute respiratory distress
and the development of BPD.
Patients
Preterm infants with respiratory distress admitted to the
neonatal intensive care unit of the Hospital for Children and
Adolescents, University Central Hospital, Helsinki, were enrolled in
this study. All were intubated at birth and underwent mechanical
ventilation during the study period. Infants with major anomalies or
with septic infections were excluded.
Chorioamnionitis was diagnosed on the basis of clinical signs in
combination with leukocytosis (white blood cell counts >15 × 109/L), concentration of C-reactive protein >50
g/L, or both. Antenatal steroids were given in 12 pregnancies as 12 mg
of betamethasone twice at a 12-hour interval. Treatment was repeated 1 week later in 5 pregnancies. The time interval between final treatment
and delivery was 4.1 ± 3.0 days. Patient data are given in Table
1.
TABLE 1
METHODS
Top
Abstract
Methods
Results
Discussion
References
Patient Characteristics
The mean initial arterial to alveolar oxygen tension ratio (aAPO2) was 0.35 ± 0.24; 6 infants had an aAPO2 < 0.22. Surfactant was administered to 9 infants; 3 of them needed 2 doses, and 4 needed 3 or more. One infant received Exosurf (Glaxo Wellcome, Greenford, UK) at a dosage of 4 mL/kg, and 8 infants received Curosurf (Chiesi Farmaceutici SPA, Parma, Italy) at a dosage of 100 mg/kg. For patent ductus arteriosus, 12 infants received indomethacin in 4 0.1-mg/kg doses at 12-hour intervals; treatment was repeated for 1 infant. All infants received ampicillin 200 mg/kg/d and netilmicin 6 mg/kg/d from the first day of life; for 1 infant ampicillin was changed to vancomycin 15 mg/kg/d during the study period (on day 5) because of clinical signs of septic infection. To facilitate weaning from mechanical ventilation, 5 infants received treatment with dexamethasone starting at the mean age of 10 ± 4 days (range 6-16); none of them started treatment during the study period.
Six infants subsequently developed BPD, defined as the need for supplemental oxygen at 36 gestational weeks, in association with chest radiographic findings typical for BPD.20 Two infants died of severe respiratory insufficiency on days 12 and 24. These infants were excluded from analysis of the development of BPD.
Informed consent was obtained from the parents, and the study was approved by the Ethics Committee of the Hospital for Children and Adolescents, University Central Hospital, Helsinki.
TAF Sampling
TAF samples were collected once daily by standardized routine
tracheal lavage as previously described.21 Briefly, 1 mL
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). Aprotinin and deferoxamine were
used to minimize oxidative and proteolytic artifacts. The tubes were stored at 
20°C until analysis.21
Lecithin/Sphingomyelin Ratio and Phosphatidyl Glycerol
To determine surfactant maturity, TAF samples were collected within 3 hours after birth before treatment with surfactant. The samples were analyzed for lecithin/sphingomyelin (L/S) ratio and phosphatidyl glycerol by thin-layer chromatography as a part of our clinical routine.
Secretory Component of Immunoglobulin A
The immunoreactivity levels of MMPs and TIMP-2 in TAF were related to concentrations of SC as the reference protein because its concentration in TAF has been shown to be independent of capillary leak and not affected by gestational age or postnatal age during the first month of life.22 The SC concentration in TAFs was determined by direct enzyme-linked immunosorbent assay. Secretory immunoglobulin A isolated from human colostrum served as the standard. The results were standardized by Dr B Götze-Speer and Prof. C Speer (Kinderklinik, Tübingen). 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 sodium bicarbonate, pH 9.5. After being washed with 200 µL of 20 mM Tris-500 mM NaCl, pH 7.5 tris-buffered saline (TBS) the plates 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 between 1:10 to 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. Then 100 µL of peroxidase conjugated rabbit anti-human SC (Dako), diluted 1:400 in diluting buffer, was added and the plates were incubated 4 hours at room temperature. After being washed with TTBS the plates were developed by use of 100 µL of substrate solution containing 8 mg of orthophenylenediamine (Dako) and 5 µL of 30% H2O2 in 12 mL water. The optical densities of the plates were read at 450 nm after 30 minutes at room temperature.
Western Blot Analysis
The molecular weight forms of MMP-2, -8, and -9 and TIMP-2 from TAF samples were analyzed by the Western immunoblot method with specific antisera. The specific polyclonal antisera against MMP-2 and TIMP-2 were as described.23,24 The polyclonal anti-human MMP-8 and -9 were as described.25,26 Briefly, the TAF samples were first treated with 4× Laemmli's sample buffer without reducing agents and then applied to 10% sodium dodecyl sulfate polyacrylamide gels. After the electrophoretic separation, proteins in the gel were transferred onto nitrocellulose membranes (Schleider 38 Schuell, Dassel, Germany). Nonspecific binding was blocked by incubation with 10 mmol/L Tris-HCl buffer, pH 7.5; 0.05% Triton X-100, 22 mmol/L NaCl (TTBS) supplemented with 3% gelatin (Merck, Darmstadt, Germany). After being washed with TTBS, the membranes were incubated with polyclonal antibodies against human MMP-2, -8, and -9 1:500 and TIMP-2 1:1000 for 12 hours at room temperature. After being washed with TTBS, the membranes were incubated with alkaline phosphatase-conjugated goat anti-rabbit immunoglobulin (1:1000; Sigma) for 1 hour at room temperature. The immunoreactive proteins were visualized with 2,2'-di-p-nitrophenyl-5,5'-diphenyl-3,3'-(3,3'-dimethoxy-4,4'-diphenylene)-ditetrazolium chloride (NBT, Sigma) and 5-bromo-4-chloro-3-indolyl phosphate (BCIP, Sigma) solution. The intensity levels of different molecular weight forms of these MMPs and TIMP-2 were evaluated with Bio-Rad Model GS-700 Imaging Densitometer using the Molecular Analyst/PC program with correction for background values.27 Results were expressed as arbitrary units/secretory component of immunoglobulin A (AU/SC).
Statistical Analysis
Patient data are given as mean ± standard deviation and results as mean ± standard error of measurement. Comparisons between unpaired items were performed with the Mann-Whitney U test. Simple regression analysis served for continuous variables. Logarithmic transformation of the data were performed when appropriate. P values less than .05 were considered statistically significant. All calculations were done with StatView 4.1 (Abacus Concepts Inc, Berkeley, CA).
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RESULTS |
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Top
Abstract
Methods
Results
Discussion
References
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There was no significant difference in gestational age between those who developed BPD and those who survived without it (26.8 ± 1.8 weeks vs 27.3 ± 2.2 weeks; P > .50); the infants developing BPD had a lower birth weight, although the difference was not statistically significant (782 ± 235 g vs 951 ± 202 g; P > .10). The 6 infants who developed BPD received more doses of surfactant (range, 0-4 vs 0-1; P < .005) and were intubated for a longer time than infants who survived without BPD (33 ± 20 days vs 7 ± 7 days; P < .005).
A total of 56 TAF samples were collected from 16 infants during the first 5 postnatal days. From 12 of the infants a TAF sample was obtained to determine surfactant maturity. In these samples the mean L/S ratio was 8.9 ± 2.0, and phosphatidyl glycerol was present in 4 cases. The presence and molecular weight forms of MMP-2, MMP-8, and MMP-9 and TIMP-2 in TAF samples were demonstrated by use of immunoblotting with specific antibodies (Fig 1). The levels of various molecular weight forms and species of the MMPs and TIMP-2 were evaluated by densitometric scanning as described in "Methods."
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MMP-2
MMP-2 was present in TAF samples from all infants. Immunoblotting
demonstrated the presence of complexed, latent, active, and fragmented
forms of MMP-2 (Fig 1). During the first 5 postnatal days, levels of
total MMP-2 immunoreactivity (complexed + latent + active + fragmented)
showed a positive correlation with gestational age (R = 0.37, P < .01) and negative correlations with
umbilical cord artery pH and base excess (both R = 0.29, P < .05).
MMP-8
Western blot analysis of TAF samples demonstrated the presence of both neutrophil-derived 70- to 80-kDa MMP-8 and 40- to 60-kDa mesenchymal cell-derived MMP-8 species, of which the former predominated (Fig 1). Neutrophil-derived MMP-8 appeared in all 16 infants, and in 13 of them mesenchymal cell-derived MMP-8 could be demonstrated. Neutrophil-derived active MMP-8 occurred in only a small number of samples (data not shown).
Neutrophil-Derived Latent MMP-8 The levels of neutrophil-derived latent MMP-8 immunoreactivity showed a negative correlation with L/S ratio, and the levels were lower in infants with phosphatidyl glycerol in TAF (Table 2). The levels were higher in infants needing treatment with surfactant, infants who were intubated for >1 week, and infants who needed later treatment with dexamethasone (Table 2). A positive correlation existed between these levels and the number of surfactant doses needed (R = 0.303, P < .05). No correlations existed between these levels and gestational age or birth weight.
|
Mesenchymal Cell-Derived Latent MMP-8 During the first 5 postnatal days, levels of mesenchymal cell-derived latent 60-kDa MMP-8 immunoreactivity showed positive correlations with gestational age (R = 0.594, P < .001) and birth weight (R = 0.369, P < .05).
MMP-9
Immunoblotting demonstrated the presence of MMP-9 in TAF samples from 13 of the 16 infants (Fig 1); in 10 of them activated MMP-9 was found. During the first 5 postnatal days, no correlations existed between MMP-9 immunoreactivity levels and gestational age or birth weight. The MMP-9 levels were not associated with surfactant treatment and showed no correlation with duration of mechanical ventilation.
TIMP-2
TIMP-2 was present in TAF samples from all but 1 infant, who died of severe respiratory distress on day 12 (Fig 1). Fragmented TIMP-2 was found in 8 of the 16 infants. During the first 5 postnatal days, a positive correlation existed between levels of total TIMP-2 (complexed + native + fragmented) and gestational age (R = 0.461, P < .001). The levels showed positive correlations with total MMP-2 and total MMP-9 levels (R = 0.684, R = 0.641; both P < .0001). TIMP-2 levels were lower in infants with an initial aAPO2 <0.22 (Fig 2A), infants who needed treatment with surfactant (5.4 ± 1.8 vs 18.4 ± 9.5 AU/SC, P < .05), and those needing mechanical ventilation for >1 week (Fig 2B).
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Association With Premature Rupture of Membranes
MMP-2, MMP-8, and MMP-9 Infants born to mothers with premature rupture of membranes (PROM) had higher TAF levels of total MMP-2, -8, and -9 than others (121.9 ± 44.4 vs 41.1 ± 40.0, P < .01; 41.6 ± 8.3 vs 37.0 ± 4.6, P < .0001; 7.9 ± 1.9 vs 9.8 ± 0.5, P < .05, respectively).
TIMP-2 There was no significant difference in the TAF levels of TIMP-2 between those who were born to mothers with PROM and those born to mothers without it.
Association With BPD
MMP-8 Significantly higher levels of neutrophil-derived latent MMP-8 were detected in infants who subsequently developed BPD (Fig 3). No association existed between mesenchymal cell-derived MMP-8 and BPD.
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MMP-2, MMP-9, and TIMP-2 No associations were found between the development of BPD and MMP-2, MMP-9, or TIMP-2. If all patients with unfavorable respiratory outcome (ie, the 6 infants who developed BPD and the 2 infants who died of severe respiratory distress on days 12 and 24) are combined, this group had significantly lower levels of TIMP-2 in TAF than those who survived without BPD (P < .05).
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DISCUSSION |
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Top
Abstract
Methods
Results
Discussion
References
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Here we show the presence, various molecular weight forms, and
species of MMP-2, -8, and -9, and TIMP-2 in tracheal aspirates from
preterm infants with RDS during the early postnatal period. RDS is
characterized by an acute inflammatory lung injury that begins to
resolve within the first 3 postnatal days.28 Infants who
subsequently develop BPD have a more enhanced inflammatory reaction,
with increased chemotactic activity and higher concentrations of
cytokines in lung lavage fluid during the first postnatal
week.15,17,18 Of them, interleukin-1
and tumor necrosis
factor- induce the expression of MMP-9 and MMP-8 and decrease the
expression of TIMPs in human macrophages, bronchial epithelial cells,
and endothelial cells.25,29,30 Moreover, at sites of
inflammation, serine proteinases such as neutrophil elastase and
reactive oxygen species can inactivate and fragment
TIMPs.31,32
We found that MMP-8 in TAF consisted of both neutrophil-derived and mesenchymal cell-derived MMP-8 species. The levels of neutrophil-derived latent MMP-8 immunoreactivity were higher in infants who needed treatment with surfactant for severe respiratory distress and in those needing prolonged mechanical ventilation or treatment with dexamethasone. In addition, later development of BPD was associated with higher levels of neutrophil-derived latent MMP-8. This is in accordance with earlier studies suggesting that an exaggerated inflammatory reaction in the lungs during the first postnatal days is important in the pathogenesis of BPD.15,17 It is noteworthy that some of the 80-kDa MMP-8 corresponding to latent nonconverted proforms of this neutrophil-derived MMP may represent an oxidatively activated form of this MMP in vivo27 because in vitro oxidative activation of MMP-8 does not necessarily involve changes in molecular sizes of MMP-8.27 This is in accordance with previous data showing that in preterm infants oxidation of pulmonary proteins during the first week of life correlates with the subsequent development of BPD.21
Previously, MMP-8 was regarded solely as a neutrophil-specific MMP or collagenase that is stored in granules and released on activation.2 Recently it has become evident that MMP-8 is expressed by the cytokine-induced mesenchymal cells such as chondrocytes, synovial fibroblasts, and endothelial cells.25,33 Our findings also indicate that during the early postnatal period, mesenchymal cell-derived MMP-8 species are expressed in the lungs of preterm infants suffering from respiratory distress. The positive correlation between gestational age and mesenchymal cell-derived latent MMP-8 levels indicates that mesenchymal cell-derived MMP-8 may play a role in the remodeling of lung structures involved in lung growth. In this respect, mesenchymal cell-derived MMP-8 resembled MMP-2, which also correlated with gestational age and appeared to be expressed constitutively. These findings are in agreement with earlier observations of elevated interstitial and type IV collagenase activities during early postnatal lung growth in rats.34 MMP-2 is constitutively expressed, at least in vitro, by a variety of mesenchymal cell lines such as fibroblasts and endothelial and epithelial cells, and its expression appears to be only moderately regulated.2
MMP-9 is released in latent form by stimulated
neutrophils.11 A recent study has shown elevated levels of
MMP-9 in TAF from preterm infants with RDS.19 In our
study, however, no associations were detected between the levels MMP-9 and the severity of respiratory distress or the development of BPD.
Interestingly, although both MMP-9 and neutrophil-derived MMP-8
seemingly originate from the same cells (ie, neutrophils), only the
latter was associated with the severity of acute and chronic lung
disease. These MMPs are stored in different neutrophil subcellular
compartments; MMP-9 is known to be stored in C-type granules (tertiary
granules) whereas MMP-8 is stored in specific (secondary)
granules.11 A likely explanation is the differences in the
order and extent of degranulation of subcellular neutrophil granules
being selectively targeted by proinflammatory mediators such as
interleukin-1
and tumor necrosis factor-.
PROM is known to be associated with intra-amnionic inflammation, and the association is stronger in lower gestational ages.35 Intrauterine inflammation is considered to be a risk factor for subsequent development of BPD.17,36 Fetal aspiration of amniotic fluid with high levels of inflammatory cytokines may lead to congenital pneumonitis that predisposes the immature newborn to BPD. Higher levels of especially MMP-8 but also MMP-2 and -9 were observed in infants born to mothers with PROM, but no significant difference was detected in TIMP-2 levels. The increase in the levels of several pulmonary MMPs insufficiently counteracted by TIMP-2 during the early postnatal period may contribute to the increased risk of BPD in these infants.
TIMP-2 was found to occur predominantly as high molecular weight complexed forms, but free native and fragmented lower molecular weight species also were detected. Of them, fragmented TIMP-2 was found in 8 of the 16 patients. The high molecular weight complexed forms are considered to reflect TIMP-2-species bound to MMPs. In 1 infant who died of severe respiratory distress on day 12, no TIMP-2 could be detected. Total TIMP-2 immunoreactivity was lower in infants with more severe respiratory distress and in infants needing long-duration mechanical ventilation. These clinical conditions were also associated with high levels of MMP-8 in TAF, suggesting that the imbalance between MMP-8 and its endogenous inhibitor TIMP-2 in the lungs of preterm infants may play a role in the acute lung disease and thereby, at least to some extent, influence the outcome of the inflammatory lung injury.
The role of TIMP-2 in inflammatory lung diseases has recently been studied in various experimental models.37,38 Exogenously administered human recombinant TIMP-2 has been shown to reduce immune complex-induced acute lung injury.37 In a murine model of bronchial asthma, exogenously administered human recombinant TIMP-2 decreases the airway accumulation of inflammatory cells by inhibiting enzymatic activities of MMP-2 and -9.38
In conclusion, we have characterized by immunoblotting MMP-2, -8, and -9 and TIMP-2 in TAF samples from preterm infants with respiratory distress during the first postnatal days. Our data suggest that in preterm infants, increased pulmonary MMP-8, insufficiently counteracted by low and fragmented TIMP-2, participates in the acute inflammatory injury of RDS. Determining whether this imbalance contributes to the development of bronchopulmonary dysplasia warrants additional studies.
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ACKNOWLEDGMENTS |
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This work was supported by Wilhelm och Else Stockmanns Stiftelse, the Foundation for the Pediatric Research, Finska Läkaresällskapet, and the Helsinki University Central Hospital Research Fund.
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FOOTNOTES |
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Received for publication Nov 1, 2000; accepted Feb 8, 2001.
Reprint requests to (K.C.) Hospital for Children and Adolescents, Stenbäckinkatu 11, 00290 Helsinki, Finland. E-mail: katariina.cederqvist{at}hus.fi
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ABBREVIATIONS |
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MMP, matrix metalloproteinase; TIMP-2, tissue inhibitor of metalloproteinases-2; RDS, respiratory distress syndrome; BPD, bronchopulmonary dysplasia; TAF, tracheal aspirate fluid; aAPO2, arterial to alveolar oxygen tension ratio; AU/SC, arbitrary unit/secretory component of immunoglobulin A; LS, lecithin/sphingomyelin; TBS, tris-buffered saline; PROM, premature rupture of membranes.
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Methods
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Discussion
References
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  C L Bose, C E L Dammann, and M M Laughon Bronchopulmonary dysplasia and inflammatory biomarkers in the premature neonate Arch. Dis. Child. Fetal Neonatal Ed., November 1, 2008; 93(6): F455 - F461. [Abstract] [Full Text] [PDF]
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 A. Chetty, G.-J. Cao, M. Severgnini, A. Simon, R. Warburton, and H. C. Nielsen Role of matrix metalloprotease-9 in hyperoxic injury in developing lung Am J Physiol Lung Cell Mol Physiol, October 1, 2008; 295(4): L584 - L592. [Abstract] [Full Text] [PDF]
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0.22. B, Levels of total TIMP-2 immunoreactivity during the first 5 postnatal days in TAF of infants who were mechanically ventilated for
>1 week and of infants who were mechanically ventilated for 
1 week.
Data corrected for dilution by adjustment with SC. Results expressed as
AU/SC.
