Department of Pediatrics and Biocenter Oulu, University of Oulu, Oulu FIN-90014, Finland
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ABSTRACT |
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Intra-amniotic lipopolysaccharide (LPS)
and cytokines may decrease respiratory distress syndrome (RDS) and
increase chronic lung disease in the newborn. The aim was to identify
the primary inflammatory mediators regulating the expression of
surfactant proteins (SP) in explants from immature (22-day-old fetus)
and mature (30-day term fetus and 2-day-old newborn) rabbits. In
immature lung, interleukin (IL)-1 and IL-1
upregulated the
expression of SP-A and SP-B. These effects of IL-1 were diminished, and
SP-C mRNA was suppressed additively in the presence of tumor necrosis factor (TNF)-
and either LPS or interferon (IFN)-
. LPS, TNF-
, or IFN-
had no effect alone. In explants from the term fetus and the
newborn, LPS, IL-1
, and TNF-
additively suppressed the SPs. LPS
acutely induced IL-1
in alveolar macrophages in mature lung but not
in the immature lung. IFN-
that generally has low expression in
intrauterine infection decreased the age dependence of the other
agonists' effects on SPs. The present study serves to explain the
variation of the pulmonary outcome after an inflammatory insult. We
propose that IL-1 from extrapulmonary sources induces the SPs in
premature lung and is responsible for the decreased risk of RDS in
intra-amniotic infection.
lung development; respiratory distress syndrome; chronic lung disease; acute respiratory distress syndrome; rabbit; lipopolysaccharide
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INTRODUCTION |
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DEFICIENCY IN PULMONARY SURFACTANT is the main cause of respiratory distress syndrome (RDS) in the newborn (11). Apart from specific phospholipids, the complex consists of surfactant-specific proteins that are important, if not essential, for its function (22). Surfactant protein (SP)-A binds to surfactant phospholipids and thereby improves surface activity in vitro (4, 48). By binding to specific microbes and alveolar macrophages, it also facilitates the phagocytosis of these microbes (13). The functions of SP-B relate to intracellular processing of the surfactant components, e.g., normal processing of SP-C (58), and to the surface tension-reducing function of the complex (42, 61). SP-C has important roles in the formation and maintenance of the surfactant monolayer (34).
The variety of hormones, growth factors, cytokines, and other agents
influences the differentiation and metabolism of the surfactant
complex. Glucocorticoid is extensively studied for its roles in the
regulation of SPs (39). The proinflammatory cytokines
interleukin (IL)-1 and tumor necrosis factor (TNF)-, which are
induced in macrophages as a result of exposure to microbial products,
influence the expression of SPs. TNF-
inhibits SP-A and SP-B and
decreases SP-A and SP-B mRNA in human pulmonary adenocarcinoma cells
(60, 63). TNF-
also downregulates SP-C mRNA after
intratracheal administration to adult mice and inhibits SP-C gene
transcription in vitro (1). IL-1
enhances the
expression of SP-A mRNA in fetal rabbit lung explants in vitro
(14). The IL-1-induced effect on the expression of SP mRNA
and proteins in vitro was dependent on lung maturity. In immature lung,
IL-1
upregulated SP-A and SP-B, whereas in mature lung it
downregulated SP-B and SP-C (19). Interferon (IFN)-
influenced SP-A content in human pulmonary adenocarcinoma cells
(63) and SP-A expression in human fetal lung explants,
whereas the expression of SP-B and SP-C was unaffected (2).
Intratracheal aerolization or injection of lipopolysaccharide (LPS) in
adult rats increases the production of TNF- (38, 55,
56) and IL-1 mRNA in the lung (55). IFN-
is
induced by LPS in monocytes and lymphocytes (35), whereas
IFN-
augments LPS-induced TNF-
production in
monocyte/macrophages, including in alveolar macrophages (62,
64). On the other hand, IFN-
did not enhance LPS-induced
upregulation of IL-1 mRNA (64). The interactions between
IL-1 and TNF-
and their capacity to induce and suppress a variety of
other cytokines (28, 51, 54) have been extensively studied
and are known to possess synergistic or additive effects on many
functions (15, 17).
Responsiveness to microbes has been shown to be deficient in pulmonary macrophages from an early age (49), which is a possible cause of an increased susceptibility to infections, neonatal pneumonia in particular. Infants born very premature because of chorioamnionitis show a decreased incidence of RDS and an increased incidence of chronic lung disease (CLD; see Ref. 59). On the other hand, in intra-amniotic infections, the concentrations of IL-1 (44) and TNF (45) are increased in amniotic fluid and in lung effluent after premature birth. In infants developing CLD, several proinflammatory cytokines and chemokines are increased in the airways, whereas the levels of certain anti-inflammatory cytokines may be decreased (31, 52).
In the present study, we hypothesized that the complex association
between the antenatal placental inflammatory disease and the incidence
of pulmonary disease in the newborn is in part because of differences
in responsiveness to microbial toxins and cytokines between
undifferentiated ("immature") and differentiated ("mature") pulmonary alveolar epithelium. We studied the age dependence of the LPS
effect on the expression of SP mRNAs, SP, and IL-1 in lung explants.
Second, we investigated the influence of the individual proinflammatory
cytokines (IL-1
, TNF-
, and IFN-
) on the expression of SPs.
According to present results, the modifying effects of proinflammatory
signals on the levels of SP expression were both developmentally
regulated and reversible. Of the proinflammatory cytokines examined,
IL-1 had the greatest effects on SPs in immature lung.
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METHODS |
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Experimental animals. The animals used were timed pregnant New Zealand White rabbits. The Animal Research Committee of the University of Oulu approved the protocol. The mating date was defined as day 0 of gestation. On days 22 (±1 h) or 30 (±1 h) of pregnancy (term 30-31 days), hysterotomy was performed on animals injected with medetomidine (0.3 mg/kg im) and ketamine (20 mg/kg im). The anesthetized fetuses and 2-day-old newborns were killed by cutting the cervical cord, and the does were killed by intravenous injection of pentobarbital sodium. The lungs were recovered under aseptic conditions. Altogether, 91 fetuses and 18 newborn animals from 30 litters were studied.
LPS and cytokines.
The LPS used was LPS Escherichia coli serotype O55:B5
(Sigma-Aldrich). Recombinant human (rh) IL-1, a generous gift of Dr. R. Chizzonite (Hoffmann-LaRoche, Nutley, NJ), has been shown to be
biologically active in rabbits (33). The rhTNF-
(R&D
Systems; see Ref. 43), rhIFN-
(Genzyme Diagnostics,
Cambridge, MA; see Ref. 53), and rhIL-1
(R&D Systems;
see Ref. 33) used in the study are also biologically
active in the rabbit.
Organ culture.
The large airways were removed, and the lungs were cut into cubes of
~2 mm3 using sterile scissors. Five pieces were placed in
a culture dish on a filter paper placed on a metallic grid. The tissue
pieces were partly in contact with the atmosphere, partly with the
culture medium. Waymouth's serum-free medium MD 705/1 (GIBCO, Paisley, Scotland) containing penicillin (100 U/ml), streptomycin (100 µg/ml),
fungizone (0.25 µg/ml), and glutamine (2 mM) was used in a humidified
atmosphere containing 5% CO2 and 95% air. The lung
explants were cultured in the presence of LPS, IL-1, TNF-
, IFN-
, different combinations of these compounds, or vehicle for 12 or 20 h at 37°C. These exposure times were chosen in preliminary experiments evaluating the influence of culture time (4-44 h). The
maximum effect of cytokines on the expression of SPs was evident within
12-20 h of incubation time (Ref. 19 and unpublished
results). The effect of LPS was also seen after 12 h and did not
change after prolonged incubation (data not shown). Different
concentrations were also used for IL-1
(19), LPS
(10-1,000 ng/ml), and TNF-
(10-100 ng/ml; data not shown).
The most informative data are shown here. After the culture, the
explants were harvested in liquid nitrogen and stored at
70°C until
used for mRNA or protein analysis. When indicated, the explants were
fixed with 4% neutral formaldehyde for immunohistochemistry.
Analysis of mRNA. Total RNA was isolated, and SP-A, -B, and -C mRNAs were quantified using Northern blot analysis, as described previously (19).
Immunohistochemistry of IL-1.
The explants for immunohistochemistry were fixed with 4% formaldehyde
in PBS overnight and embedded in paraffin. The 5-µm sections were cut
on Super Frost Plus microscopic slides (Menzel-Gläser) for
immunodetection. Deparaffinized sections were incubated for 10 min in
boiling 10 mM sodium citrate, pH 6.0, washed in PBS, and treated with
3% H2O2 in H2O for 15 min at room
temperature. After being washed with PBS, the sections were incubated
with anti-rabbit IL-1
antibody (Endogen, Woburn, MA) at a dilution of 1:250 for 1 h. The following steps were accomplished using the
Strept ABComplexes kit from Dako (Glostrup, Denmark). Detection was
done with the Liquid DAB substrate of ZYMED Laboratories (San Francisco, CA), and the sections were counterstained with hematoxylin.
Western blot analysis of SP-B. Proteins from the explants were isolated essentially according to Clark et al. (10). The lung explants were homogenized in 10 mM Tris (pH 7.5), 0.25 M sucrose, 1 mM EDTA, 5 mM benzamidine, 2 mM phenylmethylsulfonyl fluoride, and 10 µg/ml each of pepstatin A, aprotinin, leupeptin, and chymostatin, followed by centrifugation at 140 g for 10 min (4°C). Quantitation of the protein content of the supernatant was done by the Bio-Rad DC Protein Assay. Altogether, 200 µg of proteins from the supernatant were centrifuged at 22,500 g for 30 min (4°C). The pellet containing 10 µg protein was suspended in 10 µl of loading buffer, boiled for 5 min, and loaded on a 15% SDS-Tricine PAGE gel under nonreducing conditions. The gels were electrotransferred to a Protran BA85 (Schleicher & Schuell, Dassel, Germany) nitrocellulose filter. Blocking and antibody incubations were made according to ECL-Plus (Amersham, Buckinghamshire, UK). A 1:10,000 dilution of mouse antiporcine SP-B antibody (a kind gift from Dr. Y. Suzuki, Kyoto University, Kyoto, Japan) and a 1:10,000 dilution of horseradish peroxidase-conjugated goat antimouse immunoglobulin G (Bio-Rad) served as primary and secondary antibodies, respectively. The bound antibody was visualized using the ECL-Plus Detection kit (Amersham), and the bands were analyzed by video imaging and densitometry.
Expression of the results and statistics.
The mRNA and protein levels of SP-A, SP-B, and SP-C are presented as
means ± SE for convenience. To compensate for gel-loading artifacts, the Northern blot membranes were probed with a
32P-radiolabeled 28S RNA-specific cDNA clone. mRNA or
protein in the presence of IL-1, TNF-
, LPS, or IFN-
was
expressed on the basis of the mRNA or protein present in the
vehicle-treated controls. Statistical significance was analyzed using
Student's t-test for nonpaired data. When indicated,
one-way ANOVA followed by post hoc analysis using the Fisher test was
performed. A P value < 0.05 was considered significant.
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RESULTS |
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LPS and cytokine effects on SP mRNA.
LPS at two different concentrations (100 ng/ml and 1 µg/ml) did not
significantly affect the SP-A, -B, or -C expression in lung explants
from 22-day-old fetal rabbits. In LPS-treated explants from 30-day-old
fetal and 2-day-old newborn rabbits, SP-B and SP-C mRNAs were
suppressed in a concentration-dependent manner. SP-A mRNA was
suppressed only at 1 µg/ml (Fig. 1 and
see Fig. 4).
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Expression of IL-1.
In lung explants from 30-day-old fetuses and 2-day-old newborns, LPS
increased the immunoreactivity of IL-1
in future airspaces. In lung
explants from 22-day-old fetuses, after the addition of LPS, there was
some IL-1 immunoreactivity associated with macrophages from pleura and
interstitium (data not shown), but no immunoreactivity was evident in
airspaces (Fig. 5).
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SP-B.
In mature lung (30-day-old fetal, 2-day-old newborn) within 12 or
20 h (n = 7), IL-1 had no detectable effect on
the SP-B protein content compared with vehicle-treated controls
(1.13 ± 0.23, P = 0.52). In explants from mature
lung, TNF-
(0.77 ± 0.15, P = 0.16) and the
combination of IL-1
and TNF-
(0.73 ± 0.17, P = 0.14) tended to decrease SP-B (Fig.
6).
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DISCUSSION |
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LPS binds to its receptors on inflammatory cells and induces the
expression of proinflammatory cytokines, principally IL-1 and TNF-,
which bind to their receptors in macrophages and to other cells,
resulting in further propagation of the inflammatory cascade (3,
55). In the present study, we have shown that the influence of
LPS from E. coli and the cytokines on SP expression was
dependent on the age of the animals. In immature rabbit lung (day
22; term 30-31 days), LPS had no influence on the expression of SP mRNA, whereas, at term and after birth, LPS downregulated SP-A,
SP-B, and SP-C in a concentration-dependent manner. As shown in the
present and previous studies (19), IL-1
and IL-1
increased SP-A and SP-B mRNA and protein in the immature alveolar
tissue from glandular or canalicular lung. In contrast, in the saccular or alveolar stage of lung development, IL-1 suppressed or had no effect
on SP mRNA. We further found that, when administered together with IL-1
to transitional or mature lung, TNF-
additively suppressed the
expression of SPs. In contrast, IFN-
served as an effective modifier
for the other inflammatory mediators. In the canalicular lung, IFN-
decreased the expression of the SPs when LPS or the cytokines were
present, whereas after birth IFN-
tended to moderate the suppression
of SP mRNA by LPS or the cytokines. The present study serves to
explain the variation of the pulmonary outcome after an inflammatory insult.
IL-1 and LPS accelerate fetal lung maturity in vivo. Both IL-1 and LPS, given intra-amniotically to 25-day-old rabbit fetuses, increased SP-A and SP-B mRNA and improved lung stability, increasing saturated phosphatidylcholine and SP-B in bronchoalveolar lavage (6, 7). Likewise, intra-amniotic IL-1 or LPS also increased SP-A, SP-B, and saturated phosphatidylcholine concentrations in alveolar space of premature lambs and had favorable effects on lung function after premature birth (18, 30).
There was no detectable IL-1 in amniotic fluid in normal human
pregnancy and only a small increase in IL-1 levels in term labor
(44), whereas IL-1 receptor antagonist (IL-1ra)
levels have been reported to be high (8, 46).
Because, additionally, intra-amniotic IL-1ra failed to suppress the
expression of SPs, IL-1 appears to serve as a salvage pathway rather
than obligatory signaling of lung maturation (7). In
premature labor resulting from intrauterine infection, the
concentrations of IL-1 and TNF- increase in the amniotic fluid
toward levels used in the present in vitro study (44, 45).
However, the concentrations of LPS in the amniotic fluid were generally
two orders of magnitude lower than those of IL-1
, IL-
, or TNF-
(20). This is consistent with the hypothesis that
cytokines accelerate maturation of the fetal lung. Within 2-4 h
after the addition of IL-1
to lung explants from 19- to 22-day-old
rabbit fetuses, IL-1 increased the expression of SP-A and SP-B
(14, 19). This acute IL-1 effect was not affected when the
explants were preincubated in the presence of indomethacin,
prostaglandin E2, or dibutyryl-cAMP (data not shown). However, in the immature lung, LPS neither influenced the expression of
SPs nor induced IL-1
in the terminal airspaces. On the basis of
current evidence, we propose that, in intrauterine infection or after
intra-amniotic injection of LPS (6, 30), the generation of
IL-1 and as yet undefined downstream mediators are responsible for the
increase in the expression of SPs (7, 18, 19) and for the
decrease in the incidence of RDS (59). The lack of IL-1
induction in the airways after the addition of LPS to
immature lung in vitro implies that extra-alveolar
macrophages mediate the acceleration of fetal lung maturation.
Macrophages from the fetal membranes are a likely source of cytokines
since they produce IL-1 as a response to LPS (47), and the
fetal breathing movements enable the contact of amniotic fluid with the
future respiratory tract (24).
Toll-like type-1 transmembrane receptor 4 (TLR4) together with MD2 and
CD14 mediates the LPS signal that leads to the activation of
transcription factor nuclear factor (NF)-B (9, 27, 50). TLR4 may also activate the stress-activated protein kinase (SAPK)/c-Jun NH2-terminal kinase (JNK) pathway (36).
The NF-
B and SAPK/JNK pathways upregulate the expression and
synthesis of proinflammatory cytokines IL-1 and TNF-
. It has been
recently found that, in fetal murine lung, the expression of both TLR4
and TLR2 (putative receptor of gram-positive and fungal toxins) was
much lower than in the lung of newborn or adult mice (26).
The absence of the monocyte/macrophage TLR4-signaling pathway resulting
from paucity of macrophages within the terminal airways is a possible
cause for the observed failure of LPS to induce IL-1
in the immature alveolar tissue.
IL-1 binds to IL-1 receptor 1. This type-1 transmembrane protein of the
IL-1/TLR superfamily (40) is likely to be present on the
surface of alveolar epithelial cells (23). IL-1 also induces transcription factor C/EBP (CCAAT/enhancer binding
protein-
; see Ref. 32). In fetal rabbit lung, the
expression of C/EBP
is developmentally regulated and reaches its
peak level parallel to SP-A on day 28 of gestation
(5). However, there is no direct evidence of the role of
the IL-1R/TLR superfamily members or the transcription factor C/EBP
controlling the responsiveness of alveolar cells to inflammatory mediators.
IFN- is not detectable in amniotic fluid at any stage of human
pregnancy (57), not even in preterm labor with
histologically diagnosed chorioaminionitis (37). This
reflects the paucity of the Th1 cytokines in the tissues of both the
pregnant mother and the fetus (41). Addition of IFN-
to
explants from immature rabbit lung did not acutely influence the
expression of SPs. Instead, IFN-
served as a modifier of the effects
of the cytokines on the expression of SPs. In explants from the
immature lung, cultured in the presence of IL-1
and TNF-
,
addition of IFN-
suppressed SP-C mRNA. Similar suppression of SP-C
was evident when IFN-
was replaced by LPS. In contrast, IFN-
increased the expression of SP-A in human fetal lung explants from 16 to 18 wk of human pregnancy after prolonged culture (4 days;
see Ref. 2). The observed difference in the IFN-
response between the two studies may be because of the difference in
the duration of culture (19) or because of species
difference. IFN-
is derived mainly from CD4-positive T cells, where
its synthesis is activated by IL-18 in the presence of a costimulant,
such as LPS (16). IL-1 and IL-18 are structurally related,
and their receptor complexes, as members of the IL-1/TLR superfamily
(16, 40), have a cytoplasmic domain that is very similar
to that of TLR4 (40). IFN-
and LPS added to explants
from the immature lung downregulated both SP-B and SP-C mRNA. The
present results demonstrate that, although IL-1 is associated with the
inflammatory induction of SPs in immature lung, other inflammatory
mediators may prevent or reverse the induction (Fig. 3). The latter
includes IFN-
, which, however, has been found to have low expression
levels in fetal and placental tissues (41).
The downregulation of SP mRNAs by the proinflammatory cytokines and LPS
may play an important role in the pathogenesis of life-threatening
respiratory failure. As shown here and by others (19, 63),
cytokine-induced changes in SP mRNA are reflected in the levels of the
proteins. In small premature infants developing CLD (31, 52,
59), and in acute respiratory distress syndrome (ARDS; see Ref.
29), the proinflammatory cytokines are increased in the
airways. The surfactant defects evident in CLD and in ARDS include
deficiencies in SP-B (21) and SP-A (25). As
shown here and previously (1, 60, 63), the suppression of
SPs by microbial proteins is mediated by IL-1 and TNF-. Here, we have provided evidence of the role of IFN-
in moderating the effects
of LPS and cytokines on the expression of SP-A, SP-B, and SP-C.
According to current evidence, both the quality of the inflammatory challenge and the degree of differentiation of the alveolar cells determine the expression levels of the SPs. The functional consequences of the inflammatory response range from induction of SPs, leading to protection against RDS, to profound suppression of the surfactant, resulting in predisposition to CLD or ARDS. The induction of SPs takes place in rapidly growing immature lung that lacks terminal differentiation and possesses a deficient innate immune response. Individual components SP-A and SP-D bind to microbial toxins, influencing the inflammatory response and the elimination of microbes in a variety of ways (12). According to present evidence, by inducing the surfactant complex in alveolar epithelial cells, IL-1 decreases the risk of RDS in premature fetuses and contributes to activation of the pulmonary defense against microbes.
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ACKNOWLEDGEMENTS |
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We thank Dr. Tiina Kangas for help in the project. We thank Maarit Hännikäinen, Elsi Jokelainen, and Mirkka Parviainen for excellent technical assistance.
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FOOTNOTES |
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This work was supported by the Academy of Finland, Biocenter Oulu (M. Hallman), and the Foundation for Pediatric Research in Finland (O. Väyrynen).
Preliminary results were presented as an abstract at the annual meeting of the European Society of Pediatric Research in Copenhagen, Denmark, in 1999 (Pediatric Res 45: 896A, 1999).
Address for reprint requests and other correspondence: O. Väyrynen, Dept. of Pediatrics and Biocenter Oulu, Univ. of Oulu, P.O. Box 5000, Univ. of Oulu, FIN-90014 Oulu, Finland (E-mail: ovayryne{at}paju.oulu.fi).
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.
10.1152/ajplung.00274.2001
Received 19 July 2001; accepted in final form 20 November 2001.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Bachurski, CJ,
Pryhuber GS,
Glasser SW,
Kelly SE,
and
Whitsett JA.
Tumor necrosis factor-alpha inhibits surfactant protein C gene transcription.
J Biol Chem
270:
19402-19407,
1995
2.
Ballard, PL,
Liley HG,
Gonzales LW,
Odom MW,
Ammann AJ,
Benson B,
White RT,
and
Williams MC.
Interferon-gamma and synthesis of surfactant components by cultured human fetal lung.
Am J Respir Cell Mol Biol
2:
137-143,
1990[ISI][Medline].
3.
Becker, S,
Devlin RB,
and
Haskill JS.
Differential production of tumor necrosis factor, macrophage colony stimulating factor, and interleukin 1 by human alveolar macrophages.
J Leukoc Biol
45:
353-361,
1989[Abstract].
4.
Boggaram, V,
and
Mendelson CR.
Transcriptional regulation of the gene encoding the major surfactant protein (SP-A) in rabbit fetal lung.
J Biol Chem
263:
19060-19065,
1988
5.
Breed, DR,
Margraf LR,
Alcorn JL,
and
Mendelson CR.
Transcription factor C/EBPdelta in fetal lung: developmental regulation and effects of cyclic adenosine 3',5'-monophosphate and glucocorticoids.
Endocrinology
138:
5527-5534,
1997
6.
Bry, K,
and
Lappalainen U.
Intra-amniotic endotoxin accelerates lung maturation in fetal rabbits.
Acta Paediatr
90:
74-80,
2001[ISI][Medline].
7.
Bry, K,
Lappalainen U,
and
Hallman M.
Intraamniotic interleukin-1 accelerates surfactant protein synthesis in fetal rabbits and improves lung stability after premature birth.
J Clin Invest
99:
2992-2999,
1997
8.
Bry, K,
Lappalainen U,
Waffarn F,
Teramo K,
and
Hallman M.
Influence of fetal gender on the concentration of interleukin-1 receptor antagonist in amniotic fluid and in newborn urine.
Pediatr Res
35:
130-134,
1994[Abstract].
9.
Chow, JC,
Young DW,
Golenbock DT,
Christ WJ,
and
Gusovsky F.
Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction.
J Biol Chem
274:
10689-10692,
1999
10.
Clark, JC,
Weaver TE,
Iwamoto HS,
Ikegami M,
Jobe AH,
Hull WM,
and
Whitsett JA.
Decreased lung compliance and air trapping in heterozygous SP-B-deficient mice.
Am J Respir Cell Mol Biol
16:
46-52,
1997[Abstract].
11.
Clements, JA,
and
Avery ME.
Lung surfactant and neonatal respiratory distress syndrome.
Am J Respir Crit Care Med
157:
S59-S66,
1998[ISI][Medline].
12.
Crouch, E,
and
Wright J.
Surfactant proteins a and d and pulmonary host defense.
Annu Rev Physiol
63:
521-554,
2001[ISI][Medline].
13.
Crouch, EC.
Collectins and pulmonary host defense.
Am J Respir Cell Mol Biol
19:
177-201,
1998
14.
Dhar, V,
Hallman M,
Lappalainen U,
and
Bry K.
Interleukin-1 alpha upregulates the expression of surfactant protein-A in rabbit lung explants.
Biol Neonate
71:
46-52,
1997[ISI][Medline].
15.
Dinarello, CA.
Interleukin-1 and interleukin-1 antagonism.
Blood
77:
1627-1652,
1991[Abstract].
16.
Dinarello, CA.
IL-18: a TH1-inducing, proinflammatory cytokine and new member of the IL-1 family.
J Allergy Clin Immunol
103:
11-24,
1999[ISI][Medline].
17.
Elias, JA,
and
Zitnik RJ.
Cytokine-cytokine interactions in the context of cytokine networking.
Am J Respir Cell Mol Biol
7:
365-367,
1992[ISI][Medline].
18.
Emerson, GA,
Bry K,
Hallman M,
Jobe AH,
Wada N,
Ervin MG,
and
Ikegami M.
Intra-amniotic interleukin-1 alpha treatment alters postnatal adaptation in premature lambs.
Biol Neonate
72:
370-379,
1997[ISI][Medline].
19.
Glumoff, V,
Vayrynen O,
Kangas T,
and
Hallman M.
Degree of lung maturity determines the direction of the interleukin-1- induced effect on the expression of surfactant proteins.
Am J Respir Cell Mol Biol
22:
280-288,
2000
20.
Gomez, R,
Ghezzi F,
Romero R,
Munoz H,
Tolosa JE,
and
Rojas I.
Premature labor and intra-amniotic infection. Clinical aspects and role of the cytokines in diagnosis and pathophysiology.
Clin Perinatol
22:
281-342,
1995[ISI][Medline].
21.
Gregory, TJ,
Longmore WJ,
Moxley MA,
Whitsett JA,
Reed CR,
Fowler AA,
Hudson LD,
Maunder RJ,
Crim C,
and
Hyers TM.
Surfactant chemical composition and biophysical activity in acute respiratory distress syndrome.
J Clin Invest
88:
1976-1981,
1991[ISI][Medline].
22.
Haagsman, HP,
and
van Golde LM.
Synthesis and assembly of lung surfactant.
Annu Rev Physiol
53:
441-464,
1991[ISI][Medline].
23.
Haddad, JJ,
Lauterbach R,
Saade NE,
Safieh-Garabedian B,
and
Land SC.
Alpha-melanocyte-related tripeptide, Lys-d-Pro-Val, ameliorates endotoxin-induced nuclear factor kappaB translocation and activation: evidence for involvement of an interleukin-1beta193-195 receptor antagonism in the alveolar epithelium.
Biochem J
355:
29-38,
2001[ISI][Medline].
24.
Hallman, M,
Lappalainen U,
and
Bry K.
Clearance of intra-amniotic lung surfactant: uptake and utilization by the fetal rabbit lung.
Am J Physiol Lung Cell Mol Physiol
273:
L55-L63,
1997
25.
Hallman, M,
Merritt TA,
Akino T,
and
Bry K.
Surfactant protein A, phosphatidylcholine, and surfactant inhibitors in epithelial lining fluid. Correlation with surface activity, severity of respiratory distress syndrome, and outcome in small premature infants.
Am Rev Respir Dis
144:
1376-1384,
1991[ISI][Medline].
26.
Harju, K,
Glumoff V,
and
Hallman M.
Ontogeny of Toll-like receptors Tlr2 and Tlr4 in mice.
Pediatr Res
49:
81-83,
2001
27.
Hoshino, K,
Takeuchi O,
Kawai T,
Sanjo H,
Ogawa T,
Takeda Y,
Takeda K,
and
Akira S.
Cutting edge: toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product.
J Immunol
162:
3749-3752,
1999
28.
Howard, M,
Muchamuel T,
Andrade S,
and
Menon S.
Interleukin 10 protects mice from lethal endotoxemia.
J Exp Med
177:
1205-1208,
1993[Abstract].
29.
Hybertson, BM,
Lee YM,
and
Repine JE.
Phagocytes and acute lung injury: dual roles for interleukin-1.
Ann NY Acad Sci
832:
266-273,
1997[Abstract].
30.
Jobe, AH,
Newnham JP,
Willet KE,
Sly P,
Ervin MG,
Bachurski C,
Possmayer F,
Hallman M,
and
Ikegami M.
Effects of antenatal endotoxin and glucocorticoids on the lungs of preterm lambs.
Am J Obstet Gynecol
182:
401-408,
2000[ISI][Medline].
31.
Jonsson, B,
Tullus K,
Brauner A,
Lu Y,
and
Noack G.
Early increase of TNF alpha and IL-6 in tracheobronchial aspirate fluid indicator of subsequent chronic lung disease in preterm infants.
Arch Dis Child Fetal Neonatal Ed
77:
F198-F201,
1997
32.
Juan, TS,
Wilson DR,
Wilde MD,
and
Darlington GJ.
Participation of the transcription factor C/EBP delta in the acute-phase regulation of the human gene for complement component C3.
Proc Natl Acad Sci USA
90:
2584-2588,
1993[Abstract].
33.
Kulkarni, PS,
and
Mancino M.
Studies on intraocular inflammation produced by intravitreal human interleukins in rabbits.
Exp Eye Res
56:
275-279,
1993[ISI][Medline].
34.
Kuroki, Y,
and
Voelker DR.
Pulmonary surfactant proteins.
J Biol Chem
269:
25943-25946,
1994
35.
Le, J,
Lin JX,
Henriksen-DeStefano D,
and
Vilcek J.
Bacterial lipopolysaccharide-induced interferon-gamma production: roles of interleukin 1 and interleukin 2.
J Immunol
136:
4525-4530,
1986
36.
Muzio, M,
Natoli G,
Saccani S,
Levrero M,
and
Mantovani A.
The human toll signaling pathway: divergence of nuclear factor kappaB and JNK/SAPK activation upstream of tumor necrosis factor receptor-associated factor 6 (TRAF6).
J Exp Med
187:
2097-2101,
1998
37.
Negishi, H,
Yamada H,
Mikuni M,
Kishida T,
Okuyama K,
Sagawa T,
Makinoda S,
and
Fujimoto S.
Correlation between cytokine levels of amniotic fluid and histological chorioamnionitis in preterm delivery.
J Perinat Med
24:
633-639,
1996[ISI][Medline].
38.
Nelson, S,
Bagby GJ,
Bainton BG,
Wilson LA,
Thompson JJ,
and
Summer WR.
Compartmentalization of intraalveolar and systemic lipopolysaccharide-induced tumor necrosis factor and the pulmonary inflammatory response.
J Infect Dis
159:
189-194,
1989[ISI][Medline].
39.
Odom, WM,
and
Ballard PL.
Developmental and hormonal regulation of the surfactant system.
In: Lung Growth and Development, edited by McDonald JA.. New York: Dekker, 1997, p. 495-575.
40.
O'Neill, LA,
and
Dinarello CA.
The IL-1 receptor/toll-like receptor superfamily: crucial receptors for inflammation and host defense.
Immunol Today
21:
206-209,
2000[ISI][Medline].
41.
Prescott, SL,
Macaubas C,
Holt BJ,
Smallacombe TB,
Loh R,
Sly PD,
and
Holt PG.
Transplacental priming of the human immune system to environmental allergens: universal skewing of initial T cell responses toward the Th2 cytokine profile.
J Immunol
160:
4730-4737,
1998
42.
Pryhuber, GS.
Regulation and function of pulmonary surfactant protein B.
Mol Genet Metab
64:
217-228,
1998[ISI][Medline].
43.
Rampart, M,
De Smet W,
Fiers W,
and
Herman AG.
Inflammatory properties of recombinant tumor necrosis factor in rabbit skin in vivo.
J Exp Med
169:
2227-2232,
1989[Abstract].
44.
Romero, R,
Mazor M,
Brandt F,
Sepulveda W,
Avila C,
Cotton DB,
and
Dinarello CA.
Interleukin-1 alpha and interleukin-1 beta in preterm and term human parturition.
Am J Reprod Immunol
27:
117-123,
1992[ISI][Medline].
45.
Romero, R,
Mazor M,
Sepulveda W,
Avila C,
Copeland D,
and
Williams J.
Tumor necrosis factor in preterm and term labor.
Am J Obstet Gynecol
166:
1576-1587,
1992[ISI][Medline].
46.
Romero, R,
Sepulveda W,
Mazor M,
Brandt F,
Cotton DB,
Dinarello CA,
and
Mitchell MD.
The natural interleukin-1 receptor antagonist in term and preterm parturition.
Am J Obstet Gynecol
167:
863-872,
1992[ISI][Medline].
47.
Romero, R,
Wu YK,
Brody DT,
Oyarzun E,
Duff GW,
and
Durum SK.
Human decidua: a source of interleukin-1.
Obstet Gynecol
73:
31-34,
1989[Abstract].
48.
Schurch, S,
Possmayer F,
Cheng S,
and
Cockshutt AM.
Pulmonary SP-A enhances adsorption and appears to induce surface sorting of lipid extract surfactant.
Am J Physiol Lung Cell Mol Physiol
263:
L210-L218,
1992
49.
Sherman, M,
Goldstein E,
Lippert W,
and
Wennberg R.
Neonatal lung defense mechanisms: a study of the alveolar macrophage system in neonatal rabbits.
Am Rev Respir Dis
116:
433-440,
1977[ISI][Medline].
50.
Shimazu, R,
Akashi S,
Ogata H,
Nagai Y,
Fukudome K,
Miyake K,
and
Kimoto M.
MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4.
J Exp Med
189:
1777-1782,
1999
51.
Sone, S,
Yanagawa H,
Nishioka Y,
Orino E,
Bhaskaran G,
Nii A,
Mizuno K,
Heike Y,
Ogushi F,
and
Ogura T.
Interleukin-4 as a potent down-regulator for human alveolar macrophages capable of producing tumour necrosis factor-alpha and interleukin-1.
Eur Respir J
5:
174-181,
1992[Abstract].
52.
Speer, CP.
Inflammatory mechanisms in neonatal chronic lung disease.
Eur J Pediatr
158, Suppl 1:
S18-S22,
1999[ISI][Medline].
53.
Stadler, J,
Stefanovic-Racic M,
Billiar TR,
Curran RD,
McIntyre LA,
Georgescu HI,
Simmons RL,
and
Evans CH.
Articular chondrocytes synthesize nitric oxide in response to cytokines and lipopolysaccharide.
J Immunol
147:
3915-3920,
1991
54.
Standiford, TJ,
Kunkel SL,
Basha MA,
Chensue SW,
Lynch JP, III,
Toews GB,
Westwick J,
and
Strieter RM.
Interleukin-8 gene expression by a pulmonary epithelial cell line. A model for cytokine networks in the lung.
J Clin Invest
86:
1945-1953,
1990[ISI][Medline].
55.
Ulich, TR,
Watson LR,
Yin SM,
Guo KZ,
Wang P,
Thang H,
and
del Castillo J.
The intratracheal administration of endotoxin and cytokines. I. Characterization of LPS-induced IL-1 and TNF mRNA expression and the LPS-, IL-1-, and TNF-induced inflammatory infiltrate.
Am J Pathol
138:
1485-1496,
1991[Abstract].
56.
Van Helden, HP,
Kuijpers WC,
Steenvoorden D,
Go C,
Bruijnzeel PL,
van Eijk M,
and
Haagsman HP.
Intratracheal aerosolization of endotoxin (LPS) in the rat: a comprehensive animal model to study adult (acute) respiratory distress syndrome.
Exp Lung Res
23:
297-316,
1997[ISI][Medline].
57.
Veith, GL,
and
Rice GE.
Interferon gamma expression during human pregnancy and in association with labour.
Gynecol Obstet Invest
48:
163-167,
1999[ISI][Medline].
58.
Vorbroker, DK,
Profitt SA,
Nogee LM,
and
Whitsett JA.
Aberrant processing of surfactant protein C in hereditary SP-B deficiency.
Am J Physiol Lung Cell Mol Physiol
268:
L647-L656,
1995
59.
Watterberg, KL,
Demers LM,
Scott SM,
and
Murphy S.
Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops.
Pediatrics
97:
210-215,
1996[Abstract].
60.
Whitsett, JA,
Clark JC,
Wispe JR,
and
Pryhuber GS.
Effects of TNF-alpha and phorbol ester on human surfactant protein and MnSOD gene transcription in vitro.
Am J Physiol Lung Cell Mol Physiol
262:
L688-L693,
1992
61.
Whitsett, JA,
Nogee LM,
Weaver TE,
and
Horowitz AD.
Human surfactant protein B: structure, function, regulation, and genetic disease.
Physiol Rev
75:
749-757,
1995
62.
Williams, JG,
Jurkovich GJ,
Hahnel GB,
and
Maier RV.
Macrophage priming by interferon gamma: a selective process with potentially harmful effects.
J Leukoc Biol
52:
579-584,
1992[Abstract].
63.
Wispe, JR,
Clark JC,
Warner BB,
Fajardo D,
Hull WE,
Holtzman RB,
and
Whitsett JA.
Tumor necrosis factor-alpha inhibits expression of pulmonary surfactant protein.
J Clin Invest
86:
1954-1960,
1990[ISI][Medline].
64.
Yu, SF,
Koerner TJ,
and
Adams DO.
Gene regulation in macrophage activation: differential regulation of genes encoding for tumor necrosis factor, interleukin-1, JE, and KC by interferon-gamma and lipopolysaccharide.
J Leukoc Biol
48:
412-419,
1990[Abstract].