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*
Departments of Surgery, The Toronto Hospital and University of Toronto, Toronto, Ontario, Canada;
Defense and Civil Institute of Environmental Medicine, Toronto, Ontario, Canada; and
National Institutes of Health-National Institute of Dental Research, Bethesda, MD 20892
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B expression and augmented
the response to LPS. Prevention of this effect by
N-acetyl-cysteine supplementation of the resuscitation
fluid implicates a role for oxidant stress in the priming for lung
inflammation following shock. Finally, alveolar macrophages recovered
from shock-resuscitated animals released more CINC protein in vitro in
response to LPS than macrophages from sham animals. Considered
together, these findings show that augmented release of CINC, in part
from primed alveolar macrophages, contributes significantly to the
enhanced lung leukosequestration and transpulmonary albumin flux in
response to LPS following resuscitated shock. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The family of C-X-C chemokines are potent neutrophil chemoattractants that have been implicated in neutrophil influx to acute inflammatory sites (6). Patients with ARDS have elevated levels of IL-8 in their bronchoalveolar lavage fluid (BALF), and its correlation with the severity of the process suggests a role in the induction of lung inflammation (7, 8, 9). In rodent models of lung inflammation, two particular chemokines, cytokine-induced neutrophil chemoattractant (CINC) and macrophage-inflammatory protein-2 (MIP-2), have been shown to play a central role in neutrophil emigration into the lung (10, 11, 12, 13). In the present studies, we hypothesized that increased lung C-X-C chemokine expression following hemorrhage/resuscitation might contribute to the increased susceptibility to lung injury following trauma. To test this possibility, we developed a "two-hit" lung injury model characterized by hemorrhagic shock with resuscitation, followed by intratracheal LPS administration. We show that the instillation of a low dose of intratracheal LPS following resuscitated shock causes a profound increase in lung neutrophil infiltration and transpulmonary albumin leak when compared with either hemorrhage/resuscitation alone or the administration of LPS alone. Concomitant with this effect, lung expression of CINC protein and mRNA in the LPS-treated shock animals was increased. The contribution of CINC to the development of lung injury in this model was demonstrated both by the ability of anti-CINC Abs as well as the antioxidant N-acetyl-cysteine (NAC) to prevent pulmonary leukosequestration. Alveolar macrophages recovered by BAL following hemorrhage/resuscitation period secreted more CINC protein in response to LPS than LPS-treated cells recovered from sham animals. Considered together, these findings suggest that alveolar macrophage priming for CINC expression following hemorrhagic shock plays an important role in the development of postresuscitation lung injury.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male Sprague Dawley rats (300–350 g; Charles River, St. Constant, Quebec, Canada) were anesthetized with 80 mg/kg ketamine and 8 mg/kg xylazine administered i.p. The right carotid artery was cannulated with a 22-gauge angiocath (Becton Dickinson, Franklin Lakes, NJ) for monitoring of mean arterial pressure (MAP), blood sampling, and resuscitation. Hemorrhagic shock was initiated by blood withdrawal and reduction of the MAP to 40 mm Hg within 15 min. This blood pressure was maintained by further blood withdrawal if the mean arterial pressure (MAP) was >45 mm Hg, and by infusion of 0.5 ml of Ringer’s lactate (RL) if the MAP was <35 mm Hg. Shed blood was collected into 0.1 ml citrate/ml blood to prevent clotting. After a hypotensive period of 60 min, animals were resuscitated by transfusion of the shed blood and RL in a volume equal to that of shed blood, over a period of 2 h. In some studies, animals received NAC (0.5 g/kg) via the artery before the infusion of RL. The catheter was then removed, the carotid artery was ligated, and the cervical incision was closed. Sham animals underwent the same surgical procedures, but hemorrhage was not induced. NAC delivery occurred in sham animals at an equivalent time to that received in shock animals.
At 1 hour after resuscitation, a tracheotomy was performed with a 14-gauge catheter, and either LPS (Escherichia coli O11B4, 30 µg/kg in 200 µl saline) or saline (SAL) alone was administered intratracheally, followed by 20 mechanically ventilated breaths using a rodent ventilator. The animals were therefore assigned to one of four groups: sham/SAL, shock/SAL, sham/LPS, and shock/LPS.
For in vivo anti-CINC Ab blockade experiment, rats were given an intratracheal instillation of 250 µg of rabbit antiserum against rat CINC or rabbit nonimmune IgG in 100 µl of SAL at 10 min before the intratracheal LPS instillation.
Animals were sacrificed at various time points by pentobarbitol overdose.
Bronchoalveolar lavage
For BAL, the lungs were lavaged via the intratracheal angiocath with cold PBS (8 mM sodium phosphate, 2 mM potassium phosphate, 0.14 M sodium chloride, 0.01 M potassium chloride, pH 7.4, with 0.1 mM EDTA). PBS was instilled in 10-ml aliquots and gently withdrawn with a 10-ml syringe to a total volume of 40 ml (14).
BAL fluid was centrifuged at 300 x g for 10 min to pellet cells. Supernatant was discarded, and the pelleted cells were resuspended in a small volume of serum-free DMEM culture medium (Life Technologies, Burlington, Ontario, Canada). Total cell counts were determined on a grid hemocytometer. Differential cell counts were enumerated on cytospin-prepared slides that were stained with Wright-Giemsa stain. A total of 500 cells was counted in cross-section per sample, and the number of PMNs and alveolar macrophages was calculated as the total cell count times the percentage of the respective cell type in the BALF sample.
Assessment of transpulmonary albumin flux
Transpulmonary albumin flux was assessed by injecting 1 mCi of
125I-labeled albumin in a total volume of 0.2 ml SAL
into the tail vein immediately following intratracheal LPS or SAL (14).
At the end of the experimental protocol, 1 ml of blood was withdrawn by
cardiac puncture for counting cpm. Following exsanguination, lungs were
perfused via a cannula in situ with 10 ml of PBS. The perfused PBS was
withdrawn gently and aliquoted into 1 ml/tube for counting cpm. The
transpulmonary albumin flux was normalized to blood cpm as follows:
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Northern blot analysis
Total RNA from lungs was obtained using the guanidium-isothiocyanate method (15). Briefly, lungs were harvested from treated animals and immediately frozen in liquid nitrogen. Lungs were then thawed and homogenized in 10 ml of 4 M guanidine-isothiocyanate containing 25 mM sodium citrate, 0.5% sarcosyl, and 100 mM ß-mercaptoethanol. RNA was denatured, electrophoresed through a 1.2% formaldehyde-agarose gel, and transferred to nylon membrane. Hybridization was conducted using a [32P]dATP end-labeled 30-base oligunucleotide probe for CINC with the sequence 5'-GCGGCATCACCTTCAAACTCTGGATGTTCT-3', which is complementary to nucleotides 134 to 164 of CINC cDNA (see Ref. 12; kindly provided by Dr. Timothy S. Blackwell, Vanderbilt University School of Medicine, Nashville, TN). Blots were then washed under conditions of high stringency, and specific mRNA bands were detected by autoradiography in the presence of intensifying screens, as previously reported (14). Blots were stripped and reprobed for glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which is a ubiquitously expressed housekeeping gene to control for loading (16). Expression of mRNA was quantitated using a PhosphorImager and accompanying ImageQuant software (Molecular Dynamics, Sunnyvale, CA), and was normalized to the GAPDH signal.
Nuclear protein extraction
Nuclear protein extracts were prepared from lung tissue by the method of Deryckere and Gannon (17). Aliquots of 200 to 500 mg of frozen tissue were ground to powder with a mortar in liquid nitrogen. The thawed powder was homogenized in a Dounce tissue homogenizer with 4 ml of solution A (0.6% Nonidet P-40, 150 mM NaCl, 10 mM HEPES, pH 7.9, 1 mM EDTA, and 0.5 mM PMSF). The cells were lysed with five strokes of the pestle. After transfer to a 15-ml tube, debris was pelleted by briefly centrifuging at 2000 rpm for 30 s. The supernatant was transferred to 50-ml Corex tubes, incubated on ice for 5 min, and centrifuged for 10 min at 5000 rpm. Nuclear pellets were then resuspended in 300 µl of solution B (25% glycerol, 20 mM HEPES, pH 7.9, 420 mM NaCl, 1.2 mM MgCl2, 0.2 mM EDTA, 0.5 mM DTT, 0.5 mM PMSF, 2 mM benzamidine, 5 µg/ml pepstatin, 5 µg/ml leupeptin, and 5 µg/ml aprotinin) and incubated on ice for 20 min. The mixture was transferred to microcentrifuge tubes, and nuclei were pelleted by centrifugation at 14,000 rpm for 1 min. Supernatants containing nuclear proteins were aliquoted in small fractions, frozen in liquid nitrogen, and stored at -70°C. Protein quantitation was performed using the Bio-Rad protein assay dye reagent (Bio-Rad, Hercules, CA).
Electrophoretic mobility shift assay (EMSA)
The probe for EMSA is a 30-bp double-stranded construct
(5'-CCTGTGCTCCGGGAATTTCCCTGGCCTGGA-3') corresponding to a sequence
(-72 to -42) in the CINC-proximal promoter region containing the
NF-B motif (12). End labeling was performed by T4 kinase in the
presence of [32P]ATP. Labeled oligonucleotides were
purified on a Sephadex G-50 M column (Pharmacia Biotech,
Piscataway, NJ).
An aliquot of 5 µg of nuclear protein was incubated with the labeled
double-stranded probe (
50,000 cpm) in the presence of 5 µg of
nonspecific blocker, poly(dI-dC) in binding buffer (10 mM Tris-HCl, pH
7.5, 100 mM NaCl, 1 mM EDTA, 0.2% Nonidet P-40, and 0.5 mM DTT) at
25°C for 20 min. Specific competition was performed by adding 100 ng
of unlabeled double-stranded CINC olignucleotide, while for nonspecific
competition, 100 ng of unlabeled double-stranded mutant CINC
olignucleotide (5'-CCTGGCTCCAATTTCCCTGGCCTGGA-3') that does not bind
NF-B was added. The mixture was separated by electrophoresis on a
5% polyacrylamide gel in 1x Tris glycine EDTA buffer (18). Gels were
vacuum dried and subjected to autoradiography and PhosphorImager
analysis.
Western blot analysis
Lung tissue homogenate samples or aliquots of macrophage supernatant were separated on a 15% SDS-PAGE under nonreducing condition (19). Equivalent loading of the gel was determined by quantitation of protein, as well as by Coomassie staining of the gel. Separated proteins were electroblotted onto PVDF membrane and blocked for 1 h at room temperature with Tris-buffered SAL containing 1% BSA. The membranes were then incubated with a 1/1000 dilution of antiserum against rat CINC at room temperature for 1 h. Ag-Ab complexes were identified with goat anti-rabbit IgG tagged with horseradish peroxidase (Sigma, St. Louis, MO) and exposed to the enhanced chemiluminescence detection system (Amersham, Arlington Heights, IL), according to the manufacturer’s instructions.
Ex vivo macrophage release of CINC
To further evaluate the priming effect of hemorrhage/resuscitation on CINC generation, ex vivo experiments were performed using isolated alveolar macrophages. One hour after hemorrhage/resuscitation, BAL was performed on both shocked or sham animals. At this time point, there was no difference between groups with respect to the total cell count in the BAL fluid or the absolute number of alveolar macrophages recovered. A volume of 40 ml of BAL fluid was collected from each rat, and centrifuged at 300 x g for 10 min. The cell pellet was then suspended in NIM.2 neutrophil isolation medium (Cardinal Associates, Santa Fe, NM), and centrifuged at 750 x g, 20°C for 45 min for macrophage isolation (20). The isolated macrophages were washed in 5 ml of modified (calcium- and magnesium-free) HBSS and centrifuged again at 300 x g for 10 min. The pellet was resuspended in DMEM culture medium containing 10% FCS at a concentration of 1 x 106 cells/ml medium, and 1 ml was added to polypropylene tissue culture tubes. This technique generated a cell suspension with a viability in excess of 95%, as assessed by trypan blue exclusion, and a cell population of >95% macrophages, as assessed by Wright-Giemsa staining.
The macrophages obtained from hemorrhage-resuscitated or sham rats were then incubated for 1, 2, 4, and 6 h at 37°C in 5% CO2, either alone or in the presence of 0.5 µg/ml of LPS. At the end of the incubation period, cells were sedimented by centrifugation at 300 x g for 10 min. Supernatants were aspirated and frozen at -70°C for later measurement of CINC by Western blotting.
Statistics
The data are presented as mean ± SE of n determinations, as indicated in the figure legends. Data were analyzed by one-way analysis of variance; post hoc testing was performed using the Bonferroni modification of the t test. When individual studies are demonstrated, these are representative of at least three independent studies.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As shown in Figure 1
A,
neither shock alone nor a low dose of intratracheal LPS increased in
transpulmonary albumin flux compared with sham animals given
intratracheal SAL vehicle. By contrast, LPS administration following
resuscitation from a period of hemorrhagic shock caused a threefold
increase in the albumin flux. The priming effect of shock was also
observed in the magnitude of LPS-induced lung neutrophil influx. While
LPS alone caused a small increase in BALF neutrophil counts, animals
subjected to shock before LPS exhibited a further threefold increase in
neutrophil numbers (Fig. 1B). Shock alone caused
neither an alveolar neutrophilia nor a rise in total cell count in the
BALF compared with sham animals. Considered together, these data
support a priming role for hemorrhagic shock in the LPS-induced
pulmonary leukosequestration and increase in transcapillary
albumin leak.
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CINC and MIP-2 both have been shown to participate in neutrophil
infiltration into the lung following LPS administration (10, 11, 13).
To determine whether enhanced expression of either or both of these
chemokines might contribute to the priming effect of shock in this
model, we examined their expression in animals treated with LPS with or
without prior shock. Figure 2 illustrates
representative Western blots of whole lung for each of these
chemoattractants. Shock alone had little effect on whole lung CINC
protein, while LPS caused an increase by 4 h (Fig. 2A). However, antecedent shock followed by LPS caused
a marked increase in CINC by 2 h, increasing further by 4 h.
Figure 2B demonstrates levels of MIP-2. Both shock alone and
LPS alone caused an increase in this protein by 4 h. In contrast
to CINC expression, the levels of MIP-2 in shock/LPS animals were not
consistently greater than sham/LPS at either 2 or 4 h.
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, A and B).
Shock alone failed to induce CINC mRNA expression, while LPS caused a
fourfold increase. However, the effect of LPS was markedly enhanced by
prior shock/resuscitation (eightfold compared with sham/SAL,
p < 0.01 vs sham/LPS). The priming was also observed
in time course studies (Fig. 3, C and D).
Sham/LPS caused a slight increase by 2 h with clear up-regulation
by 4 h. By contrast, CINC mRNA expression was observed in
shock/LPS animals as early as 1 h and remained elevated above
sham/LPS for up to 4 h.
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B consensus
binding sequence that is believed to contribute to the regulation of
gene transcription (12, 21, 22, 23). Previous studies have reported the
ability of shock to induce NF-B translocation in the lung
mononuclear cells using the B DNA sequence from the Ig gene (24, 25). In the present studies, we evaluated the effect of shock on
NF-B translocation using the B DNA sequence from the CINC gene.
Gel-shift assays on whole lungs were performed to discern whether
increased nuclear translocation of NF-B might contribute to the
priming observed in animals exposed to prior shock. As demonstrated in
Figure 4, sham/LPS animals exhibit a
slight increase in NF-B translocation at 1 h, which reaches a
maximum at 2 h and fades over the ensuing 4 h. In shocked
animals, there is evidence for NF-B translocation before LPS
administration (t = 0 h). Following LPS
treatment, the increase is clearly present at 1 h, reaching a
maximum at 2 h and dissipating over the next 4 h.
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The data presented above show that the priming effect of
hemorrhagic shock is associated with increased NF-B translocation
and an increased rate and magnitude of CINC expression in the lung. Two
approaches were used to determine a causative role for CINC in the
enhanced PMN influx in animals subjected to shock/LPS. First, the
effect of intratracheal anti-CINC Ab was examined. As shown in
Figure 5, anti-CINC Ab caused a
66% reduction in BALF neutrophil counts in sham/LPS animals
compared with nonspecific IgG. In shock/LPS animals, anti-CINC Ab
totally abrogated the shock-induced rise in alveolar neutrophil
sequestration and further reduced neutrophil levels to those observed
in sham/LPS animals treated with anti-CINC. These findings suggest
that the augmented influx of neutrophils in the shock/LPS animals
requires the enhanced expression of CINC.
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A shows the effect of NAC
administered in the resuscitation fluid on CINC mRNA levels. As noted
above, CINC mRNA was increased in shock/LPS animals to a higher level
than sham/LPS (compare lanes 2 and 3 to
lanes 7 and 8). NAC in the resuscitation
fluid markedly reduced CINC mRNA in shock/LPS animals
(lanes 4 and 5), while having a
modest and inconsistent effect in LPS-treated animals
(lanes 9 and 10). Densitometry
normalized for GAPDH is shown in Figure 6B. In a parallel
fashion, NAC prevented the enhanced expression of CINC protein in
shock/LPS animals, while having little effect on CINC expression in
sham/LPS animals (Fig. 6C). Figure 7 demonstrates the effect of NAC
administration on BALF neutrophil counts. Consistent with the effects
of NAC on CINC gene and protein expression, NAC reduced alveolar
neutrophil sequestration to levels observed in animals treated with
sham/LPS. Furthermore, NAC had no effect on neutrophil numbers in
animals treated with sham/LPS. Considered together with the
anti-CINC Ab data, the findings suggest that the major chemokine
contributing to the augmented neutrophil influx in animals exposed to
LPS following shock/resuscitation is CINC.
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B translocation in shock priming
Previous studies have implicated a role for oxidants in the
induction of increased NF-B translocation following shock (24). To
determine whether oxidants might contribute to the shock-induced
priming for lung CINC expression, the effect of NAC on NF-B
translocation was studied. Figure 8A is a representative study
illustrating NF-B translocation at 2 h following intratracheal
SAL or LPS in sham or shock animals. Both sham/LPS (lane
3) and shock/SAL (lane 5) induced
increases in NF-B translocation, while antecedent shock primed the
lung for a marked enhancement of NF-B translocation in response to
LPS (lane 7). Inclusion of NAC in the
resuscitation fluid completely prevented the shock-induced priming for
increased NF-B translocation in shock/LPS animals (lane
8). Treatment of sham animals with NAC at 1 h before
intratracheal LPS instillation caused a small reduction in NF-B
translocation, while NAC caused a significant reduction in NF-B
translocation following shock alone. Densitometric data showing the
average of four animals per group are demonstrated in Figure 8B. In conjunction with the data regarding the effect of NAC
on CINC expression, these findings suggest that shock induces an
oxidant stress that primes for enhanced NF-B translocation and CINC
expression following exposure to LPS.
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CINC is produced by a variety of cells, including neutrophils,
epithelial cells, and macrophages (26). To determine whether alveolar
macrophages contributed to the enhanced whole lung CINC expression, BAL
cells were recovered at the end of resuscitation and enriched for
macrophages. These cells were then incubated ex vivo in the presence or
absence of LPS to evaluate CINC release. As shown in Figure 9, CINC is released from the macrophages
of shock animals as early as 1 h following treatment with LPS,
reaching a peak at 2 h and then decreasing slightly at 4 h.
By contrast, LPS-treated macrophages from sham animals generated a
small quantity of CINC at 4 h. Similarly, supernatant derived from
untreated macrophages, either from sham or shock animals, contained
small and inconsistent levels of CINC. These data demonstrate that
alveolar macrophages may be one of the sources of increased CINC
release in animals following shock/resuscitation and subsequent
exposure to LPS.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previous studies have shown that both CINC and MIP-2 are increased in the lung in response to LPS (10, 11, 12, 13). These reports further suggest that both chemokines might contribute to neutrophil sequestration, as evidenced by the fact that specific neutralizing Abs directed against either of these chemokines caused partial inhibition of neutrophil influx. Shanley and colleagues reported similar findings in a model of immune complex-induced lung injury (28). Consistent with these reports, the present studies demonstrate that LPS, without prior shock, increases both CINC and MIP-2 protein in the lung. The present data suggest, however, that the augmented neutrophil influx in response to LPS in animals subjected to shock/resuscitation is primarily due to a differential increase in CINC expression. Several lines of evidence support this conclusion. First, CINC levels were increased in shock/LPS animals compared with LPS alone, while MIP-2 levels in response to LPS did not differ between shock and sham. Second, anti-CINC Ab completely reversed the shock-induced augmentation in BALF neutrophils in response to LPS. Finally, the ability of NAC treatment to reduce CINC levels in shock/LPS animals to those detected in sham/LPS animals correlated with its ability to prevent the increased neutrophil influx observed in the shock/LPS animals. Considered together, these findings provide strong evidence that antecedent shock selectively primed for increased CINC expression, and this accounted for the augmented neutrophil sequestration and consequent lung injury in shock/LPS animals.
The augmented CINC production in the lung appears to be related to
increased levels of CINC gene expression. Previous studies have
suggested that activation of xanthine oxidase during
hemorrhage/resuscitation might lead to inflammatory gene activation
through oxidant-induced NF-B translocation (24, 29). Our studies
show that shock alone may cause a small increase in NF-B
translocation by a similar mechanism, since the effect is partially
prevented with the antioxidant NAC. Furthermore, we believe that the
increased NF-B in animals at the end of shock/resuscitation is
indicative of a primed macrophage in the lung. The primed state is
evidenced by a more rapid and heightened translocation of NF-B and
expression of CINC mRNA in response to LPS. In this regard, Mendez et
al. (30) showed that macrophages exposed to oxidants in vitro exhibited
increased NF-B translocation and levels of TNF mRNA following LPS.
Two lines of evidence suggest that priming occurs in resident
macrophages rather than those recruited into the lung. First,
macrophage numbers in the BAL do not differ between sham and shock
animals at the end of resuscitation and before LPS. Second, when these
macrophages are recovered and stimulated in vitro, the shock
macrophages generate more CINC protein. Thus, these primed resident
macrophages are sufficient to explain increased CINC, and thus enhanced
neutrophil sequestration. Different sensitivities to the effects of
oxidants may be one possible explanation for the differential priming
for CINC vs MIP-2 expression following shock. In addition to xanthine
oxidase, release of endogenous LPS may also have contributed to NF-B
activation through oxidant generation. Circulating LPS is known to be
increased transiently following hemorrhage/resuscitation (31), and
studies have shown its ability to stimulate NF-B expression both in
vivo and in vitro in an oxidant-dependent manner (12, 32). This
possibility is consistent with studies by Smith and colleagues
demonstrating the ability of systemic endotoxin administration to prime
alveolar macrophages for increased production of inflammatory mediators
in response to a second dose of endotoxin (33). Further investigation
is required to define the precise nature of the oxidant stress, its
source, and its effect on lung chemokine expression.
The present studies provide data that show similarities to those in a
recent report evaluating the effect of NAC on lung injury following the
i.p. administration of LPS (12). The finding that NAC caused a small
reduction in NF-B binding in sham/LPS animals was similar to that
described by Blackwell and colleagues (12), consistent with in vitro
data demonstrating an effect of redox manipulation on LPS-induced
NF-B translocation (32, 34). In the study by Blackwell and
colleagues, NAC caused a 48% reduction in CINC mRNA expression and
complete prevention of neutrophil influx (12), while our data show
little effect on CINC mRNA or neutrophil number in the BALF in sham/LPS
animals. The disparity may in part be related to differences in
experimental models. For example, whereas our neutrophil determinations
were performed at 4 h after a single dose of NAC, studies by
Blackwell et al. (12) were performed at 24 h following multiple
NAC doses. Furthermore, the route of administration of LPS may
influence the local cytokine milieu in the lung, and possibly the
response to antioxidant therapy (35).
Recent clinical reports have demonstrated a beneficial effect of antioxidant therapy in patients with established ARDS (6, 36, 37). The experiments presented in this study suggest the intriguing possibility that the use of antioxidants in the resuscitation fluid of hypotensive patients may lessen their susceptibility to the subsequent development of ARDS in response to a second stimulus. This approach may be applicable not only to trauma victims, but also to patients undergoing major surgical procedures.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Ori D. Rotstein, Toronto Hospital, General Division, 200 Elizabeth Street, Eaton North #9-232, Toronto, Ontario M5G 2C4. E-mail address:
3 Abbreviations used in this paper: ARDS, adult respiratory distress syndrome; BAL, bronchoalveolar lavage; BALF, bronchoalveolar lavage fluid; CINC, cytokine-induced neutrophil chemoattractant; EMSA, electrophoretic mobility shift assay; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MAP, mean arterial pressure; MIP-2, macrophage-inflammatory protein-2; NAC, N-acetyl-cysteine; NF-B, nuclear factor-B; PMN, polymorphonuclear; RL, Ringer’s lactate; SAL, saline.
Received for publication December 11, 1997. Accepted for publication March 3, 1998.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B in endotoxin-tolerant rats is associated with down-regulation of chemokine gene expression and inhibition of neutrophilic lung inflammation. J. Immunol. 158:5934.[Abstract]
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B activation in intact cells. J. Exp. Med. 175:1181.B mobilization and TNF production in human monocytes. J. Immunol. 151:6986.[Abstract]
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 M. L. Mackenzie, N. Bedard, S. S. Wing, and V. E. Baracos A proinflammatory tumor that activates protein degradation sensitizes rats to catabolic effects of endotoxin Am J Physiol Endocrinol Metab, October 1, 2005; 289(4): E527 - E533. [Abstract] [Full Text] [PDF]
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J. L. Lomas-Neira, C.-S. Chung, D. E. Wesche, M. Perl, and A. Ayala In vivo gene silencing (with siRNA) of pulmonary expression of MIP-2 versus KC results in divergent effects on hemorrhage-induced, neutrophil-mediated septic acute lung injury J. Leukoc. Biol., June 1, 2005; 77(6): 846 - 853. [Abstract] [Full Text] [PDF]
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T. J. Murphy, H. M. Paterson, S. Kriynovich, Y. Zang, E. A. Kurt-Jones, J. A. Mannick, and J. A. Lederer Linking the "two-hit" response following injury to enhanced TLR4 reactivity J. Leukoc. Biol., January 1, 2005; 77(1): 16 - 23. [Abstract] [Full Text] [PDF]
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J. L. Lomas-Neira, C.-S. Chung, P. S. Grutkoski, E. J. Miller, and A. Ayala CXCR2 inhibition suppresses hemorrhage-induced priming for acute lung injury in mice J. Leukoc. Biol., July 1, 2004; 76(1): 58 - 64. [Abstract] [Full Text] [PDF]
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R. F. Hamilton Jr., E. Parsley, and A. Holian Alveolar macrophages from systemic sclerosis patients: evidence for IL-4-mediated phenotype changes Am J Physiol Lung Cell Mol Physiol, June 1, 2004; 286(6): L1202 - L1209. [Abstract] [Full Text] [PDF]
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 R. G. Khadaroo, A. Kapus, K. A. Powers, M. I. Cybulsky, J. C. Marshall, and O. D. Rotstein Oxidative Stress Reprograms Lipopolysaccharide Signaling via Src Kinase-dependent Pathway in RAW 264.7 Macrophage Cell Line J. Biol. Chem., November 28, 2003; 278(48): 47834 - 47841. [Abstract] [Full Text] [PDF]
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J. Sasaki, S. Fujishima, H. Iwamura, K. Wakitani, S. Aiso, and N. Aikawa Prior burn insult induces lethal acute lung injury in endotoxemic mice: effects of cytokine inhibition Am J Physiol Lung Cell Mol Physiol, February 1, 2003; 284(2): L270 - L278. [Abstract] [Full Text] [PDF]
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 A. Ayala, C.-S. Chung, J. L. Lomas, G. Y. Song, L. A. Doughty, S. H. Gregory, W. G. Cioffi, B. W. LeBlanc, J. Reichner, H. H. Simms, et al. Shock-Induced Neutrophil Mediated Priming for Acute Lung Injury in Mice: Divergent Effects of TLR-4 and TLR-4/FasL Deficiency Am. J. Pathol., December 1, 2002; 161(6): 2283 - 2294. [Abstract] [Full Text] [PDF]
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J. Fan, A. Kapus, P. A. Marsden, Y. H. Li, G. Oreopoulos, J. C. Marshall, S. Frantz, R. A. Kelly, R. Medzhitov, and O. D. Rotstein Regulation of Toll-Like Receptor 4 Expression in the Lung Following Hemorrhagic Shock and Lipopolysaccharide J. Immunol., May 15, 2002; 168(10): 5252 - 5259. [Abstract] [Full Text] [PDF]
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M. Christofidou-Solomidou, S. Kennel, A. Scherpereel, R. Wiewrodt, C. C. Solomides, G. G. Pietra, J.-C. Murciano, S. A. Shah, H. Ischiropoulos, S. M. Albelda, et al. Vascular Immunotargeting of Glucose Oxidase to the Endothelial Antigens Induces Distinct Forms of Oxidant Acute Lung Injury : Targeting to Thrombomodulin, But Not to PECAM-1, Causes Pulmonary Thrombosis and Neutrophil Transmigration Am. J. Pathol., March 1, 2002; 160(3): 1155 - 1169. [Abstract] [Full Text] [PDF]
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J. Fan, R. D. Ye, and A. B. Malik Transcriptional mechanisms of acute lung injury Am J Physiol Lung Cell Mol Physiol, November 1, 2001; 281(5): L1037 - L1050. [Abstract] [Full Text] [PDF]
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 D. Altavilla, A. Saitta, S. Guarini, M. Galeano, G. Squadrito, L. B. Santamaria, F. S. Venuti, C. Bazzani, A. Bertolini, and F. Squadrito Nuclear Factor-{kappa}B as a target of cyclosporin in acute hypovolemic hemorrhagic shock Cardiovasc Res, October 1, 2001; 52(1): 143 - 152. [Abstract] [Full Text] [PDF]
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 J.-M. Cavaillon, M. Adib-Conquy, I. Cloez-Tayarani, and C. Fitting Review: Immunodepression in sepsis and SIRS assessed by ex vivo cytokine production is not a generalized phenomenon: a review Innate Immunity, April 1, 2001; 7(2): 85 - 93. [Abstract] [PDF]
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C. M. Calkins, D. D. Bensard, J. K. Heimbach, X. Meng, B. D. Shames, E. J. Pulido, and R. C. McIntyre Jr. L-Arginine attenuates lipopolysaccharide-induced lung chemokine production Am J Physiol Lung Cell Mol Physiol, March 1, 2001; 280(3): L400 - L408. [Abstract] [Full Text] [PDF]
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 M Bhatia, M Brady, J Zagorski, S E Christmas, F Campbell, J P Neoptolemos, and J Slavin Treatment with neutralising antibody against cytokine induced neutrophil chemoattractant (CINC) protects rats against acute pancreatitis associated lung injury Gut, December 1, 2000; 47(6): 838 - 844. [Abstract] [Full Text] [PDF]
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J. Fan, A. Kapus, Y. H. Li, S. Rizoli, J. C. Marshall, and O. D. Rotstein Priming for Enhanced Alveolar Fibrin Deposition after Hemorrhagic Shock . Role of Tumor Necrosis Factor Am. J. Respir. Cell Mol. Biol., April 1, 2000; 22(4): 412 - 421. [Abstract] [Full Text]
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J. A. Nemzek, D. R. Call, S. J. Ebong, D. E. Newcomb, G. L. Bolgos, and D. G. Remick Immunopathology of a two-hit murine model of acid aspiration lung injury Am J Physiol Lung Cell Mol Physiol, March 1, 2000; 278(3): L512 - L520. [Abstract] [Full Text] [PDF]
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 R. Shahani, J. G. Marshall, B. B. Rubin, R.-K. Li, P. M. Walker, and T. F. Lindsay Role of TNF-alpha in myocardial dysfunction after hemorrhagic shock and lower-torso ischemia Am J Physiol Heart Circ Physiol, March 1, 2000; 278(3): H942 - H950. [Abstract] [Full Text] [PDF]
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A. J. Boyd, B. B. Rubin, P. M. Walker, A. Romaschin, T. B. Issekutz, and T. F. Lindsay A CD18 monoclonal antibody reduces multiple organ injury in a model of ruptured abdominal aortic aneurysm Am J Physiol Heart Circ Physiol, July 1, 1999; 277(1): H172 - H182. [Abstract] [Full Text] [PDF]
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 M. N. Devalaraja, D. Z. Wang, D. W. Ballard, and A. Richmond Elevated Constitutive I{{kappa}}B Kinase Activity and I{{kappa}}B-{{alpha}} Phosphorylation in Hs294T Melanoma Cells Lead to Increased Basal MGSA/GRO-{{alpha}} Transcription Cancer Res., March 1, 1999; 59(6): 1372 - 1377. [Abstract] [Full Text] [PDF]
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J. A. Wiley and A. G. Harmsen Bone Marrow-Derived Cells Are Required for the Induction of a Pulmonary Inflammatory Response Mediated by CD40 Ligation Am. J. Pathol., March 1, 1999; 154(3): 919 - 926. [Abstract] [Full Text] [PDF]
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