Division of Pulmonary Biology, Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039
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ABSTRACT |
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The
adenoviral E3-14.7K protein is a cytoplasmic protein synthesized after
adenoviral infection. To assess the contribution of E3-14.7K-sensitive
pathways in the modulation of inflammation by the respiratory
epithelium, inflammatory responses to intratracheal lipopolysaccharide
(LPS) and tumor necrosis factor (TNF)- were assessed in transgenic
mice bearing the adenoviral E3-14.7K gene under
the direction of the surfactant protein (SP) C promoter. When
E3-14.7K transgenic mice were administered LPS intratracheally, lung inflammation as indicated by macrophage and neutrophil
accumulation in bronchoalveolar lavage fluid was decreased compared
with wild-type control mice. Lung inflammation and epithelial cell
injury were decreased in E3-14.7K mice 24 and 48 h after LPS
administration. Intracellular staining for surfactant proprotein
(proSP) B, proSP-C, and SP-B was decreased and extracellular staining
was markedly increased in wild-type mice after LPS administration,
consistent with LPS-induced lung injury. In contrast, intense
intracellular staining of proSP-B, proSP-C, and SP-B persisted in type
II cells of E3-14.7K mice, whereas extracellular staining of
proSP-B and proSP-C was absent. Inhibitory effects of intratracheal LPS
on SP-C mRNA were ameliorated by expression of the E3-14.7K
gene. Similar to the response to LPS, lung inflammation after
intratracheal administration of TNF-
was decreased in
E3-14.7K transgenic mice. Levels of TNF-
after LPS
administration were similar in wild-type and E3-14.7K-bearing
mice. Cell-selective expression of E3-14.7K in the respiratory
epithelium inhibited LPS- and TNF-
-mediated lung inflammation,
demonstrating the critical role of respiratory epithelial cells in LPS-
and TNF-
-induced lung inflammation.
lipopolysaccharide; tumor necrosis factor-; adenovirus
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INTRODUCTION |
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A CASSETTE OF ADENOVIRAL GENES located within the
E3 gene region encodes a number of proteins that modulate host
responses to the virus during infection (9, 37). The adenoviral
E3-14.7K gene encodes a 14.7-kDa, nonsecreted cytoplasmic
protein that blocks tumor necrosis factor (TNF)--mediated
cytotoxicity after adenoviral infection in vitro (10, 11, 15, 38).
Mutant adenovirus deficient in the E3-14.7K gene produces
increased inflammation when administered to the lungs of rodents (27).
Likewise, an in vivo study (13) demonstrated that expression of the
E3-14.7K gene in the distal respiratory epithelium of
transgenic mice blunted lung inflammation and epithelial cell turnover
after administration of E1- to E3-deleted adenoviral
vectors to the lung. These studies suggest that the E3-14.7K protein
may interfere with signaling in respiratory epithelial cells, thereby
modulating lung inflammation and injury after adenoviral infection.
Acute respiratory distress syndrome is an often fatal respiratory
disease seen after infection or injury. Proinflammatory cytokines such
as TNF- mediate the infiltration of inflammatory cells into the
pulmonary air spaces through the induction of adhesion and chemotactic
molecules. Because a number of distinct cell types are responsive to
TNF-
, it is presently unclear whether inflammatory signals arise
from the respiratory epithelium or from infiltrating cells. Pulmonary
inflammation is also associated with increased alveolar permeability,
causing a leak into the alveolar spaces of serum proteins that inhibit
pulmonary surfactant function (12, 23, 24). Surfactant protein (SP) B
and SP-C enhance surfactant spreading and stability and protect
surfactant against inactivation by serum proteins (3). SPs are
decreased in the bronchoalveolar lavage fluid (BALF) of acute
respiratory distress syndrome patients (12). Intratracheal
administration of TNF-
into laboratory animals caused increased lung
inflammation, pulmonary edema, and pulmonary dysfunction (21, 31, 33).
Previous work (2, 25) from this laboratory demonstrated that SP-B and
SP-C mRNAs were decreased in the lungs of mice after intratracheal
TNF-
administration and that these effects are mediated, at least in part, at the transcriptional level.
Pulmonary response to infection is a complex inflammatory event
involving integrated interactions between pathogens and a number of
cell types in the lungs. To assess the contribution of signaling
through the respiratory epithelium during acute lung injury, transgenic
mice that express E3-14.7K, a nonsecreted, cytosolic protein,
specifically in the distal lung epithelium were administered
lipopolysaccharide (LPS) or TNF- intratracheally. LPS administration
to the lungs of mice is a well-recognized model for studying the role
of TNF-
-mediated signaling events during pulmonary inflammation and
injury. Lung inflammation and SP dysregulation after LPS or TNF-
administration were attenuated in the lungs of E3-14.7K mice.
These results suggest that signaling through E3-14.7K-sensitive
pathways in respiratory epithelial cells contributes to lung
inflammation and altered SP homeostasis in vivo after LPS-induced lung injury.
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MATERIALS AND METHODS |
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Intratracheal LPS and TNF- administration. Six-
to twelve-week-old SP-C/E3-14.7K and FVB/N wild-type control
mice (n = 6-12 mice/group) were used. Briefly, mice were
anesthetized with methoxyflurane vapor, and an anterior midline
incision was made to expose the trachea. Intratracheal inoculation of
30 µg of LPS (Salmonella typhymurium) or 50 µg of
recombinant mouse TNF-
(Endogen, Woburn, MA) in 100 µl of delivery
vehicle (PBS, pH 7.4) was performed with a bent, 27-gauge tuberculin
syringe (Monoject, St. Louis, MO). The incision was closed with one
drop of Nexaband liquid, and the mice were allowed to recover. Mice
recovered rapidly and remained active after the procedure. At 24 or 48 h after administration, mice were killed by injection of pentobarbital
sodium. A midline incision was made in the abdomen. Exsanguination was
accomplished by transection of the inferior vena cava to reduce
hemorrhage in the lung. For histological examination, the left lung
lobe was inflated with 4% paraformaldehyde (Electron Microscopy
Sciences, Ft. Washington, PA) and fixed overnight. For studies of cell
counts and cell differential analysis, BALF was collected after
intratracheal instillation of 1 ml of PBS. Samples from three
installations per mouse were pooled for analysis.
TNF- and granulocyte-macrophage colony-stimulating
factor mRNA analysis. Abundance of TNF-
and
granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA was
determined by RT-PCR analysis of whole lung total RNA. Briefly, whole
lung total RNA was isolated by phenol-chloroform extraction and
precipitation with isopropanol with the Phase-Lock protocol (5 Prime
3 Prime, Boulder, CO). Total RNA quantitation was confirmed by
gel electrophoresis. Total RNA was converted to cDNA by the RT reaction
(GIBCO BRL, Life Technologies, Gaithersburg, MD). PCR for TNF-
and
-actin cDNAs was performed as described previously (1) with the
following primer tandems:
-actin primer 1, 5'-GTG GGC
CGC TCT AGG CAC CAA-3';
-actin primer 2, 5'-CTC
TTT GAT GTC ACG CAC GAT TTC-3'; TNF-
primer 1,
5'-CCA GAC CCT CAC ACT CAG AT-3'; and TNF-
primer
2, 5'-AAC ACC CAT TCC CTT CAC AG-3'. PCR with OptiPrime
reagents (Stratagene, La Jolla, CA) was performed for 25 cycles on a
Perkin-Elmer 2400 Gene Amp System thermal cycler with the following
parameters: initiation at 94°C for 30 s, annealing at 59°C for
30 s, and elongation of 72°C for 30 s. Ethidium bromide staining of
2% agarose gel electrophoresis was used to visualize PCR products.
Primers used for analysis of GM-CSF mRNA were reported previously (39).
Inflammatory cell populations. Inflammatory cell numbers and percentages were evaluated 24 and 48 h after LPS administration. BALF (n = 6 mice/group) was obtained by intratracheal instillation of 1 ml of PBS into the exposed lungs that were maintained within the thoracic cavity. Lavage fluid was reinfused twice into the lung before final collection. BALF cells were isolated by centrifugation at 500 g and resuspended in 500 µl; 100 µl of cell suspension were mixed with 100 µl of 0.4% trypan blue (GIBCO BRL, Life Technologies, Grand Island, NY), and the cells were counted with a hemocytometer. To determine inflammatory cell types in BALF, 50 × 104 cells were mounted on slides by cytospin centrifugation in 100 µl of PBS at 600 rpm for 3 min. Cell types were identified and counted by differential staining microscopy with Diff-Quik (Baxter Healthcare, Miami, FL). Cell populations were determined by counting 100 cells, and a percentage was calculated based on five sample sets from three animals per group.
Histology and immunohistochemistry. Histopathological changes and surfactant proprotein (proSP) B and proSP-C and mature SP-B immunohistochemical staining were evaluated 24 and 48 h after LPS administration in the inflation-fixed mouse lung. Inflation-fixed lungs were washed in PBS three times and processed in serial alcohol washes. Paraffin-embedded lungs were sectioned at 5 µm and stained with hematoxylin and eosin for morphological analysis. Pathological assessment of lung inflammation was graded blindly on a scale of 0-4, and a score was determined from the mean of six animals.
ProSP-B, proSP-C, and SP-B staining was performed on paraffin-embedded lung sections as described previously (35). Sections were blocked with 2% normal goat serum for 1-2 h at room temperature and incubated overnight at 4°C with the appropriate murine SP antibody at various dilutions. Sections were rinsed five times with 0.2% Triton X-100 in PBS and incubated for 1 h at room temperature with the peroxidase-conjugated IgG secondary antibody at a dilution of 1:100 or 1:200. Sections were rinsed five times with 0.2% Triton X-100 in PBS, and peroxidase staining was detected with the ABC Elite kit (Vector Laboratories, Burlingame, CA). SP staining was observed by light microscopy with a Nikon microscope.
In situ hybridization for SP-C mRNA. In situ hybridization for SP-C mRNA was performed as described previously (36). Radiolabeled riboprobes were generated by in vitro transcription of linearized full-length SP-C cDNA fragments. Paraffin-embedded lung sections (5 µm) were air-dried on RNase-free silanated glass slides, rehydrated, and treated with proteinase K for 5 min at room temperature. Riboprobes were applied to the sections and hybridized for 16 h at 55°C. RNA-RNA hybrids were washed at high stringency with 50% formamide, 2× saline-sodium citrate (SSC), and 10 mM dithiothreitol at 65°C for 30 min and treated with RNase A (20 µg/ml) for 30 min at 37°C. Lung sections were rinsed again at high stringency, followed by lower stringency washes in 2× SSC and 0.1× SSC. All slides were dehydrated through a graded series of alcohol washes followed by xylene and dipped in 50% Ilford K5 nuclear track photographic emulsion. Slides were developed at 2 or 7 days in D-19 developer for 2 min at 16°C and fixed with Kodak fixer. Selected samples were photographed with dark-field illumination and then counterstained with hematoxylin and eosin for bright-field examination and photomicroscopy.
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RESULTS |
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Pulmonary inflammation after LPS administration. Cell counts in
BALF of wild-type mice were increased 24 and 48 h after intratracheal administration of LPS compared with those in untreated wild-type mice
(Fig. 1A). LPS-induced
increase in BALF cellularity was significantly decreased after 24 and
48 h in the lungs of E3-14.7K mice compared with that in
wild-type mice. Cell counts in BALF of E3-14.7K mice were only
modestly increased compared with those in untreated mice. There were no
differences in cell counts in BALF of wild-type and E3-14.7K
mice before LPS administration (data not shown).
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Inflammatory cells from BALF of LPS-treated wild-type and
E3-14.7K mice were analyzed by differential staining and light
microscopy. Cells in BALF from untreated mice consisted primarily of
alveolar macrophages. Both macrophages and neutrophils were increased
24 and 48 h after LPS treatment in wild-type mice (Table
1). After intratracheal LPS, the number of
cells in BALF from E3-14.7K mice was moderately increased and
consisted of both alveolar macrophages and neutrophils.
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Pulmonary inflammation after TNF- administration.
Cell counts in BALF from wild-type mice were increased 24 h after
intratracheal administration of recombinant mouse TNF-
compared with
those in untreated wild-type mice (Fig. 1B). In contrast, cell
counts in BALF from E3-14.7K mice 24 h after intratracheal
TNF-
were not increased and were similar to those in BALF from
untreated wild-type mice. Cell counts in BALF from untreated wild-type
and untreated E3-14.7K mice were not different (data not shown).
TNF- mRNA expression in the lungs of E3-14.7K mice
after LPS and TNF-
administration. Because
LPS-induced lung injury is thought to be mediated, in part, by TNF-
,
the effect of E3-14.7K in the respiratory epithelium on TNF-
expression was assessed in lung tissue after intratracheal LPS. TNF-
mRNA was measured by RT-PCR of total RNA from lung homogenates of
wild-type and E3-14.7K mice 24 h after LPS administration.
TNF-
mRNA was not detected in the lungs of untreated mice (Fig.
2). However, TNF-
mRNA was
readily detectable in lung homogenates of the lungs of both wild-type
and E3-14.7K mice after LPS administration. No difference in
the level of TNF-
mRNA was noted in wild-type compared with
E3-14.7K mice after LPS treatment. Likewise, GM-CSF mRNA was
increased in lungs of LPS-treated mice, and the levels were similar in
wild-type and E3-14.7K transgenic mice (data not shown).
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Lung histology of E3-14.7K mice after LPS administration.
Paraffin-embedded lung sections from wild-type and E3-14.7K
mouse lungs after LPS administration were assessed by hematoxylin and eosin staining and light microscopy (Fig.
3). Increased pulmonary infiltration of
macrophages and neutrophils was readily observed in the lungs of
wild-type mice 24 and 48 h after intratracheal LPS. Increased septal
wall thickening and cellular sloughing of the respiratory epithelium
were observed. In contrast, cellular infiltrates were decreased in the
lungs of LPS-treated E3-14.7K mice. In addition, alveolar
septal wall thickening and cellular sloughing were decreased in lungs
from E3-14.7K mice.
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E3-14.7K attenuates LPS-mediated SP dysregulation. To assess
the role of E3-14.7K signaling pathways in SP expression after LPS
injury, proSP-B, proSP-C, and mature SP-B were assessed by immunohistochemistry in wild-type and E3-14.7K mice. ProSP-B
staining in the lungs of untreated wild-type mice was observed in type II cells, bronchi, and the bronchiolar epithelium and was not observed
in alveolar macrophages or in the alveolar air spaces (Fig.
4). ProSP-B staining was
decreased in alveolar type II cells of wild-type mice 48 h after
treatment of LPS and was readily detected in the alveolar air spaces.
ProSP-B staining in the alveolar air spaces of wild-type mice after LPS
treatment was confined to inflammatory cells. In contrast, treatment of
E3-14.7K mice with LPS was associated with proSP-B staining in
alveolar and bronchiolar epithelial cells. ProSP-B staining was not
noted in the air spaces, similar to the staining pattern of proSP-B in untreated wild-type mice. Thus after LPS exposure, pathological changes
in proSP-B staining induced by LPS were ameliorated in E3-14.7K
mice compared with wild-type mice.
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Immunostaining for the active SP-B peptide was assessed in
E3-14.7K mice and wild-type mice after LPS administration (Fig. 5). In untreated wild-type mice, SP-B
staining was confined to alveolar type II cells and was rarely detected
in the alveolar air spaces. In contrast, large aggregates of SP-B
staining material were observed in the alveolar air spaces of wild-type
mice after LPS treatment. Likewise, SP-B staining was observed in
inflammatory cells within the alveolar air spaces. After LPS treatment,
SP-B staining in E3-14.7K mice was confined to alveolar type II
cells and was rarely detected in the air spaces or associated with
inflammatory cells, a pattern similar to SP-B staining in untreated
wild-type mice. The intensity of SP-B protein staining in mononuclear
cells was decreased in the lungs of E3-14.7K mice compared with
that in wild-type mice after LPS administration.
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ProSP-C was also assessed by immunostaining in E3-14.7K and
wild-type mice after LPS administration (Fig.
6). In untreated wild-type mice, proSP-C
staining was observed in alveolar type II cells, whereas no staining
was observed in alveolar macrophages. After LPS administration to
wild-type mice, proSP-C was decreased in alveolar type II cells and
readily detectable in mononuclear cells within the alveoli. In the
lungs of LPS-treated E3-14.7K mice, proSP-C staining was
detected in alveolar type II cells, with little or no staining observed
in alveolar macrophages, findings similar to those in untreated
wild-type mice.
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Effects of LPS on SP-C mRNA in E3-14.7K mice. To assess the
role of E3-14.7K-regulated pathways in SP-C mRNA, the lungs of wild-type and E3-14.7K mice were analyzed by in situ
hybridization for SP-C mRNA expression after LPS treatment. In
untreated wild-type mice, SP-C mRNA was readily detected in alveolar
type II cells (Fig. 7). SP-C mRNA was
markedly decreased in the lungs of wild-type mice after LPS
administration. Decreased SP-C mRNA expression in the lungs of
wild-type mice was localized to regions of increased inflammatory cells
and alveolar septal wall thickening. In contrast, SP-C mRNA
hybridization signal was maintained in the lungs of LPS-treated
E3-14.7K mice. The intensity and number of cells expressing SP-C mRNA in the lungs of E3-14.7K mice after LPS resembled the pattern and intensity of SP-C mRNA in the lungs of untreated wild-type mice.
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DISCUSSION |
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The present study demonstrates the role of E3-14.7K-sensitive pathways
in the modulation of lung inflammation and SP dysregulation after LPS-
and TNF--induced injury. LPS administration to the lungs of
wild-type mice caused acute lung inflammation and SP dysregulation,
findings similar to those reported for TNF-
in vitro and in vivo (2,
19, 22, 25). The expression of E3-14.7K in the respiratory epithelium
of mice decreased acute lung inflammation and attenuated the inhibitory
effects of LPS on SP expression in alveolar type II cells. E3-14.7K did
not alter TNF-
mRNA abundance in the lungs of mice, consistent with
the concept that E3-14.7K inhibits TNF-
signaling pathways and not TNF-
production. Taken together, these findings suggest that LPS-
and TNF-
-induced lung inflammation and LPS-induced SP dysregulation occur through E3-14.7K-regulated pathways in respiratory epithelial cells and that signaling through the respiratory epithelium plays a
critical role in the inflammatory response during LPS-induced lung injury.
In the present study, the infiltration of inflammatory cells into the
alveolar air spaces after acute LPS injury was attenuated by the
expression of E3-14.7K in the respiratory epithelium. E3-14.7K protein,
a nonsecreted, cytoplasmic protein, was expressed selectively in
respiratory epithelial cells in SP-C/E3-14.7K transgenic mice (13). The finding that lung inflammation after intratracheal LPS or
TNF- administration was abrogated by selective expression of
E3-14.7K in respiratory epithelial cells supports the concept that
E3-14.7K-sensitive pathways in respiratory epithelial cells are
required for the inflammatory responses to TNF-
or LPS in vivo.
Intratracheal LPS administration in rodents causes an acute lung injury
that is mediated, at least in part, through TNF-
-regulated cellular
events in the lung (22, 26, 28, 32). Intratracheal administration of
LPS to rodents induces TNF-
to peak levels within 3 h after
administration (22), and the stimulation of inflammatory cell
migration, including neutrophils and monocytic cell types into the lung
air spaces and lung parenchyma, occurs at time points that coincide
with TNF-
induction (28, 31). Indeed, the administration of LPS and
the subsequent activation of TNF-
are known to induce the expression
of intracellular adhesion molecule-1 and facilitate inflammatory cell
migration into the lung in animal models (28). Chronic TNF-
exposure
through the constitutive expression of TNF-
specifically in the
lungs of transgenic mice causes progressive lung inflammation and
alveolitis, with marked lung damage and remodeling (20). Interestingly, the induction of TNF-
mRNA by LPS was not altered in the lungs of
E3-14.7K mice. Likewise, abundance of GM-CSF mRNA was not
changed in the lungs of E3-14.7K mice compared with that in
wild-type mice after LPS administration (data not shown), suggesting
that E3-14.7K protein in respiratory epithelial cells did not influence lung inflammation via GM-CSF signaling in alveolar macrophages. The
findings in this study are consistent with the concept that signaling
events in the respiratory epithelium per se are important determinants
of pulmonary inflammation after LPS administration.
The loss of SP expression after intratracheal LPS treatment was
inhibited by the expression of E3-14.7K in respiratory epithelial cells. The decreased proSP-B and proSP-C staining in alveolar type II
cells and the appearance of proSPs in the alveolar air spaces in the
lungs of wild-type mice after LPS injury is consistent with LPS-induced
type II cell injury or aberrant secretion from type II cells. For
instance, alveolar type II cell turnover after LPS-induced lung injury
and subsequent phagocytosis of cellular debris, including proSPs may
explain the presence of proSPs in the alveolar air spaces. Likewise, SP
secretion by alveolar type II cells may also occur after lung injury.
The difficulty in precise identification of alveolar cell types in
light of the decreased expression of proSPs should be noted. In the
present study, E3-14.7K expression in respiratory epithelial cells
inhibited the LPS-induced appearance of proSPs in the alveolar air
spaces. Indeed, E3-14.7K has been shown to alter cell turnover after
TNF- treatment in vitro (11) and in the lungs of transgenic mice
after adenoviral infection in vivo (13).
In the present study, the expression of E3-14.7K in the distal lung
epithelium corrected the LPS-induced decrease in SP-C mRNA. SP-C mRNA
was decreased both in vivo and in cultured cell studies after exposure
to TNF- (2). The reduction in SP-C mRNA abundance by TNF-
appears
to occur, in part, at the level of gene transcription (2). A 320-bp
promoter element for the SP-C gene was sufficient to mediate
the inhibitory effects of TNF-
on SP-C expression in a lung
epithelial cell culture system (2). Likewise, the intratracheal
administration of human or mouse recombinant TNF-
reduced SP-C mRNA
abundance and SP-C promoter activity in the lungs of transgenic mice
(2). The results from the present study suggest that the presence of
E3-14.7K protein in the respiratory epithelium is capable of
attenuating the downregulation of SP-C promoter-driven transgene
expression in vivo. The expression of E3-14.7K in the lungs of
transgenic mice attenuated the loss of SP-C mRNA expression during
LPS-mediated lung injury, providing further evidence that signaling
through E3-14.7K-sensitive pathways in alveolar epithelial cells may
play an important role in the SP dysregulation during acute lung injury.
The adenoviral E3-14.7K protein is a 14.7-kDa cytosolic, nonsecreted
protein that blocks TNF--induced cell death in vitro (10, 11, 14).
The adenoviral E3 gene region encodes a number of viral
proteins that likely allow adenovirus to escape host immunosurveillance
or attenuate host immune responses that mediate viral clearance (37).
After adenoviral infection in vitro, the expression of the adenoviral
transcriptional regulator gene E1A sensitizes infected cells to
cell lysis after exposure to TNF-
(4, 6). The expression of
E3-14.7K, either encoded by the infecting virion or through
transfection of the gene in vitro, blocks
E1A-sensitized cell lysis by TNF-
(10, 14). Cytotoxicity of
sensitized cells by TNF-
is dependent on the activation of cytosolic
phospholipase A2 (15, 29) and likely occurs through an
apoptosis-mediated mechanism (16, 34). E3-14.7K inhibits both cytosolic
phospholipase A2 activation and induction of intracellular proteases after TNF-
in sensitized cells (15, 34). The ectopic expression of E3-14.7K in vivo blocks inflammation in a number of
animal models, including the lung (7, 8, 13, 30). The precise molecular
interaction of E3-14.7K is not known; however, recent studies (5, 17,
18) suggest that E3-14.7K may bind proteins involved in apoptotic
pathways. The current study supports the concept that
E3-14.7K-sensitive pathways within the respiratory epithelium are
critical in the initiation of inflammation and SP dysregulation during
LPS-induced acute lung injury.
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ACKNOWLEDGEMENTS |
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We thank Dr. William S. M. Wold for assistance in providing the E3-14.7K cDNA and for thoughtful discussion. We also thank Timothy Cho, Seema Bhatt, and Lorie Stuart for technical assistance.
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FOOTNOTES |
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Present address of K. S. Harrod: Asthma and Immunology Group, Lovelace Respiratory Research Institute, PO Box 5890, Albuquerque, NM 87185.
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: J. A. Whitsett, Div. of Neonatology and Pulmonary Biology, Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229-3039 (E-mail: whitj0{at}chmcc.org).
Received 30 July 1999; accepted in final form 3 November 1999.
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