Departments of 1 Pediatrics, 2 Environmental Medicine, 3 Medicine, and 5 Pathology and 4 The Cancer Center, Strong Children's Research Center, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642
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ABSTRACT |
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Hyperoxic lung injury, believed to be mediated by
reactive oxygen species, inflammatory cell activation, and release of
cytotoxic cytokines, complicates the care of many critically ill
patients. The cytokine tumor necrosis factor (TNF)- is induced in
lungs exposed to high concentrations of oxygen; however, its
contribution to hyperoxia-induced lung injury remains unclear. Both
TNF-
treatment and blockade with anti-TNF antibodies increased
survival in mice exposed to hyperoxia. In the current study, to
determine if pulmonary oxygen toxicity is dependent on either of the
TNF receptors, type I (TNFR-I) or type II (TNFR-II), TNFR-I or TNFR-II
gene-ablated [(
/
)] mice and wild-type control
mice (WT; C57BL/6) were studied in >95% oxygen. There was no
difference in average length of survival, although early survival was
better for TNFR-I(
/
) mice than for either
TNFR-II(
/
) or WT mice. At 48 h of hyperoxia, slightly more alveolar septal thickening and peribronchiolar and periarteriolar edema were detected in WT than in TNFR-I(
/
) lungs. By 84 h of oxygen exposure, TNFR-I(
/
) mice demonstrated greater
alveolar debris, inflammation, and edema than WT mice. TNFR-I was
necessary for induction of cytokine interleukin (IL)-1
, IL-1
receptor antagonist, chemokine macrophage inflammatory protein
(MIP)-1
, MIP-2, interferon-
-induced protein-10 (IP-10), and
monocyte chemoattractant protein (MCP)-1 mRNA in response to
intratracheal administration of recombinant murine TNF-
. However,
IL-1
, IL-6, macrophage migration inhibitory factor, MIP-1
, MIP-2,
and MCP-1 mRNAs were comparably induced by hyperoxia in
TNFR-I(
/
) and WT lungs. In contrast, mRNA for manganese
superoxide dismutase and intercellular adhesion molecule-1 were induced
by hyperoxia only in WT mice. Differences in early survival and
toxicity suggest that pulmonary oxygen toxicity is in part mediated by
TNFR-I. However, induction of specific cytokine and chemokine mRNA and
lethality in response to severe hyperoxia was independent of TNFR-I
expression. The current study supports the prediction that therapeutic
efforts to block TNF-
receptor function will not protect against
pulmonary oxygen toxicity.
oxygen toxicity; C57BL/6 mice; tumor necrosis factor receptor I knockout; tumor necrosis factor receptor II; lung inflammation; manganese superoxide dismutase; intercellular adhesion molecule-1
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INTRODUCTION |
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THE LUNGS OF ADULT ANIMALS, including humans, develop
acute lung injury when exposed to greater than ambient oxygen
concentrations. Because many patients require oxygen therapy to survive
illness or injury, pulmonary oxygen toxicity and its prevention are
significant clinical issues. Exogenous delivery or stimulation of
endogenous antioxidants correlate with decreased oxygen toxicity,
supporting a role of reactive oxygen species (ROS) in hyperoxia-induced
lung injury (10, 28). High-dose oxygen and ROS also induce an
inflammatory response observed as an influx and activation of
polymorphonuclear cells (PMN) and macrophages and increased expression
of cytokines, including tumor necrosis factor (TNF)- and interleukin
(IL)-1
.
TNF- is a cytokine produced primarily by activated macrophages in
response to numerous stimuli including hyperoxia (11). TNF-
induces
acute inflammation by enhancing endothelial permeability, adherence,
and transmigration of inflammatory cells into lung interstitium, as
well as by increasing production of superoxide anion in PMN and of
additional cytokines and chemokines by several cell types (for review,
see Ref. 4). TNF-
also causes endothelial injury, platelet
aggregation, and sequestration, resulting in thrombosis and edema (2,
18). In addition, TNF-
is recognized as a classic regulator of cell
survival or death by apoptosis or necrosis. In this context, it is not
surprising that anti-TNF-
antibodies reduced hyperoxia-induced lung
injury, supporting a role for TNF-
in the pathogenesis of pulmonary
toxicity. In contrast, however, low-dose administration of TNF-
to
rats and mice also reduced oxygen-induced interstitial pneumonitis,
edema, and lethality induced by subsequent exposure to 100% oxygen for
up to 3 days (36). The protective effect of TNF-
is thought to be
related to induction of manganese superoxide dismutase (Mn SOD), an
enzyme that scavenges the extremely reactive superoxide radicals in the mitochondria.
The role of TNF- in hyperoxic lung injury remains particularly
unclear due to a seemingly paradoxical effect of TNF-
on susceptibility to oxygen toxicity (13). Treatment with either TNF-
or antibodies to TNF-
resulted in increased survival in mice exposed
to high-dose oxygen (13, 32, 36). The current study utilized mouse
models in which the receptors through which TNF-
functions, TNFR-I
(p55) and TNFR-II (p75), were eliminated by targeted gene ablation to
test their role in pulmonary oxygen toxicity. TNFR-I is the most
abundant TNF receptor in the lung and has been most tightly linked with
TNF-
-induced cytolysis, apoptosis, and induction of cellular
adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1)
(19, 20). The function of TNFR-II is less well defined and may depend
on interactions with TNFR-I (8, 31). The goals of the current study
were to determine the importance of signaling through the predominant TNFR-I p55 receptor in hyperoxia-induced acute lung injury and to
define differences in the inflammatory and epithelial cell response to
hyperoxia in the presence and the absence of the p55 receptor.
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MATERIALS AND METHODS |
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Animals.
Control C57BL/6 and TNFR-II(/
) (9) strains were
purchased as breeding pairs from Jackson Laboratories (Bar Harbor, ME). The TNFR-I(
/
) strain was generated by homologous
recombination in C57BL/6-derived embryonic stem cells as
previously described (22). Age- and sex-matched 8- to 10-wk-old mice
utilized in the current protocol were bred and maintained in
microisolator cages in specific pathogen-free rooms in the animal care
facility at the University of Rochester Medical Center (Rochester, NY). Sentinel animals maintained in the same rooms, on bedding mixed with
bedding taken from other cages within the room, routinely tested
negative for common murine pathogens including murine hepatitis, pinworm, and Sendai virus. All animal care and experimental protocols were approved by the University of Rochester Committee on Animal Research and follow the guidelines of International Animal Care and Use Committee.
Intratracheal TNF- exposure.
Instillation of a 50-µl volume of control, sterile,
nonpyrogenic saline or recombinant murine TNF-
diluted in the same
saline (rmTNF-
; 5 µg/mouse; R&D Systems, Minneapolis, MN) was
accomplished by blunt needle endotracheal intubation. The mice were
anesthetized briefly with isoflurane before being gently suspended by
the incisors. The mouth was opened, and the tongue was displaced by
forceps. Intubation was detected by the feel of the cartilaginous rings of the trachea and was documented to be reliable by vital dye instillation in >90% of instillations. Greater than 95% of the mice
recovered without incident. Total lung RNA was isolated 18 h after
delivery of TNF-
.
Oxygen exposure.
The mice were exposed to >95% oxygen (hereafter referred to as 100%
oxygen) by delivery of 100% oxygen at 4 l/min to standard plastic
housing cages (10 in. × 8 in. × 12 in.) with metal wire covers as previously described (1). Free access to food and water was
provided. Three cages (3 or 4 mice/cage) were placed inside a Plexiglas
chamber. The oxygen gas was humidified and filtered through a 0.22-µm
filter before passage into the chamber. The percentage of inspired
oxygen within the animal cage was >95% oxygen at all times as
verified by an oxygen analyzer calibrated to room air and to a pure
source of 100% oxygen. Pressure within the cages remains atmospheric.
The chambers themselves were further isolated from the external
environment by placement within existing "Rochester chambers"
located in the Department of Environmental Medicine at the University
of Rochester. The gas exposure system is a single-pass system with
exhaust air vented to the outside through the chamber vents. Control
mice exposed to room air were maintained in plastic cages in a
Rochester chamber adjacent to the oxygen exposure chamber. After the
indicated exposures, the mice were euthanized by intraperitoneal
injection of pentobarbital sodium (150 mg/kg; Abbott Laboratories,
Chicago, IL) and transection of the abdominal aorta. The lungs were
allowed to deflate by opening the diaphragm, and the trachea was
cannulated by 20-gauge catheter. The sternum was removed, and the left
bronchus was isolated by a hemostat. The left lung was removed,
immediately frozen in liquid nitrogen, and stored at 80°C
before isolation of total RNA. After removal of the left lung, the
right lung was inflation fixed via the trachea with 2% glutaraldehyde
in 0.1 M cacodylic acid (pH 7.4; Sigma, St. Louis, MO) at 10 cmH2O pressure for 10 min. After ligation of the trachea,
the lung was removed en bloc, immersion fixed for 16-20 h, washed,
then stored in 0.1 M cacodylic acid at 4°C until it was dehydrated
and embedded in paraffin. Sections (4 µm) were analyzed by routine
hematoxylin and eosin stain and light microscopy for evidence of
inflammation and oxygen toxicity. The tissue sections, identified by
sequential code number, were examined without knowledge of the
experimental exposure. An oxygen toxicity score of 0 (no
histopathology) to 4+ (maximum severity seen in previous
hyperoxia exposed murine lung) was assigned to each tissue based on the
degree of alveolitis, bronchiolitis, bronchitis, fibrosis, and extent
of diffuse involvement. All histological comparisons of WT to
TNFR-I(
/
) lungs presented were performed on tissues
harvested, processed, and stained concurrently.
Analysis of receptor, cytokine, chemokine, ICAM-1, and Mn SOD mRNA.
Total lung RNA was isolated from left lung lobes that were homogenized
(Tekmar tissuemizer) in 1 ml of 4 M guanidine isothiocyanate (Kodak
Chemical, Rochester, NY), 0.5% N-lauroyl sarcosine (Sigma), and 25 mM sodium citrate and stored at 80°C. Total RNA was
recovered by an acid phenol extraction method utilizing Phase Lock Gel
II (5 Prime
3 Prime, Boulder, CO). The RNA was quantified by
absorbance at 260 nm in 10 mM Tris and 0.1 mM EDTA, pH 8.0. Cytokine
and chemokine mRNAs were detected in total lung RNA by RNase protection assay (RPA) utilizing commercially available DNA templates and protocol
(Riboquant, mCK5, mCK3b, mCK2, mCR4; PharMingen, San Diego, CA).
Radiolabeled, single-strand cRNA for the indicated genes was
synthesized at room temperature utilizing
[
-32P]UTP (3,000 Ci/mmol; EasyTides, New
England Nuclear) and T7 polymerase. RNA samples (5-10 µg),
including murine control RNA and yeast tRNA (2 µg) as positive and
negative controls, were dried, then resuspended in 8 µl of
hybridization buffer and 2 µl of radiolabeled probe (~3 × 105 cpm/µl). The hybridization mixtures were overlaid
with mineral oil, denatured at 90°C, and incubated for 16-18 h
in a prewarmed 56°C oven. After incubation, single-strand RNA was
digested in an RNase A/T1 cocktail, followed by proteinase K digestion.
The remaining radiolabeled RNA fragments, protected from degradation by
hybridization to homologous cellular mRNA, were electrophoresed on a
6% acrylamide-urea gel (GIBCO BRL) with a radiolabeled probe set
(1-2 × 103 cpm) as size markers. The gels were
dried and analyzed by phosphorimaging. The data were normalized to
ribosome-associated protein L32 (rpL32) mRNA content.
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RESULTS |
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TNF receptor mRNA expression in murine lung.
Expected absence of TNF receptor mRNA was confirmed in
TNFR-I(/
) and TNFR-II(
/
) mouse total
lung RNA analyzed by RPA (Fig. 1).
Compensatory increase in TNFR-II or I mRNA in the TNFR-I or II(
/
) mice was not detected. WT mouse lung expressed
predominantly TNFR-I mRNA and detectable, but much less abundant,
TNFR-II. There was no significant change in either TNFR-I or
TNFR-II mRNA levels in any of the three strains exposed to 100% oxygen
for up to 84 h.
|
Lack of cytokine and chemokine response to intratracheal
TNF- in TNFR-I-ablated mice.
TNF-
is an early response cytokine, initiating an inflammatory
cascade by induction of other cytokines and chemokines such as IL-1
,
macrophage inflammatory protein-2 (MIP-2), macrophage inflammatory
protein (MIP)-1
, monocyte chemoattractant protein (MCP)-1, and
interferon (IFN)-
-induced protein-10 (IP-10), factors also known to
be induced in hyperoxic models of lung injury (4, 7). To determine if
the TNFR-I is necessary for TNF-
-mediated induction of these genes,
total RNA was isolated from lungs of WT and TNFR-I(
/
)
mice 18 h after instillation of rmTNF-
and subjected to RPA
utilizing template sets represented in Fig.
2, A and B.
The regulated on activation normal T cell expressed and secreted
(RANTES) chemokine and macrophage migration inhibitory factor (MIF)
cytokine were constitutively expressed in both strains of mice.
IL-1
, IL-1 receptor antagonist (RA), MIP-1
, MIP-2, IP-10, and
MCP-1 mRNAs were induced by intratracheal TNF-
in lungs of WT mice
but not in TNFR-I(
/
) mice (Fig. 2, C and
D).
|
Survival of TNFR-I- and TNFR-II-ablated mice in hyperoxia.
To determine the importance of the two TNF receptors in oxygen-induced
mortality, the length of survival of TNFR-I(/
),
TNFR-II(
/
), and control, WT C57BL/6J mice exposed
simultaneously to 100% oxygen was compared. As demonstrated in Fig.
3A, there was no strain difference
in overall survival (P = 0.4 by Mantel-Cox log rank test). The
average time of death for WT mice was 103 ± 14.6 (SD) h (range
76-132 h) compared with 110 ± 9.3 h (range 92-124 h) for
the TNFR-I(
/
) mice and 108 ± 16.5 h (range 76-132
h) for TNFR-II(
/
) mice. Analysis of the natural log
cumulative hazard plot (Fig. 3B), which considers the natural
log of the cumulative hazard as a function of the natural log of the
time of death and allows an estimation of relative hazard of each
strain over time, suggests that the early survival of the TNF
receptor-deficient mice was improved in comparison with WT and
TNFR-II(
/
) mice (5).
|
Histological evidence of oxygen toxicity in TNFR-I-ablated mice.
After the survival analysis, an additional 74 mice were exposed to
100% oxygen for defined periods of time [37
TNFR-I(/
) and 37 C57BL/6J mice]. Of these
animals, four TNFR-I(
/
) mice died before planned time
point [64 h (n = 1), 69 h (n = 1), and 90 h
(n = 2)] while five WT died prematurely [64 h
(n = 1), 83 h (n = 1), and 92 h (n = 3)].
Tissues from these mice were excluded from further analysis.
TNFR-II(
/
) mice were not further studied at this time
because there was no difference in survival characteristics compared
with WT mice.
|
|
Induction of cytokines TNF-, IL-1
,
MIF, and IL-6 mRNAs by hyperoxia.
TNF-
mRNA was mildly induced by 72-84 h of exposure to
hyperoxia in both WT and TNFR-I(
/
) mice (Fig.
6A). To determine if differences in
oxygen susceptibility were due to differential induction of cytokines
previously shown to be induced under hyperoxic conditions (14),
oxygen-induced changes in mRNAs for MIF, IL-1
, and IL-6 were
measured by RPA (Fig. 6B). MIF mRNA (inhibitor of macrophage
migration) was consistently elevated by 48 h of oxygen exposure in both
WT and TNFR-I(
/
) mice. IL-1
and IL-6 mRNAs were also
induced in some animals of both strains at 84 h. However, the increase
in IL-1
and IL-6 was animal dependent, and the cytokine induction
pattern was not significantly different between WT and TNFR-I(
/
) mice. Levels of IL-1
, IL-1RA, the IL-6
receptor IFN-
-inducing factor, TNF-
,
lymphotoxin-
, IFN-
, transforming growth factor (TGF)-
1, and TGF-
3 mRNAs were not significantly altered by
hyperoxia in either strain of mice. IFN-
mRNA was significantly
decreased and TGF-
2 mRNA was increased by 84 h of exposure to
hyperoxia (P < 0.01), with no significant difference between
strains of mice. All analyses were performed by ANOVA on data
normalized by rpL32 mRNA content.
|
Induction of chemokine mRNA by hyperoxia.
To determine if differences in oxygen susceptibility between strains
were due to differential induction of chemokine mRNA previously shown
to be elevated by hyperoxia, RPA was used to determine changes in
expression levels of RANTES, eotaxin, MIP-1, MIP-1
, MIP-2, IP-10,
and MCP-1 (Fig. 7). Notably, RANTES and eotaxin mRNA levels were constitutively expressed independent of oxygen
exposure and of genotype. MIP-1
, MIP-2, MCP-1, and, to a lesser
extent, IP-10 mRNAs were nondetectable at 0 h but induced in all
animals by 72 h and persistently elevated at 93 h of exposure to
hyperoxia (data not shown). There was a trend toward earlier increase
in MIP-1
and MCP-1 in TNFR-I(
/
) mice and greater
increase in MIP-2 in WT mice at 84 h; however, these were not
significant differences (Fig. 7B). All analyses were performed
on data normalized by rpL32 mRNA content.
|
Induction of Mn SOD and ICAM-1 mRNA.
Because previous studies (10, 16, 34) suggested that
TNF--mediated protection from hyperoxia was due to induction of Mn
SOD, mRNA levels of the antioxidant enzyme were quantified by Northern
analysis, normalized to rpL32 mRNA content (Fig.
8A). Likewise, TNF-
is
implicated in hyperoxia-induced inflammation by induction of ICAM-1
mRNA levels (Fig. 8B). Induction of Mn SOD mRNA following 48 and 84 h exposure to 100% oxygen was dependent on genotype, suggesting
that induction of the enzyme was dependent on signal transduction via
TNFR-I. Worsening toxicity in TNFR-I(
/
) mice at later
time points may be due to failure to induce Mn SOD. Likewise,
ICAM-1 mRNA was increased in the majority of WT mice by 48-84 h of
oxygen exposure. No increase in ICAM-1 mRNA was detected in
TNFR-I(
/
) mice, suggesting that induction of the adhesion molecule is also TNFR-I dependent.
|
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DISCUSSION |
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Hyperoxia-induced lung injury is the product of direct toxicity of ROS
and indirect effects of inflammatory cell activation and resulting
synthesis of cytokines. The current study and others confirm the
increase in TNF- mRNA within 48-72 h of exposure to 100%
oxygen (11, 25, 32). The role that TNF-
plays in oxygen-induced lung
injury remains unclear because the cytokine is multifunctional,
inducing, for example, both inflammatory and protective proteins such
as ICAM-1 and Mn SOD. TNFR-I mRNA is the predominant TNF receptor mRNA
detected in murine lung tissue and, based on current knowledge, TNFR-I
is the dominant effector in TNF-
biology capable of inducing
apoptosis, tissue necrosis, and nonspecific immunity (9, 12, 23).
TNFR-II is implicated in fewer activities such as thymocyte growth,
T-cell cytotoxicity, and granulocyte-macrophage colony-stimulating
factor expression (29, 30, 33). In the current study, mice lacking
either TNF receptor, TNFR-I or TNFR-II, remained susceptible to
hyperoxia, although the early survival of TNFR-I(
/
)
tended to be prolonged.
Several cell types can express the cytokine, but the major source of
TNF- in the lung is the alveolar macrophage (11). Consistent with
the results of the current study, macrophage depletion, expected to
decrease pulmonary TNF-
release, modestly increased survival of rats
in 100% oxygen (3). Likewise, pentoxifylline, a methylxanthine that
inhibits both TNF-
synthesis and function, attenuated oxygen
toxicity in rats exposed to continuous hyperoxia (17). Anti-TNF-
antibodies also increased survival and lessened injury in rats exposed
to hyperoxia (13, 32). However, pretreatment or even concurrent
treatment with TNF-
also decreased oxygen toxicity (36). In the
current study, we sought to determine if the protective and toxic
effects of TNF-
in the hyperoxia model segregates by function of the
two TNF receptors. Our results indicate that under hyperoxic
conditions, the TNFR-I receptor mediates both favorable and
nonfavorable effects.
mRNA levels of several genes, induced by high doses of oxygen and
regulated by TNF-, were measured to determine if hyperoxia-induced changes in these mRNAs are TNFR-I dependent. IL-1
, IL-6, IL-8, and
TNF-
have been implicated in mediating pulmonary oxygen toxicity due
to their early induction during oxygen exposure and their pleiotropic
effects in the lung. IL-8 is not found in mice but is functionally
replaced by MIP-2. Cytokines IL-1
, IL-1
, and IL-6 were previously
demonstrated to be increased in mice exposed to hyperoxia for more than
48 h (14). In the current study, the increase in these cytokine mRNA
levels was highly variable, appearing to be animal specific and
independent of the function of TNFR- I(
/
). No
correlation was found between severity of oxygen toxicity and level of
cytokine mRNA.
Chemokines MCP-1, MIP-2, and MIP-1 were induced in WT and
TNFR-I(
/
) mice beginning at 48 h and consistently by 72 h
of exposure. This finding is in agreement with previous reports of MCP-1, MIP-1
, and MIP-2 induction in adult mice within 72 h of beginning exposure to >95% oxygen (7). The chemokine induction patterns tended to differ between WT and TNFR-I(
/
) mice
in the current study. The increase in MIP-1
and MCP-1 occurred
slightly earlier in TNFR-I(
/
) mice, and the level of
MIP-2 mRNA was greater in WT mice by 84 h; however, these strain
differences were not statistically significant given the numbers
of animals tested. Overall, the extent of induction of these chemokine
mRNAs was TNFR-I independent, consistent with the increase in PMN
and macrophages noted histologically in both murine strains.
Several lines of evidence support a protective role for Mn SOD in
pulmonary oxygen toxicity (6). In vitro studies demonstrated that
TNF--dependent induction of Mn SOD was protective against oxidant-induced death (34). Overexpression of Mn SOD by transfection also protected endothelial cells from hyperoxic damage (16). In an
adult baboon model of hyperoxia, aerosolized recombinant Mn SOD
preserved gas exchange and attenuated toxicity (26, 35). The
amelioration of injury and prolonged survival in hyperoxia induced by
IL-1 and TNF-
treatment was associated with increases in antioxidant
enzymes (36). In the current study, we demonstrate that induction of Mn
SOD mRNA in hyperoxia is TNFR-I dependent. We speculate that the
increase in alveolar debris and inflammation reported in the
TNFR-I(
/
) mice at the late time points of oxygen exposure
reflects increased injury due to failure of Mn SOD induction. Length of
survival in hyperoxia, however, was independent of induction of Mn SOD mRNA.
ICAM-1 is a protein involved in the migration, binding, and activation
of leukocytes, in particular neutrophils. ICAM-1 was increased in
pulmonary artery and umbilical cord endothelial cells exposed to
hyperoxia in vitro in association with enhanced neutrophil adhesion
(27). In the current study, the modest but significant increase in
ICAM-1 mRNA in WT mice is consistent with previous reports (15, 24). In
a few of our WT animals, no increase in ICAM-1 mRNA was seen, which may
reflect mouse to mouse variability or the lack of sensitivity inherent
in analyzing cell-specific changes in mRNA levels in total lung RNA
preparations. No increase in ICAM-1 mRNA was detected in any of the
TNFR-I-ablated mice, demonstrating the importance of this receptor in
regulation of the adhesion molecule. The lack of ICAM-1 induction and
resulting decreased translocation of leukocytes may contribute to the
reduction in early lung injury (48 h) in the TNFR-I(/
)
mice. It is also possible that the lack of ICAM-1 expression in the
presence of increased neutrophil chemoattractants, such as MIP-2,
accounts for later increased alveolar and airway PMN in the
TNFR-I(
/
) mice. PMN that are attracted to the lung may be
more apparent in TNFR-I(
/
) mice because the adhesion
molecule that keeps them closely associated with the interstitium and
epithelium is not active. The current study does suggest that induction
of ICAM-1 mRNA is not critical for the development of oxygen-induced
lung injury or mortality.
Many critically ill patients are supported with high doses of oxygen at
the expense of oxygen-induced lung injury. To minimize this iatrogenic
disease, it is necessary to understand the toxic and protective
functions of endogenous factors stimulated by oxygen exposure. Agents
that provide selective blockade of function of specific cytokines or
receptors are or will soon be available for therapeutic use (21). The
current study supports the prediction that global blockade of TNF-
signaling or more specifically of TNFR-I signal transduction will not
protect against hyperoxia-induced pulmonary inflammation and toxicity.
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ACKNOWLEDGEMENTS |
---|
We thank J. Peschon, Immunex Research & Development (Seattle, WA),
for providing p55 knockout mice and reviewing the manuscript. We thank
Nancy Corson, Department of Environmental Medicine, University of
Rochester (Rochester, NY), for help in intratracheal administration of
tumor necrosis factor-.
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FOOTNOTES |
---|
Funding of this work by National Heart, Lung, and Blood Institute Grants K08-HL-03203 (to G. S. Pryhuber) and HL-56002 (to R. Phipps); National Institute of Environmental Health Sciences Grant P30-ES-01247 (to R. Phipps and R. Baggs); National Cancer Institute Grant CA-11198 (to R. Phipps); and National Institute of Allergy and Infectious Diseases Grant AI-31473 (to M. H. Nahm) is gratefully acknowledged.
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: G. S. Pryhuber, Univ. of Rochester Medical Center, 601 Elmwood Ave., Box 651, Rochester, NY 14642 (E-mail: pryh{at}uhura.cc.rochester.edu).
Received 15 June 1999; accepted in final form 15 December 1999.
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