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Departments of
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Pulmonary and Critical Care Medicine and
Pathology, University of Colorado Health Sciences Center, Denver, Colorado 80262
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, is seen in the lungs of
patients with ARDS (12, 13, 14, 15). These observations suggest that cytokines
play a prominent role in the inflammatory responses that lead to acute
lung injury and ARDS.
IL-1ß is thought to be a major participant in the pulmonary
inflammatory cascade in ARDS. IL-1ß, rather than TNF-, was found
to be the major proinflammatory bioactive substance in the
bronchoalveolar lavage fluid (BALF) of patients with ARDS (16).
Intratracheal instillation of IL-1 produces acute inflammatory injury
in the lungs (5, 17). In vitro, IL-1 induces IL-8 expression in
alveolar macrophages, thus indirectly increasing neutrophil chemotaxis
into the lung (18). IL-1 also appears to occupy an important role in
sepsis-induced organ dysfunction and lung injury (2, 5, 15).
IL-1-converting enzyme-deficient mice that cannot produce mature
IL-1ß are resistant to endotoxic shock (19). Additionally, IL-1 has
multiple immunoregulatory and systemic effects that may contribute to
the development of inflammatory injury in the lungs and other organ
systems. Some of these effects include increased expression of adhesion
molecules, such as ICAM-1; induction of lymphocyte NF-
B activity;
increased fibroblast proliferation; and systemic effects, including
hypotension and lactic acidosis (16, 20, 21, 22, 23).
The neutrophil is often considered to be the final effector cell
responsible for lung injury, due to its ability to express multiple
cytotoxic products, including reactive oxygen metabolites and
proteinases. However, recent evidence suggests that the neutrophil may
be a more active participant during the process of inflammation. In
vitro data show that neutrophils can express IL-1Ra, IL-1ß, IL-8,
IL-10, TGF-ß1, and TNF- (3, 24). Human neutrophils produce IL-8
(25), and, in endotoxemic mice, neutrophils express TNF-, IL-10, and
IL-1 (3, 24). However, despite the potential for neutrophils to
contribute to an acute inflammatory response through the expression of
proinflammatory and immunoregulatory cytokines and chemokines, there is
little in vivo information to suggest that neutrophils produce such
cytokines in the initial stages of an inflammatory response or that
such neutrophil-derived cytokines can initiate or potentiate
inflammatory responses in the lung.
Neutrophils rapidly enter the pulmonary parenchyma after endotoxin administration (4, 5), ischemia/reperfusion (26), and hypovolemic shock (27). These neutrophils appear in advance of discernible lung injury, which occurs after 48 to 72 h in such models. Induced neutropenia followed by endotoxin challenge (4, 28) or complement activation (29) attenuates increases in lung vascular permeability and lung injury. These data suggest that there may be two distinct phases of the neutrophil response in acute lung injury: an early phase characterized by rapid neutrophil influx and a later phase characterized by neutrophilic alveolitis, interstitial infiltration, and a developing inflammatory response.
Because neutrophils are capable of expressing proinflammatory cytokines, such as IL-1ß, we hypothesized that rapid trafficking of cytokine-producing neutrophils to the lungs could be important in initiating acute inflammatory lung injury. To investigate this issue, we examined IL-1ß production among intraparenchymal lung cell populations after hemorrhage and endotoxemia.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Esherichia coli 0111:B4 endotoxin was obtained from Sigma Chemical Company (St. Louis, MO). Polyclonal rabbit anti-mouse IL-1ß and control rabbit anti-mouse antiserum were obtained from PharMingen (San Diego, CA). Biotinylated goat anti-rabbit Abs were obtained from Southern Biotechnology Associates (Birmingham, AL). Streptavidin-horseradish peroxidase was obtained from Amersham Biologics (Arlington Heights, IL). Methoxyflurane was obtained from Pitman-Moore, Inc. (Mundelein, IL). The Bio-Rad DC protein assay was obtained from Bio-Rad (Hercules, CA). Percoll was obtained from Pharmacia (Uppsala, Sweden). Ab-coated magnetic beads were obtained from Dynal Corporation (New York, NY). Chemiluminescent detection on Western blots was performed using the Ultra Supersignal Detection system (Pierce, Rockford, IL). Immunohistochemistry was performed using the Vectrastain Quick Kit (Vector, Burlingame, CA). Low melting point agarose was obtained from SeaKem (FMC Bioproducts, Rockland, ME). Glucose oxidase was obtained from Boehringer Manheim (Indianapolis, IN). Gill’s hematoxylin was obtained from Fisher (Springfield, NJ). Male BALB/c mice, 8- to 12-wk-old, were obtained from Harlan Biologics (Indianapolis, IN).
Models of hemorrhage and endotoxemia
All experiments were performed according to a protocol approved
by the University of Colorado Health Sciences Institutional Animal Care
Use Committee. A murine hemorrhage model was used as previously
described by our laboratory (11, 30, 31). Briefly, male BALB/c mice,
aged 8 to 12 wk, were used for this procedure. Mice were anesthetized,
followed by cardiac puncture and removal of 30% of the calculated
blood volume (
0.55 ml for a 20-g mouse). Control mice were
anesthetized and subjected to cardiac puncture without hemorrhage. The
mortality rate with this hemorrhage protocol is 12% (32).
Hemothorax, bleeding into the pericardial space, and lung or cardiac
contusions do not occur in surviving mice (11). When blood pressure is
monitored with femoral artery catheters in this model, removal of 30%
blood volume decreases mean arterial blood pressure to 40 mm Hg,
with restoration to normal levels over the 60 min following
hemorrhage (6).
In those experiments in which the effects of endotoxin administration were examined, i.p. injections of 25 mg/kg E. coli 0111:B4 endotoxin in 0.2 ml PBS were used. This dose has been described as causing lung injury 72 h after administration (2). Control mice were given i.p. injections of 0.2 ml PBS.
Purification of intraparenchymal pulmonary neutrophil/mononuclear cells (IPNMC)
IPNMC were obtained as previously described by our laboratory using collagenase/DNase digestion and Percoll gradient purification (30, 32, 33). Of note, collagenase, DNase, and Percoll are tested routinely for endotoxin in our laboratory and are used only if endotoxin levels of <1 U/ml are detected.
Neutrophil enrichment
Neutrophil enrichment was performed according to the method of Sugawara et al. using a discontinuous Percoll gradient (34). Briefly, pulmonary parenchymal cells suspended in PBS and 0.1% BSA were layered over Percoll gradients with densities of 1.097 and 1.085. Isolated cells were then collected from the Percoll gradient interface, washed with PBS, and lysed in SDS sample buffer containing PMSF. Protein content was determined using the Bio-Rad DC protein assay. Aliquots of cells were stained and visualized using either modified Wright’s staining or in situ myeloperoxidase (MPO) staining and were found to be >90% neutrophils. The remaining cells were mononuclear cells.
Lymphocyte isolation and depletion
In those experiments in which lymphocytes were isolated, anti-B220- and anti-Thy 1.1-coated magnetic beads were added, in succession, to the IPNMC using the manufacturer’s protocol (Dynal Corporation). Magnetic beads with attached lymphocytes were separated using a magnet. Cells were lysed in sample buffer and centrifuged after boiling to make postnuclear preparations and remove residual beads. Negatively selected cells were likewise lysed and postnuclear preparations were used for electrophoresis. These negatively selected cells were found to be 98% neutrophils as determined by Wright’s staining.
Cyclophosphamide (CTX) treatment
Mice were injected i.p. with 150 mg/kg CTX in 0.2 ml sterile water 4 days and 1 day before use in experiments, according to the protocol of Proietti et al. (35). Control mice were treated i.p. with 0.2 ml sterile water at the same time points. Whole blood smears were prepared at the time of hemorrhage and analyzed by Wright’s staining. Red cell-depleted samples of blood were used to measure the total number of white blood cells.
MPO assay
MPO was measured using a modification of the method described by Goldblum et al. (36). Briefly, lungs isolated from mice were washed, blotted dry, and frozen in liquid nitrogen. After weighing, frozen lungs were homogenized, centrifuged at 20,000 x g for 30 min, and resuspended in 50 mM potassium phosphate buffer, pH 6.0, with 0.5% hexadecyltrimethylammonium bromide. Samples were sonicated, incubated at 60°C for 2 h, and assayed for activity in a hydrogen peroxide/o-dianisidine buffer at 460 nm. Results are expressed as units of MPO activity per gram of lung tissue.
Western blotting
Cell samples were lysed in SDS sample buffer containing PMSF and boiled for 10 min. Cytoplasmic extracts were prepared by centrifugation. Protein content was measured using the Bio-Rad DC protein assay. ß-mercaptoethanol was then added, and the samples were boiled again and run on 12% polyacrylamide gels in the amounts noted, following the method of Laemmli (37). Gels were blotted onto nitrocellulose and immunoblotted using anti-IL-1ß Ab. Horseradish peroxidase second-step reagents were then used and blots were developed using the Pierce Ultra chemiluminescent system. Blots were finally exposed to Kodak X-OMAT AR film and developed.
In situ immunolocalization of IL-1ß
Immunohistochemistry was performed as described previously (38, 39). Briefly, unmanipulated control mice, hemorrhaged mice, or endotoxin-treated mice were prepared as described above. After the right ventricle was perfused with 5 cc PBS (4°C), the lungs were gently infiltrated with 1% low melting point agarose (Seakem) at 42°C through the trachea. Lungs were then removed en bloc, and fixed in a 4% paraformaldehyde, 0.23 M sucrose solution overnight. Tissue was then embedded and 5-µm sections prepared as described previously (39). Briefly, embedded sections were treated with 0.2 M glucose, 1.5 U/ml glucose oxidase in PBS for 30 min followed by 10% hydrogen peroxide in PBS for 15 min. Immunohistochemistry was conducted using either anti-IL-1ß or normal rabbit serum at a dilution of 1:1000 using the Vectrastain immunohistochemistry kit following the manufacturer’s protocol (Vector). Sections were then developed using a diaminobenzidine/peroxide-based development system (Vector) followed by counterstaining with Gill’s hematoxylin (Fisher).
Data analysis
All experimental groups consisted of three mice or more (where noted). Data are presented as the mean ± SEM. Densitometry was performed using an Ultraviolet Products (Cambridge, U.K.) charge-coupled device camera and image capture software together with Ultraviolet Products Gelblot image analysis software. Significance was determined using GraphPad Instat software (GraphPad Software, San Diego, CA) using either two tailed t testing or ANOVA analysis, as appropriate. A p value of <0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine the cellular composition in the pulmonary parenchyma
after hemorrhage or endotoxemia, mice were subjected to either
anesthesia and cardiac puncture with hemorrhage of 30% blood volume,
anesthesia and cardiac puncture without blood removal (i.e., sham
hemorrhage), i.p. endotoxin administration, or i.p. PBS administration
(i.e., sham endotoxin treatment), and killed 1 h later. There was
a significant increase in neutrophil infiltration into the lungs 1
h after hemorrhage or endotoxin administration as measured by MPO
content (Fig. 1
). These findings were
also evident by Wright’s staining, in situ MPO staining, and flow
cytometric analysis of IPNMC.
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We sought to determine whether hemorrhage or endotoxemia induce expression of IL-1ß in IPNMC. One hour after hemorrhage or endotoxemia, IPNMC were isolated and cytoplasmic extracts were immunoblotted for IL-1ß.
There was a rapid increase in pro-IL-1ß expression in IPNMC 1 h
after hemorrhage or endotoxemia compared with control mice (Fig. 2). Because mature IL-1ß is
predominantly extracellular, only the precursor form of IL-1ß,
pro-IL-1ß, was detected in isolated cells, although some processed
pro-IL-1ß consistent with IL-1ß can be seen at m.w.s consistent
with the various cleavage sites found on pro-IL-1ß (Fig. 2)
(40).
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To determine whether lymphocytes were the source of IL-1ß production in the lung after hemorrhage, IPNMC were subjected to positive and negative selection using Ab-coated magnetic beads. IPNMC isolated from sham-hemorrhaged mice and mice hemorrhaged 1 h previously were incubated with anti-B220-coated magnetic beads to isolate B cells. T cells were then isolated by incubating the B cell-depleted preparation with anti-Thy-1-coated magnetic beads. The remaining nonadherent cells, depleted of T and B cells (Non-B, Non-T) were then collected. The latter cells were found to be 98% neutrophils according to Wright’s staining. Equivalent amounts of protein from purified T and B cells, as well as the remaining negatively selected cell population, were loaded onto polyacrylamide gels and the resulting immunoblots were probed for IL-1ß.
Pro-IL-1ß was only detected after hemorrhage in the
lymphocyte-depleted lung cell population and not detected in B cell- or
T cell- enriched samples (Fig. 3A). Sham-hemorrhaged
mice had no detectable pro-IL-1ß in any sample (Fig. 3A). Because macrophages and platelets are
effectively excluded from the IPNMC by the Percoll gradient isolation
step, these results suggest that either neutrophils or monocytes were
producing the observed IL-1ß. Furthermore, because monocytes are
relatively few in number in these samples (<2%), these results
indicate that neutrophils are the main source of IL-1ß among the
IPNMC following hemorrhage.
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To examine further the role of neutrophils in producing IL-1ß in the lungs after endotoxemia and blood loss, we purified neutrophils from the IPNMC. To do so, pulmonary parenchymal cells were isolated and then subjected to discontinuous Percoll gradient density isolation using the method of Sugawara et al. (34). The resulting preparation was found to be >90% neutrophils according to Wright’s staining, with the remaining cells consisting of mononuclear cells. Neutrophil-enriched fractions from mice hemorrhaged or treated with endotoxin 1 h previously were lysed and subjected to immunoblotting for IL-1ß.
Pro-IL-1ß is detected in the neutrophil-enriched fraction of
intraparenchymal lung cells from hemorrhaged or endotoxemic mice (Fig. 3
B). Because the neutrophil enrichment procedure
results in the isolation of significantly less protein,
neutrophil-enriched fractions consist of 2 µg protein/lane, while the
total IPNMC contain 20 µg protein/lane. Twenty micrograms of total
IPNMC are required to yield a detectable amount of IL-1ß under the
conditions used. Of note, the numbers of neutrophils among the IPNMC
are too low in normal unmanipulated mice to permit isolation of enough
of these cells to perform Western blots (Fig. 1).
We then determined whether IPNMC from neutropenic mice produced as much
IL-1ß as those from normal mice. To this end, mice were treated with
CTX. By 4 days after treatment, there was a decrease in peripheral
neutrophils from 9.5 ± 1.5 x 105
polymorphonuclear leukocytes (PMN)/ml at baseline to 1.8 ±
0.4 x 104 PMN/ml (p = 0.04).
Concomitantly, there was a decrease in neutrophils in the pulmonary bed
as assessed by MPO assays. CTX-treated mice had very little detectable
MPO activity, even after hemorrhage or endotoxemia (Fig. 1). Control or
CTX-treated mice were either hemorrhaged or treated with endotoxin, and
the resulting IPNMC was isolated 1 h later. Lysates were probed
for the presence of IL-1ß. There is a significant decrease of
pro-IL-1ß expression in the IPNMC of CTX-treated mice compared with
that seen in non-neutropenic control mice subjected to either
hemorrhage or endotoxin administration (Fig. 2).
IL-1ß is localized to neutrophils in the lung parenchyma after hemorrhage or endotoxemia
To localize IL-1ß and determine the relative importance of
neutrophils in the production of IL-1ß after hemorrhage or
endotoxemia, we performed immunohistochemical studies of IL-1ß
protein in the lung after hemorrhage and endotoxemia. The occasional
neutrophils seen in the lungs of control mice expressed no detectable
IL-1ß (Fig. 4A). By
contrast, after either hemorrhage (Fig. 4B) or
endotoxemia (Fig. 4D), IL-1ß was detected in the
neutrophils infiltrating the lung parenchyma. The predominant
populations of neutrophils expressing IL-1ß were those seen in the
pulmonary vasculature and those migrating into the lung through the
endothelium. Endothelial cells were also noted to express IL-1ß (Fig. 4, B and D). Serial sections stained with
control normal rabbit serum as the primary Ab showed no significant
staining of any cell types (Fig. 4, C and
E). Alveolar macrophages were not clearly positive
for IL-1ß staining in any sample.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2% of the cells in our samples makes this highly
unlikely. The neutrophil-enriched fraction contained more pro-IL-1ß
relative to the amount of protein loaded per lane (Fig. 3) to yield the
same intensity band on Western blots. This indicates that the
enrichment of neutrophils also increases the IL-1ß content of the
samples, further supporting neutrophils as the source of IL-1ß.
Neutropenic mice, in contrast to non-neutropenic animals, failed to
express significant IL-1ß among lung mononuclear cell populations in
response to either hemorrhage or endotoxin administration. Finally,
IL-1ß was visualized in lung neutrophils using immunohistochemistry
after either hemorrhage or endotoxemia. Together, these data indicate
that neutrophils express the majority of detectable IL-1ß in IPNMC
after hemorrhage or endotoxemia. Our data do not exclude cell sources other than neutrophils as sources of IL-1ß in the pulmonary parenchyma after hemorrhage or endotoxemia. Clearly, alveolar macrophages can produce IL-1ß, and often represent the major cell type in BALF (5, 6, 41, 42, 43). Endotoxin induces IL-1ß expression in alveolar macrophages in vitro (5). However, our previous studies did not show any increase in IL-1ß mRNA levels in alveolar macrophages isolated over the 4 h after hemorrhage (6). Likewise, the present studies fail to demonstrate significant alveolar macrophage-derived IL-1ß in the first hour after hemorrhage or endotoxemia. Because alveolar macrophages are poor Ag-presenting cells (44), our findings support the hypothesis that alveolar macrophages are relatively unimportant in the inflammatory response that occurs immediately after insults that may lead to lung injury.
We previously demonstrated that lung IL-1ß protein levels increase
within 1 h after hemorrhage (45). Pro-IL-1ß contains cleavage
sites for a variety of enzymes, including IL-1ß-converting enzyme and
neutrophil elastase, which can produce biologically active IL-1ß (40, 46). Mature IL-1ß is processed and excreted to the extracellular
compartment (23). In our experiments, IPNMC are thoroughly washed
during the steps required during processing. Therefore, most of the
extracellular mature IL-1ß is lost during processing, accounting for
the detection of predominantly intracellular pro-IL-1ß. Because
neutrophil elastase is capable of producing biologically active IL-1ß
and we have seen the cleavage products of pro-IL-1ß in our
experiments (see Fig. 3), pro-IL-1ß measurements should parallel
IL-1ß biologic activity.
Although neutrophil production of proteases, reactive oxygen species, and other cytotoxic mediators clearly plays a role in the effector phase of lung injury, our data suggest an expanded role for neutrophils in initiating this inflammatory process. The present results indicate that lung injury may be, at least in part, a "bystander phenomenon", caused by IL-1ß-producing neutrophils that traffic to the lungs, rather than by resident pulmonary cells. The role of IL-1ß as a proinflammatory cytokine is well established, and it appears to have a central role in inducing acute lung injury (5, 16, 17). The decrease in IL-1ß in neutropenic mice reported here may explain the observation that neutropenia decreases alveolar leak and acute lung injury in endotoxin-treated animals (4).
Because most in vivo studies of lung IL-1ß expression are performed on whole lung homogenates (3, 5) or BALF (13, 14), the cellular source of IL-1ß is uncertain. BALF used in measuring of IL-1 content may contain a significant number of neutrophils or other cells, particularly late in inflammation (5, 6). Therefore, the IL-1ß detected in these studies may originate from neutrophils. Indeed, measures of neutrophil numbers in BALF often parallel the IL-1ß content of the BALF (6, 47).
Our previous studies (6, 7, 9), showing different patterns of cytokine expression in alveolar macrophages and intraparenchymal lung cells, coupled with the present results, indicating a central role for neutrophil-derived IL-1ß cytokine production in the lung after hemorrhage and endotoxemia, underscore the distinct contributory roles of intraparenchymal and alveolar cell populations in acute lung inflammation. These findings suggest that analysis of BALF samples from human or experimental models may incompletely reflect events in the lungs. For example, we previously found that IL-1ß in BALF was increased only 72 h after hemorrhage, even though elevated protein levels were present in lung homogenates within 1 h of blood loss (6). Thus, reliance upon BALF analysis in human and experimental studies to determine the importance of various cytokines may underestimate the role of events in the pulmonary parenchyma, in which the inflammatory process is histologically most intense.
The present studies also suggest that endotoxin or hemorrhage induce IL-1ß production by neutrophils before these cells enter the lung parenchyma. Neutrophils seen in the pulmonary vasculature on immunohistochemical sections were noted to express IL-1ß. It is possible that interactions between the neutrophils and the vasculature induce the expression of IL-1ß within the lumen of the blood vessels. Future studies will be directed at determining whether neutrophils from other sites, such as the peritoneum and the peripheral blood, also express IL-1ß.
Both hemorrhage and endotoxemia cause an increase in neutrophil trafficking to the lung. Studies have implicated adhesion molecules (48, 49, 50, 51), catecholamines (52), oxygen radicals (27), cytokines (53, 54), and changes in neutrophil deformability (41, 55) as possible mechanisms for the accumulation of neutrophils in the lungs under these conditions. Our findings suggest that there may be a common pathway for lung injury after sepsis and blood loss that involves neutrophils that traffic to the lungs, produce proinflammatory cytokines such as IL-1ß, and initiate an acute inflammatory response.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Edward Abraham, Division of Pulmonary and Critical Care Medicine, University of Colorado Health Sciences Center, Box C272, 4200 East Ninth Avenue, Denver, CO 80262.
3 Abbreviations used in this paper: ARDS, acute respiratory distress syndrome; BALF, bronchoalveolar lavage fluid; MPO, myeloperoxidase; IPNMC, intraparenchymal pulmonary neutrophil/mononuclear cells; CTX, cyclophosphamide; PMN, polymorphonuclear leukocytes.
Received for publication April 28, 1997. Accepted for publication October 6, 1997.
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References |
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B through its type I but not type II receptor in lymphocytes. J. Biol. Chem. 267:15836.B regulation and cytokine expression. J. Clin. Invest. 99:1516.[Medline]
-induced transendothelial neutrophil migration is IL-8 dependent. Am. J. Physiol. 266:L238. B activation. Am. J. Respir. Cell Mol. Biol. 11:464.[Abstract]
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 J. Arcaroli, K.-Y. Yang, H.-K. Yum, J. Kupfner, T. M. Pitts, J. S. Park, D. Strassheim, and E. Abraham Effects of catecholamines on kinase activation in lung neutrophils after hemorrhage or endotoxemia J. Leukoc. Biol., September 1, 2002; 72(3): 571 - 579. [Abstract] [Full Text] [PDF]
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J. G. Kupfner, J. J. Arcaroli, H.-K. Yum, S. G. Nadler, K.-Y. Yang, and E. Abraham Role of NF-{kappa}B in Endotoxemia-Induced Alterations of Lung Neutrophil Apoptosis J. Immunol., December 15, 2001; 167(12): 7044 - 7051. [Abstract] [Full Text] [PDF]
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H.-K. Yum, J. Arcaroli, J. Kupfner, R. Shenkar, J. M. Penninger, T. Sasaki, K.-Y. Yang, J. S. Park, and E. Abraham Involvement of Phosphoinositide 3-Kinases in Neutrophil Activation and the Development of Acute Lung Injury J. Immunol., December 1, 2001; 167(11): 6601 - 6608. [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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T. M. Carlos Leukocyte recruitment at sites of tumor: dissonant orchestration J. Leukoc. Biol., August 1, 2001; 70(2): 171 - 184. [Abstract] [Full Text] [PDF]
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J.-F. Pittet, L. N. Lu, D. G. Morris, K. Modelska, W. J. Welch, H. V. Carey, J. Roux, and M. A. Matthay Reactive Nitrogen Species Inhibit Alveolar Epithelial Fluid Transport After Hemorrhagic Shock in Rats J. Immunol., May 15, 2001; 166(10): 6301 - 6310. [Abstract] [Full Text] [PDF]
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E. Abraham, J. Arcaroli, and R. Shenkar Activation of Extracellular Signal-Regulated Kinases, NF-{{kappa}}B, and Cyclic Adenosine 5'-Monophosphate Response Element-Binding Protein in Lung Neutrophils Occurs by Differing Mechanisms After Hemorrhage or Endotoxemia J. Immunol., January 1, 2001; 166(1): 522 - 530. [Abstract] [Full Text] [PDF]
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E. Abraham, A. Carmody, R. Shenkar, and J. Arcaroli Neutrophils as early immunologic effectors in hemorrhage- or endotoxemia-induced acute lung injury Am J Physiol Lung Cell Mol Physiol, December 1, 2000; 279(6): L1137 - L1145. [Abstract] [Full Text] [PDF]
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E. Abraham, J. Arcaroli, A. Carmody, H. Wang, and K. J. Tracey Cutting Edge: HMG-1 as a Mediator of Acute Lung Inflammation J. Immunol., September 15, 2000; 165(6): 2950 - 2954. [Abstract] [Full Text] [PDF]
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M. Laffon, L. N. Lu, K. Modelska, M. A. Matthay, and J. F. Pittet alpha -Adrenergic blockade restores normal fluid transport capacity of alveolar epithelium after hemorrhagic shock Am J Physiol Lung Cell Mol Physiol, October 1, 1999; 277(4): L760 - L768. [Abstract] [Full Text] [PDF]
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R. Shenkar and E. Abraham Mechanisms of Lung Neutrophil Activation After Hemorrhage or Endotoxemia: Roles of Reactive Oxygen Intermediates, NF-{kappa}B, and Cyclic AMP Response Element Binding Protein J. Immunol., July 15, 1999; 163(2): 954 - 962. [Abstract] [Full Text] [PDF]
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E. Abraham, D. J. Kaneko, and R. Shenkar Effects of endogenous and exogenous catecholamines on LPS-induced neutrophil trafficking and activation Am J Physiol Lung Cell Mol Physiol, January 1, 1999; 276(1): L1 - L8. [Abstract] [Full Text] [PDF]
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