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*
Departments of Medicine and Pediatrics, Divisions of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, MI 48109; and
Department of Immunology, Schering-Plough Research Institute, Kenilworth, NJ 07033
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, IFN-
, IL-12, and IL-10 were noted. However,
inducible macrophage inflammatory protein-2 levels were significantly
decreased in the KC-transgenic mice compared with the wt mice. This
study indicates that the compartmentalized overexpression of KC in vivo
results in increased lung bacterial clearance and improved survival,
which occurs in association with enhanced polymorphonuclear
leukocyte influx to the lung. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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)3 that are vigorously
recruited and/or activated at the site of infection (4). Leukocyte
recruitment is an inherently integral component of the host defense
cascade and is mediated in part by the production of chemotactic
cytokines (5).
Four closely related polypeptide chemotactic cytokine or chemokine
families, C-C, C-X-C, C, and C-X-X-X-C chemokines, are now known to
exist in humans; most have murine homologues (6, 7, 8, 9). The C-C and C-X-C
chemokines, in particular, have been recognized as crucial mediators in
several inflammatory disease states (8, 9). More importantly, both
families of chemokines have been shown to be critical participants in
host defense against infection (10, 11, 12, 13). In Cryptococcus
neoformans pneumonia, the neutralization of M inflammatory
protein (MIP)-1 and monocyte chemoattractant protein-1 (MCP-1/JE),
which are members of the C-C chemokine family, resulted in a
significant decrease in M and lymphocyte influx and a consequential
increase in fungal burden and mortality (11, 12). In a murine
Klebsiella pneumonia model, the C-X-C chemokine MIP-2 has
been shown to be an important contributor of neutrophil recruitment and
bacterial clearance (13). Specifically, neutralization with
anti-MIP-2 Abs significantly attenuated neutrophil influx,
resulting in increased bacterial burden and early mortality (13).
KC is a member of the C-X-C chemokine family. Like other members
of the family, KC is broadly produced by numerous cells, including
fibroblasts, endothelial cells, and peritoneal and alveolar M
(14, 15, 16, 17). In vitro, these cells express KC in response to inflammatory
signals, such as LPS and the host-derived cytokines IFN- and
platelet-derived growth factor, suggesting a prominent role for KC in
the inflammatory cascade (18, 19). Similar to other members of the
C-X-C chemokine family, KC induces neutrophil chemotaxis and weakly
stimulates respiratory burst to levels that are comparable with those
of its human homologue, growth-regulated gene- (20). In vivo,
KC is expressed in the rat models of acute pulmonary inflammation that
are induced by endotoxin, sulfur dioxide-mediated chronic bronchitis,
and vanadium exposure (20, 21, 22, 23), while the inhibition of KC has been
shown to substantially attenuate the accumulation of neutrophils in the
lungs after the intratracheal (i.t.) administration of LPS (20).
Furthermore, the intrapulmonary administration of KC induces a
dose-dependent neutrophilic influx that is compartmentalized to the
lungs (20). Finally, KC and other chemokines have been implicated in
extrapulmonary inflammatory responses, including the thrombogenesis
that occurs in injured endothelium (24).
Several KC-transgenic mouse models have been developed and have been shown to promote controlled neutrophilic recruitment in selectively targeted compartments (25, 26, 27, 28). The programmed expression of the KC transgene using a thymus-specific or a human keratin promoter resulted in neutrophilic aggregates in the thymic cortical and juxtamedullary regions or epidermis, respectively (25). Moreover, transgenic mice that were generated under control of a myelin basic protein promoter expressed the KC transgene only in the central nervous system, resulting in site-specific polymorphonuclear leukocyte (PMN) sequestration (26). More recently, Lira and colleagues have constitutively expressed KC within the lungs using the transgenic KC gene fused to a Clara cell-specific promoter (27). The increased KC expression resulted in enhanced neutrophil migration within the lungs of transgenic mice (27). The lung overexpression of KC did not result in a substantial activation of recruited neutrophils, as evidenced by the lack of tissue damage histologically. This transgenic model allowed us the unique opportunity to examine the role of KC in lung host defense against Gram-negative bacterial organisms.
In this study, we describe the time-dependent expression of KC protein within the lungs after i.t. K. pneumoniae administration and correlate the changes in KC expression with an influx of neutrophils. In addition, transgenic mice were employed to determine whether overexpression of the KC chemokine could have a beneficial effect on bacterial clearance and survival in the setting of Gram-negative bacterial pneumonia.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Specific pathogen-free transgenic KC mice, CC51+/+ (2–3-mo-old males and females), on a B6D2 background were generated from a microinjection of fertilized eggs carrying the KC transgene in their genome. The expression of the KC transgene was localized to the lung by incorporating regulating elements from the CC10 gene, which encodes for a 10-kDa protein of unknown function that is produced by nonciliated bronchial epithelial cells (Clara cells) (25, 26, 27). Age- and gender-matched wild-type (wt) B6D2 mice of the same species as the transgenic mice served as control animals. All mice were housed under specific pathogen-free conditions within the animal care facility at the University of Michigan until the day of sacrifice.
K. pneumoniae inoculation
We chose to use K. pneumoniae strain 43816, serotype
2 (American Type Culture Collection, Manassas, VA) in our studies, as
this strain has been shown to induce an impressive inflammatory
response in mice (13, 28, 29). K. pneumoniae was grown in
tryptic soy broth (Difco, Detroit, MI) for 18 h at 37°C. The
concentration of bacteria in the broth was determined by measuring the
amount of absorbance at 600 nm. A standard of absorbancies based on
known CFU was used to calculate the inoculum concentration. A dose of
3 x 103 organisms per transgenic or wt mouse was
chosen, since this dose allowed for the development of substantial
inflammation by 36 to 48 h without excessive mortality at that
timepoint. Animals were anesthetized i.p. with 
1.8 to 2 mg of
pentobarbital per animal. The trachea was exposed, and 30 µl of
inoculum or saline was administered via a sterile 26-gauge needle. The
skin incision was closed with surgical staples.
Bronchoalveolar lavage (BAL)
Bronchoalveolar lavage was performed to obtain BAL cells. The trachea was exposed and intubated using a 1.7-mm OD polyethylene catheter. BAL was performed by instilling PBS containing 5 mM EDTA in 1-ml aliquots. Approximately 5 ml of lavage fluid was retrieved per mouse. Cytospins were subsequently prepared from BAL cells and stained with Diff-Quick (Baxter, McGaw Park, IL); next, differential counts were determined.
Myeloperoxidase (MPO) assay
Lung MPO activity (as a measure of neutrophil quantity) was determined using a method that has been described previously (13). Briefly, lungs were homogenized in 2 ml of a solution containing 50 mM potassium phosphate (pH 6.0) with 5% hexadecyltrimethylammonium bromide and 5 mM EDTA. The resultant homogenate was sonicated and centrifuged at 12,000 x g for 15 min. The supernatant was then mixed with assay buffer to a 1:15 ratio and read at 490 nm. MPO units were calculated as the change in absorbance over time.
Lung histologic evaluation
Mice were sacrificed by carbon dioxide inhalation. The pulmonary vasculature was perfused with 4% paraformaldehyde in PBS via the right ventricle. Lungs were then excised en bloc and inflation-fixed in 4% paraformaldehyde in PBS. The lungs were then embedded in paraffin, and sections were cut and stained with hematoxylin and eosin using standard techniques.
Lung harvesting for cytokine analysis
Mice were sacrificed by carbon dioxide inhalation at designated timepoints, and blood was collected by orbital bleeding or direct cardiac puncture. Whole lungs were then harvested for assessment of the various cytokine protein levels. Before lung removal, the pulmonary vasculature was perfused via the right ventricle with 1 ml of PBS containing 5 mM EDTA. After removal, whole lungs were homogenized in 1.5 ml of complete protease inhibitor lysis buffer (Boehringer Mannheim, Indianapolis, IN). Homogenates were incubated on ice for 30 min and then centrifuged at 2500 rpm for 10 min. Supernatants were collected, passed through a 0.45-µ filter (Gelman Sciences, Ann Arbor, MI), and then stored at -20°C for an assessment of cytokine levels.
Determination of plasma and lung K. pneumoniae CFU
At the time of sacrifice, plasma was collected, the right ventricle was perfused with 1 ml PBS, and then the lungs were removed aseptically and placed in 3 ml of sterile saline. The tissues were subsequently homogenized with a tissue homogenizer under a vented hood. The lung homogenates were placed on ice, and serial 1/10 dilutions were made. A total of 10 µl of each dilution was plated on soy-based blood agar plates (Difco) and incubated for 18 h at 37°C; colonies were counted after the incubation.
Murine cytokine ELISA
Murine TNF-, IFN-, IL-12, IL-10, MIP-2, MCP-1/JE, and KC
were quantitated using a modification of a double ligand method as
described previously (13). Briefly, flat-bottom, 96-well microtiter
plates (Immuno-Plate I 96-F, Nunc, Fisher Scientific, Itasca,
IL) were coated with 50 µl/well of rabbit Ab against the
various cytokines (1 µg/ml in 0.6 M NaCl, 0.26 M
H3BO4, and 0.08 M NaOH, pH 9.6) for 16 h
at 4°C and then washed with PBS (pH 7.5) plus 0.05% Tween 20 (wash
buffer). Microtiter plate nonspecific binding sites were blocked with
2% BSA in PBS and incubated for 90 min at 37°C. The plates were
rinsed four times with wash buffer, and diluted (neat and 1/:10)
cell-free supernatants (50 µl) in duplicate were added; next, the
plates were incubated for 1 h at 37°C. The plates were washed
four times, 50 µl/well of biotinylated rabbit Abs against the
specific cytokines was added (3.5 µg/ml in PBS (pH 7.5) 0.05% Tween
20, and 2% FCS), and the plates were incubated for 30 min at 37°C.
Next, the plates were washed four times, streptavidin-peroxidase
conjugate (Bio-Rad, Richmond, CA) was added, and the plates were
incubated for 30 min at 37°C. The plates were washed four additional
times, and chromogen substrate (Bio-Rad) was added. We incubated the
plates at room temperature to the desired extinction, and the reaction
was terminated with 50 µl/well of 3 M H2SO4
solution. The plates were read at 490 nm in an ELISA reader. Standards
were one-half log dilutions of recombinant murine cytokines from
1 pg/ml to 100 ng/ml. This ELISA method consistently detected murine
cytokine concentrations that were >25 pg/ml. The ELISA did not
cross-react with IL-1, IL-2, IL-4, or IL-6. In addition, the ELISA did
not cross-react with other members of the murine chemokine family,
including murine RANTES or epithelial neutrophil-activating
protein-78.
Statistical analysis
Data were analyzed by a Macintosh computer using the
Statview II statistical package (Abacus Concepts, Berkeley, CA). The
survival data were compared using by 
2 analysis. All
other data were expressed as the mean ± SEM and compared using a
two-tailed Student’s t test. Data were considered
statistically significant if p values were <0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In uninfected mice at baseline, there was a significant quantity
of KC detected within the lungs of KC-transgenic mice, whereas no KC
was detected in the lungs of wt control animals (Fig. 1
, p < 0.001). The i.t.
administration of K. pneumoniae (3 x 103
CFU) resulted in a time-dependent production of KC in the lungs of both
KC-transgenic and wt mice as determined by a specific ELISA. Maximal
lung KC levels peaked at 48 h following bacterial inoculation; the
levels of KC were significantly greater in transgenic mice compared
with the levels observed in wt controls (p =
0.01). In both KC-transgenic mice and wt control mice, the levels of KC
remained elevated at 6 days postinoculation compared with noninfected
controls. No increase in KC was observed in the blood of either
infected KC-transgenic or wt mice compared with noninfected
counterparts (data not shown).
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Given the potent neutrophil chemotactic effects of KC, we next
sought to determine whether compartmentalized overexpression of KC
within the lung would provide protective effects in animals challenged
with intrapulmonary K. pneumoniae. For these studies,
KC-transgenic and wt mice were administered K. pneumoniae
i.t. at 3 x 103 CFU, which us an approximately
LD80–90 dose in wt mice. At 48 h after K.
pneumoniae inoculation, both transgenic and wt animals developed
signs of pneumonia, including lethargy and ruffled fur. However,
survival was significantly greater in KC-transgenic mice that had been
challenged with K. pneumoniae, with 80% long-term survival
observed in this group compared with only 10% survival in the wt
infected control mice (Fig. 2).
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To determine whether the observed improvement in survival in
KC-transgenic mice was due to an enhancement in bacterial clearance,
transgenic mice and wt control mice were administered K.
pneumoniae (3 x 103 CFU) i.t., and lungs and
plasma were harvested at 24 and 48 h postinoculation. At 24
h, wt animals had an approximately eightfold greater number of K.
pneumoniae CFU in the lung compared with KC-transgenic animals
that had been challenged with K. pneumoniae (data not
shown). In addition, 66% of wt animals were bacteremic by 24 h,
whereas no mice overexpressing KC were bacteremic at this timepoint
after K. pneumoniae administration. By 48 h, a more
than fourfold increase in K. pneumoniae CFU in blood was
noted in wt control mice compared with transgenic KC mice
(p < 0.05). An even more striking 13-fold
increase in K. pneumoniae CFU was noted in the lungs
(p < 0.005) of wt animals compared with mice
overexpressing KC at the latter timepoint (Table I). These results indicate that KC
overexpression significantly augmented effective bacterial clearance in
the lung and limited the dissemination of the organism to the
bloodstream.
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To determine whether the improvement in bacterial clearance in
transgenic KC mice was due to alterations in the recruitment of
inflammatory cells to the airspace, KC-transgenic animals or wt
controls were challenged with K. pneumoniae, and BAL was
performed at 48 h postinoculation. This timepoint was chosen
because a maximum influx of neutrophils in response to the i.t.
administration of K. pneumoniae occurs at 48 to 72 h
postchallenge (11, 17). In uninfected mice, no differences in the
percent or absolute number of total BAL cells, alveolar M, or
lymphocytes was noted in KC-transgenic mice compared with control
animals. However, a significant increase in the percent neutrophils
(12.2 ± 4.1% KC-transgenic vs 0.17 ± 0.17% wt;
p < 0.05) and total neutrophils (10.8 ± 3.1
x 104 KC-transgenic vs 0.67 ± 0.67 x
104 wt; p < 0.05) was observed in
KC-transgenic mice compared with wt mice. The intrapulmonary
administration of K. pneumoniae in transgenic mice resulted
in a marked increase in the total number of cells; this increase was
largely due to a substantial increase in BAL fluid neutrophils
(p < 0.05) (Fig. 3). Challenge with K.
pneumoniae did not significantly alter the numbers of BAL fluid
M or lymphocytes in either the transgenic or wt mice. To confirm the
BAL findings, lungs were harvested at 48 h postinoculation with
K. pneumoniae or saline and assayed for lung MPO activity.
In animals that were challenged with K. pneumoniae, there
was a significant increase in lung MPO activity in the KC-transgenic
mice compared with wt controls (data not shown). These results indicate
that the augmented host response observed in KC-transgenic mice is
associated with an enhanced influx of neutrophils into the airspace.
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The transgenic expression of KC using a Clara cell-specific
promoter has been shown to result in a predominant expression of KC
within the terminal bronchioles, with lesser quantities observed in
larger airways, including bronchi (25). Given this anatomic
distribution of KC transgene expression, we subsequently wanted to
determine whether differences in the distribution of the inflammatory
response to Klebsiella challenge were observed in
KC-transgenic mice compared with wt control animals. Little to no
pulmonary inflammation was observed in either KC or wt mice at
48 h or at 7 or 14 days after the i.t. administration of saline
(data not shown). At 48 h following the administration of 3
x 103 CFU of K. pneumoniae, the lungs of
infected wt mice showed focal consolidation with an infiltration of
moderate numbers of neutrophils into the airspaces; some airspaces
contained large numbers of extracellular K. pneumoniae (Fig. 4A). In contrast, the lungs of
KC mice contained focal areas of dense airspace neutrophil accumulation
and no visible extracellular bacteria. In addition, neutrophil
aggregates were observed in the terminal airways that were contained
and adjacent to areas of alveolar consolidation (Fig. 4B).
By 7 days after Klebsiella administration, a partial
resolution of the alveolar inflammatory cell infiltrates was observed
in transgenic mice, although persistent neutrophil aggregates within
distal airways were also observed (data not shown).
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Subsequent experiments were performed to determine whether the
compartmentalized overexpression of KC resulted in an altered
production of important pro- and antiinflammatory cytokines. Several
cytokines have been shown to be crucial to antibacterial host defense
in Gram-negative infection, particularly TNF-, T1 phenotype
cytokines (IFN- and IL-12), the T2 phenotype cytokine IL-10, and
members of the C-X-C and the C-C chemokine families (MIP-2 and
MCP-1/JE, respectively). The baseline levels of TNF-, IFN-,
IL-12, IL-10, MIP-2, and MCP-1/JE were low or undetectable in the
uninfected lungs of KC-transgenic animals, and no differences were seen
in these levels compared with wt animals. The i.t. administration
of K. pneumoniae resulted in a maximal expression of
cytokines at 48 h in both KC-transgenic and wt mice, representing
at least a fourfold increase in the protein levels of all cytokines
assessed (TNF-, IFN-, IL-12, IL-10, MCP-1/JE, and MIP-2), when
compared with the expression seen in lung homogenates prepared from
saline-treated control animals. There were no differences in the
protein levels of TNF-, IFN-, IL-12, IL-10, or MCP-1/JE in
transgenic infected mice compared with wt infected mice (data not
shown). However, the expression of MIP-2 in wt mice was delayed
compared with the expression of KC; maximal lung MIP-2 levels were
noted at 72 h after K. pneumoniae challenge, whereas
maximal KC levels were noted at 24 h postchallenge and decreased
toward baseline thereafter (Fig. 5).
Furthermore, maximal MIP-2 levels tended to be lower or were
significantly decreased in KC-transgenic mice at 48 and 72 h after
bacterial challenge, respectively, compared with wt infected mice
(p = 0.08 and 0.01, respectively). These
results suggest that KC does not appear to regulate the expression of
the other relevant cytokines involved in host defense against
Klebsiella pneumonia. However, the overabundance of KC in
transgenic mice was associated with a reduction in the expression of
another C-X-C chemokine, MIP-2.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this study, we used transgenic mice in which the KC gene was fused
to a Clara cell-specific promoter (26, 27), which resulted in an
enhanced constitutive and time-dependent expression of KC within the
lungs during the course of Klebsiella pneumonia. This
transgenic model allowed us to modulate a single chemokine, KC, in our
in vivo bacterial pneumonia model to examine whether the overexpression
of KC in these transgenic mice would affect overall antibacterial host
defense. The enhancement of KC significantly improved survival when
compared with wt control mice and was a result of increased bacterial
clearance. The mechanism for enhanced bacterial clearance is likely
attributable to significantly augmented neutrophil recruitment, as we
observed a greater magnitude of neutrophil influx into the airspaces of
KC-transgenic mice after K. pneumoniae challenge compared
with wt controls. Given that the predominant site of KC transgene
expression in transgenic mice is the terminal bronchioles (26, 27), it
appears that the enhanced alveolar PMN influx results from the
spillover of KC into the airspace. We also observed neutrophil
aggregates in the terminal airways in proximity to the sites of
airspace inflammation; this finding was distinctly unique to
KC-transgenic animals and probably reflects site-directed PMN migration
as a result of KC production from the airway epithelium. We cannot
exclude a concomitant effect on neutrophil activation, as KC and other
C-X-C chemokines have been shown to activate PMN effector cell
activities, including respiratory burst and antimicrobial activity in
vitro (8, 9, 20). There is also a modest but significant BAL
neutrophilia in KC-transgenic animals at baseline, and it is plausible
the these neutrophils facilitate the initial clearance of K.
pneumoniae after intrapulmonary challenge. Although alveolar M
and other M populations have been shown to play a critical role in
the clearance of Gram-negative organisms from the lung (30), there is
no evidence to suggest that KC or other C-X-C chemokines have direct
stimulatory effects on M antimicrobial activity.
While the enhanced production of KC in KC-transgenic mice provided protective effects in murine Klebsiella pneumonia, we also observed a substantial early induction of KC in wt mice in response to the intrapulmonary delivery of K. pneumoniae. Indeed, the marked beneficial effect of compartmentalized KC overexpression taken together with the fact that KC is maximally expressed early (at 24 h) in the host response suggests that KC may play a more important role in antibacterial host defense than MIP-2, which is expressed in a delayed fashion (maximal at 72 h in wt mice); the neutralization of MIP-2 during the evolution of Klebsiella pneumonia resulted in relatively modest although significant reductions in bacterial clearance and survival (13). However, in vivo neutralization studies have not been possible due to the lack of an appropriate anti-murine KC-neutralizing Ab and of KC-deficient mice.
Unlike C-C chemokines (31, 32), there is no evidence to support a role
of C-X-C chemokines in directly regulating the expression of other
cytokines. Similarly, the compartmentalized overexpression of KC in
infected mice did not alter the expression of the cytokines TNF-,
IFN-, IL-12, and IL-10 compared with wt animals that had been
challenged with K. pneumoniae, suggesting that KC likely
occupies a terminal and distal position in the overall cytokine network
involved in the host defense cascade. However, we did observe a
significant decrease in the inducible, but not the constitutive,
expression of MIP-2 in KC transgenic mice that were administered
K. pneumoniae compared with wt animals. This observation
raises the possibility that a substantial redundancy in chemokine
responses exists, such that the overexpression of a specific chemokine
may obviate the need for (or directly inhibit) the production of
another family member with similar biologic activities. The attenuated
expression of one chemokine by the overexpression of other functionally
and structurally related chemokines has not been reported previously.
The compartmentalized augmentation of KC within the lung improved the innate host defense system against K. pneumoniae in our murine model of bacterial pneumonia. Given the emergence of highly resistant bacterial pathogens and the increasing population of immunocompromised hosts (1, 2, 3, 33), the treatment of bacterial infection has and will continue to be quite difficult. Therefore, the immunomodulation of host responses, especially if delivered in a site-directed fashion, may prove to be an attractive adjuvant to conventional antibiotic therapy. Because C-X-C chemokines appear to occupy a distal position in the cytokine network and exhibit more neutrophil chemotactic than activating effects, these favorable characteristics suggest that the augmentation of chemokines such as KC may potentially improve the clinical outcome of patients with severe bacterial pneumonias while limiting the potentially serious adverse effects that are mediated by overzealous leukocyte activation and/or the regulation of other potentially injurious cytokines.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Theodore J. Standiford, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, 6301 MSRBIII, Box 0642, Ann Arbor, Michigan 48109-0642.
3 Abbreviations used in this paper: M, macrophage(s); MIP, macrophage inflammatory protein; MCP-1/JE, monocyte chemoattractant protein-1; i.t., intratracheal; PMN, polymorphonuclear leukocyte; wt, wild-type; BAL, bronchoalveolar lavage; MPO, myeloperoxidase.
Received for publication January 20, 1998. Accepted for publication May 5, 1998.
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S. J. Skerrett, H. D. Liggitt, A. M. Hajjar, R. K. Ernst, S. I. Miller, and C. B. Wilson Respiratory epithelial cells regulate lung inflammation in response to inhaled endotoxin Am J Physiol Lung Cell Mol Physiol, July 1, 2004; 287(1): L143 - L152. [Abstract] [Full Text] [PDF]
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N. A. Maris, K. F. van der Sluijs, S. Florquin, A. F. de Vos, J. M. Pater, H. M. Jansen, and T. van der Poll Salmeterol, a {beta}2-receptor agonist, attenuates lipopolysaccharide-induced lung inflammation in mice Am J Physiol Lung Cell Mol Physiol, June 1, 2004; 286(6): L1122 - L1128. [Abstract] [Full Text] [PDF]
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 B. Liu, I. Mori, M. J. Hossain, L. Dong, K. Takeda, and Y. Kimura Interleukin-18 improves the early defence system against influenza virus infection by augmenting natural killer cell-mediated cytotoxicity J. Gen. Virol., February 1, 2004; 85(2): 423 - 428. [Abstract] [Full Text] [PDF]
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M. Pichavant, Y. Delneste, P. Jeannin, C. Fourneau, A. Brichet, A.-B. Tonnel, and P. Gosset Outer Membrane Protein A from Klebsiella pneumoniae Activates Bronchial Epithelial Cells: Implication in Neutrophil Recruitment J. Immunol., December 15, 2003; 171(12): 6697 - 6705. [Abstract] [Full Text] [PDF]
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J. C. Leemans, M. Heikens, K. P. M. van Kessel, S. Florquin, and T. van der Poll Lipoteichoic Acid and Peptidoglycan from Staphylococcus aureus Synergistically Induce Neutrophil Influx into the Lungs of Mice Clin. Vaccine Immunol., September 1, 2003; 10(5): 950 - 953. [Abstract] [Full Text] [PDF]
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C. E. O. Baleeiro, S. E. Wilcoxen, S. B. Morris, T. J. Standiford, and R. Paine III Sublethal Hyperoxia Impairs Pulmonary Innate Immunity J. Immunol., July 15, 2003; 171(2): 955 - 963. [Abstract] [Full Text] [PDF]
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N. Mukaida Pathophysiological roles of interleukin-8/CXCL8 in pulmonary diseases Am J Physiol Lung Cell Mol Physiol, April 1, 2003; 284(4): L566 - L577. [Abstract] [Full Text] [PDF]
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X. Zeng, T. A. Moore, M. W. Newstead, R. Hernandez-Alcoceba, W. C. Tsai, and T. J. Standiford Intrapulmonary Expression of Macrophage Inflammatory Protein 1{alpha} (CCL3) Induces Neutrophil and NK Cell Accumulation and Stimulates Innate Immunity in Murine Bacterial Pneumonia Infect. Immun., March 1, 2003; 71(3): 1306 - 1315. [Abstract] [Full Text] [PDF]
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G. B. Huffnagle Investigating Invasive Aspergillosis Am. J. Respir. Crit. Care Med., November 1, 2002; 166(9): 1159 - 1160. [Full Text] [PDF]
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B. Mehrad, M. Wiekowski, B. E. Morrison, S.-C. Chen, E. C. Coronel, D. J. Manfra, and S. A. Lira Transient Lung-Specific Expression of the Chemokine KC Improves Outcome in Invasive Aspergillosis Am. J. Respir. Crit. Care Med., November 1, 2002; 166(9): 1263 - 1268. [Abstract] [Full Text] [PDF]
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F. N. Lauw, J. Branger, S. Florquin, P. Speelman, S. J. H. van Deventer, S. Akira, and T. van der Poll IL-18 Improves the Early Antimicrobial Host Response to Pneumococcal Pneumonia J. Immunol., January 1, 2002; 168(1): 372 - 378. [Abstract] [Full Text] [PDF]
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D. M. Lindell, T. J. Standiford, P. Mancuso, Z. J. Leshen, and G. B. Huffnagle Macrophage Inflammatory Protein 1{alpha}/CCL3 Is Required for Clearance of an Acute Klebsiella pneumoniae Pulmonary Infection Infect. Immun., October 1, 2001; 69(10): 6364 - 6369. [Abstract] [Full Text] [PDF]
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 M. J. SCHULTZ, A. W. RIJNEVELD, S. FLORQUIN, P. SPEELMAN, S. J. H. VAN DEVENTER, and T. VAN DER POLL Impairment of host defence by exotoxin A in Pseudomonas aeruginosa pneumonia in mice J. Med. Microbiol., September 1, 2001; 50(9): 822 - 827. [Abstract] [Full Text] [PDF]
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 D. G. Remick, L. B. Green, D. E. Newcomb, S. J. Garg, G. L. Bolgos, and D. R. Call CXC Chemokine Redundancy Ensures Local Neutrophil Recruitment during Acute Inflammation Am. J. Pathol., September 1, 2001; 159(3): 1149 - 1157. [Abstract] [Full Text] [PDF]
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I. Fillion, N. Ouellet, M. Simard, Y. Bergeron, S. Sato, and M. G. Bergeron Role of Chemokines and Formyl Peptides in Pneumococcal Pneumonia-Induced Monocyte/Macrophage Recruitment J. Immunol., June 15, 2001; 166(12): 7353 - 7361. [Abstract] [Full Text] [PDF]
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M. E. Sewnath, D. P. Olszyna, R. Birjmohun, F. J. W. ten Kate, D. J. Gouma, and T. van der Poll IL-10-Deficient Mice Demonstrate Multiple Organ Failure and Increased Mortality During Escherichia coli Peritonitis Despite an Accelerated Bacterial Clearance J. Immunol., May 15, 2001; 166(10): 6323 - 6331. [Abstract] [Full Text] [PDF]
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S.-C. Chen, B. Mehrad, J. C. Deng, G. Vassileva, D. J. Manfra, D. N. Cook, M. T. Wiekowski, A. Zlotnik, T. J. Standiford, and S. A. Lira Impaired Pulmonary Host Defense in Mice Lacking Expression of the CXC Chemokine Lungkine J. Immunol., March 1, 2001; 166(5): 3362 - 3368. [Abstract] [Full Text] [PDF]
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D. R. Call, J. A. Nemzek, S. J. Ebong, G. L. Bolgos, D. E. Newcomb, and D. G. Remick Ratio of Local to Systemic Chemokine Concentrations Regulates Neutrophil Recruitment Am. J. Pathol., February 1, 2001; 158(2): 715 - 721. [Abstract] [Full Text] [PDF]
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P. G. Knott, P. R. Gater, P. J. Dunford, M. E. Fuentes, and C. P. Bertrand Rapid Up-Regulation of CXC Chemokines in the Airways after Ag-Specific CD4+ T Cell Activation J. Immunol., January 15, 2001; 166(2): 1233 - 1240. [Abstract] [Full Text] [PDF]
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 M. J. Schultz, P. Speelman, C. E. Hack, W. A. Buurman, S. J. H. van Deventer, and T. van der Poll Intravenous infusion of erythromycin inhibits CXC chemokine production, but augments neutrophil degranulation in whole blood stimulated with Streptococcus pneumoniae J. Antimicrob. Chemother., August 1, 2000; 46(2): 235 - 240. [Abstract] [Full Text] [PDF]
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W. C. Tsai, R. M. Strieter, B. Mehrad, M. W. Newstead, X. Zeng, and T. J. Standiford CXC Chemokine Receptor CXCR2 Is Essential for Protective Innate Host Response in Murine Pseudomonas aeruginosa Pneumonia Infect. Immun., July 1, 2000; 68(7): 4289 - 4296. [Abstract] [Full Text] [PDF]
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A. G. Frick, T. D. Joseph, L. Pang, A. M. Rabe, J. W. St. Geme III, and D. C. Look Haemophilus influenzae Stimulates ICAM-1 Expression on Respiratory Epithelial Cells J. Immunol., April 15, 2000; 164(8): 4185 - 4196. [Abstract] [Full Text] [PDF]
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T. A. Moore, M. W. Newstead, R. M. Strieter, B. Mehrad, B. L. Beaman, and T. J. Standiford Bacterial Clearance and Survival Are Dependent on CXC Chemokine Receptor-2 Ligands in a Murine Model of Pulmonary Nocardia asteroides Infection J. Immunol., January 15, 2000; 164(2): 908 - 915. [Abstract] [Full Text] [PDF]
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B. Mehrad, R. M. Strieter, T. A. Moore, W. C. Tsai, S. A. Lira, and T. J. Standiford CXC Chemokine Receptor-2 Ligands Are Necessary Components of Neutrophil-Mediated Host Defense in Invasive Pulmonary Aspergillosis J. Immunol., December 1, 1999; 163(11): 6086 - 6094. [Abstract] [Full Text] [PDF]
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 R. M. Strieter, S. L. Kunkel, M. P. Keane, and T. J. Standiford Chemokines in Lung Injury: Thomas A. Neff Lecture Chest, July 1, 1999; 116 (2009): 103S - 110S. [Full Text]
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M. J. Schultz, A. W. Rijneveld, S. Florquin, C. K. Edwards, C. A. Dinarello, and T. van der Poll Role of interleukin-1 in the pulmonary immune response during Pseudomonas aeruginosa pneumonia Am J Physiol Lung Cell Mol Physiol, February 1, 2002; 282(2): L285 - L290. [Abstract] [Full Text] [PDF]
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