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*
Departments of Pathology and
Division of Pulmonary and Critical Care, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109; and
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94309
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, eotaxin, or MCP-3 were
instilled into the airways of normal mice or when mast cells were
treated in vitro. Airway hyperreactivity was mediated by MCP-1 through
CCR2 because allergen-induced as well as direct MCP-1 instilled-induced
changes in airway hyperreactivity were significantly attenuated in CCR2
-/- mice. The neutralization of MCP-1 in allergic animals
and instillation of MCP-1 in normal animals was related to leukotriene
C4 levels in the bronchoalveolar lavage and was directly
induced in pulmonary mast cells by MCP-1. Thus, these data identify
MCP-1 and CCR2 as potentially important therapeutic targets for the
treatment of hyperreactive airway disease. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A number of studies have linked the induction of airway reactivity in atopic asthma with the presence of mononuclear cell and eosinophilic inflammation in the lung. Earlier work from our group demonstrated that inhibition of monocyte chemotactic protein-1 (MCP-1)3 in a murine model of Schistosoma mansoni egg Ag-induced allergic airway inflammation attenuated the associated mononuclear cell infiltration and airway hyperreactivity (27). MCP-1 is not a potent eosinophil chemoattractant but has been shown to be an important mediator of monocyte and CD4+/CD8+ lymphocyte recruitment (28, 29, 30). In addition, this chemokine also is a potent histamine-releasing agent for basophils and mast cells (31, 32, 33, 34). In this study, we have investigated the relationship between MCP-1 and the induction of bronchial hyperreactivity using a cockroach Ag-induced model of allergic airway disease. We present evidence that MCP-1 is critically involved in the induction of changes in airway resistance in allergic and normal mice through the activation of local mast cell populations.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female CBA/J mice were purchased from The Jackson Laboratory (Bar Harbor, ME) and were maintained under standard pathogen-free conditions. CCR2-targeted mice (50:50 129SV:C57BL6) (35) were bred in the University of Michigan (Ann Arbor, MI) animal facilities.
Measurement of airway hyperreactivity
Airway hyperreactivity was measured using a Buxco mouse
plethysmograph, which is specifically designed for the low tidal
volumes (Buxco, Troy, NY) as previously described (27).
Briefly, the mouse to be tested was anesthetized with sodium
pentobarbital and intubated via cannulation of the trachea with an
18-gauge metal tube. The mouse was subsequently ventilated with a
Harvard pump ventilator (tidal volume, 0.4 ml; frequency, 120
breaths/min; positive end-expiratory pressure, 2.5–3.0 cm
H2O), and the tail vein was cannulated with a
2-gauge needle for injection of the methacholine challenge. The
plethysmograph was sealed, and readings were monitored by computer.
Because the box was a closed system, a change in lung volume was
represented by a change in box pressure
(Pbox) which was measured by a
differential transducer. The system was calibrated with a syringe that
delivered a known volume of 2 ml. A second transducer was used to
measure the pressure swings at the opening of the trachea tube
(Paw), referenced to the body box
(i.e., pleural pressure), and to provide a measure of transpulmonary
pressure (Ptp =
Paw -
Pbox). The trachea
transducer was calibrated at a constant pressure of 20 cm
H2O. Resistance is calculated by the Buxco
software by dividing the change in pressure
(Ptp) by the change in flow
(F)
(
Ptp/F; units =
centimeters H2O/ml/s) at two time points from the
volume curve based on a percentage of the inspiratory volume. The mouse
was attached to the box and ventilated for 5 min before acquiring
readings. Once baseline levels were stabilized and initial readings
were taken, a methacholine challenge was given via the cannulated tail
vein. After determination of a dose-response curve (0.001 to 0.5 mg),
an optimal dose was chosen, 0.1 mg of methacholine. This dose was used
throughout the rest of the experiments in this study. After the
methacholine challenge, the response was monitored, and for each animal
the peak airway resistance minus the baseline resistance was recorded
as a measure of change in airway reactivity. Data are means ± SE
peak change in airway resistance (centimeters
H2O/ml/s) for n animals.
Sensitization and induction of the airway response
Normal CBA/J mice were sensitized and challenged with cockroach Ag to induce a Th2-type response. Briefly, mice were immunized i.p. with 10 µg cockroach allergen (Bayer Corporation, Elkhart, IN) in IFA on day 0. On day 14, the mice were given an intranasal challenge of 10 µg cockroach allergen in 10 µl diluent to localize the response to the airway. This initial intranasal challenge with Ag induced little cellular infiltrate into the lungs of the mice on histological examination. Mice were then rechallenged 6 days later by intratracheal administration of 10 µg cockroach allergen in 50 µl sterile PBS or with PBS alone (vehicle). In depletion studies, mice were pretreated i.p. with polyclonal anti-murine MCP-1 (JE) Abs at 1 h before intratracheal challenge (106/ml titer, 0.5 ml).
Direct intratracheal instillations of recombinant murine chemokines
Normal CBA/J mice were anesthetized with ketamine (Bayer), the trachea exposed and preholed with an 24-gauge needle before direct instillation of 100 ng (50 µl) endotoxin-free recombinant murine CC chemokines (R&D Systems, Rochester, MN) into the airways. The animals were allowed to recover before lung function assessment.
Analysis of leukocyte accumulation in the airway
To assess migration of cells into the airway, we subjected the mice to a 1-ml bronchoalveolar lavage (BAL) with PBS (PBS) containing 25 mM EDTA at various time points postchallenge. The cells were then dispersed using a cytospin (Shandon Scientific, Runcorn, U.K.) and differentially stained with Wright-Giemsa stain. The cell types (mononuclear phagocytes, lymphocytes, neutrophils, and eosinophils) were expressed as a percentage based on 200 total cells counted/sample. Morphometric analysis of eosinophils was accomplished by examining 100 high power fields (x1000 magnification) in histological sections from each lung.
Isolation, culture, and activation of primary mast cells
Murine bone marrow cells were removed from isolated femurs by
cannulating one end with a 26-gauge needle and washing with 2 ml of
DMEM containing 1 mM D-glutamic acid, 10 mM HEPES,
antibiotics, and 10% FCS with 10% rat T cell-stimulated culture
supplement (Collaborative Biomedical Products, Bedford, MA). The cells
were cultured in the above medium, supplemented with 0.1 ng/ml murine
stem cell factor (SCF, Sigma) for 2–3 wk and passaged every 3 days.
Pulmonary mast cells were isolated from the upper airways by cutting
the tissue into 
3-mm3 pieces and gently
teasing apart with fine forceps before being cultured in medium
containing murine SCF in a manner similar to that for the bone marrow
cells as previously described (36). Briefly, the pulmonary
mast cells were >95% c-kit positive by flow cytometry and
could be induced to release histamine using classical degranulating
reagents, such as 48/80 and SCF. Cells were stimulated at 1 x
106/ml in DMEM without murine SCF for 1 h
using recombinant murine chemokines (50 nM). As a positive control,
some cells were sensitized with 1 µg/ml monoclonal
anti-DNP-albumin IgE (Sigma) for 3 h, washed twice with
medium, and incubated for 1 h with 100 ng/ml DNP-albumin.
Quantitation of MCP-1 by ELISA
The level of MCP-1 protein in whole lung homogenate was measured
by specific ELISA with a modification of a double-ligand method as
previously described (27). Briefly, lung tissue was
homogenized on ice with a tissue tearer (Biospec Products, Racine, WI)
for 30 s in 1 ml PBS containing 0.05% Triton X-100. The resulting
supernatant was isolated after centrifugation (10,000 x
g). To measure MCP-1 levels in this supernatant, flat-bottom
96-well microtiter plates (Nunc Immunoplate I 96-F, Roskilde, Denmark)
were coated with 50 µl/well rabbit anti-MCP-1 polyclonal Abs for
16 h at 4°C and then washed with PBS and 0.05% Tween 20.
Nonspecific binding sites were blocked with 2% BSA in PBS and
incubated for 90 min at 37°C. Plates were rinsed four times with wash
buffer, and cell-free supernatants were added (neat and 1/10) followed
by an incubation for 1 h at 37°C. 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. Plates were washed
again, and chromogen substrate (Bio-Rad) was added and incubated at
room temperature to the desired extinction. The reaction was terminated
with 50 µl/well 3 M H2SO4
solution, and the plates were read at 490 nm in an ELISA reader.
Standards were 0.5-log dilutions of recombinant murine
macrophage-inflammatory protein-1 (MIP-1) or eotaxin from 1 pg/ml
to 100 ng/ml. ELISAs for these chemokines did not cross-react with each
other, MIP-1, eotaxin, recombinant murine MCP-3, murine MCP-5,
MIP-1ß, MIP-2, KC IL-6, or murine TNF.
Assessment of histamine and leukotriene C4 (LTC4) levels by specific ELISA
Cell-free lavage fluid or culture supernatants were immediately frozen before analysis by specific ELISA for histamine (Immunotech, Marseille, France) and/or LTC4 (Caymen Chemical, Ann Arbor, MI) according to the manufacturers’ instructions, using a 1/3 dilution in PBS for BAL samples.
Statistics
Statistical significance was determined by unpaired Student’s t test with p values < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Sensitization and challenge with cockroach Ag induced
time-dependent changes in airway resistance, peaking at 8 h and
sustained at 24 and 48 h postchallenge (Fig. 1
A). Airway hyperreactivity
did not follow the temporal accumulation of peribronchial eosinophilia,
which increased 72 h postchallenge (Fig. 1B). We have
previously proposed that MCP-1, which does not have chemotactic
activity for eosinophils, may be a key mediator in induction of airway
hyperreactivity (27). Analysis of whole lung homogenates
by specific ELISA revealed increases in chemokine levels for MCP-1,
peaking at 8 h and declining by 24 h (Fig. 2). Similar patterns of protein
expression were also observed for other CC chemokines, including
eotaxin and MCP-3 (data not shown).
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compared with NRS time-matched controls. Thus, MCP-1 appears to play a
critical role in the development of allergen-induced airway
hyperreactivity.
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Previous studies have demonstrated that MCP-1 can induce
degranulation of mast cells (34). Analysis of sensitized
CBA/J mice 8 h post-cockroach allergen challenge, the time of peak
MCP-1 production, revealed that anti-MCP-1 Ab pretreatment reduced
histamine levels in the BAL compared with NRS controls (Fig. 4). Because the most likely source of
histamine in the mouse lung is from resident mast cells, cultures of
isolated murine pulmonary and bone marrow mast cells were stimulated
with recombinant murine MCP-1 (JE), and supernatants were analyzed at
1 h for histamine release. Murine MCP-1 (50 nM) induced
degranulation of the pulmonary mast cells (Fig. 5A) but had no effect on bone
marrow-derived mast cells (Fig. 5B) even though these cells
clearly degranulated through IgE cross-linking. These latter results
suggest that mast cell maturation may be relevant to MCP-1
responsiveness. In comparison, no significant mast cell
histamine-releasing activity was observed from mast cells after
stimulation with recombinant murine MCP-3, MIP-1, or eotaxin, above
vehicle control levels.
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Because MCP-1 can directly induce mast cell activation and mast
cells appear to be involved in asthma, we assessed the ability of these
chemokines to influence airway resistance in the absence of airway
inflammation. We instilled 100 ng murine MCP-1, MCP-3, MCP-5, eotaxin,
MIP-1, or vehicle into the lung of normal, nonsensitized CBA/J mice.
At 1 h after administration, MCP-1-instilled mice demonstrated a
significant increase in airway resistance (Fig. 6A), which was dose dependent
(Fig. 6B). MCP-5 also appeared to induce hyperreactivity,
although to a much lesser extent. Interestingly, both of these
chemokines bind to and activate CCR2. In contrast, MCP-3, mMIP-1,
and eotaxin had no significant effect on lung function compared with
vehicle-instilled animals. This ability of MCP-1 to induce a
hyperreactive response in mice 1 h postinstillation was associated
with increased levels of histamine in the BAL (57.1 ± 8.4 nM
compared with 28.7 ± 4.5 nM from saline-instilled mice).
Importantly, the ability of MCP-1 to induce hyperreactivity was
prolonged, and 24 h postinstillation these animals demonstrated a
significant increase (p < 0.01) in airway
resistance of 23.8 ± 4.8 cm H2O/ml/s,
compared with a value of 5.2 ± 2.5 cm
H2O/ml/s for saline instillation. Although
significant differences in the numbers of monocytes in the BAL were
observed 8 h post-MCP-1 instillation compared with the saline
controls (1.1 ± 0.14 x 106 and
0.6 ± 0.2 x 106, respectively;
p < 0.02), the values between the treatment groups
were not significantly different at 24 h.
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To assess whether the effects of MCP-1 on hyperreactivity were
mediated through the CCR2 receptor, which is the primary receptor for
MCP-1, CCR2-/- animals were sensitized and challenged
with cockroach allergen. At the time of peak production of MCP-1, i.e.,
8 h post-allergen challenge, CCR2-/- mice
demonstrated attenuated hyperreactivity compared with littermate
controls (Fig. 7A).
Furthermore, the measurement of histamine levels in the
CCR2-/- mice demonstrated a significant decrease in BAL
histamine levels compared with littermate control animals (Fig. 7B). Likewise, mast cells from CCR2-/- mice
stimulated with MCP-1 demonstrated no histamine release over
background, whereas those from littermate control mice had a 2.5-fold
increase over background release levels (data not shown). In contrast,
both CCR2-/-- and CCR2+/+-derived mast cells
demonstrated similar IgE + Ag-stimulated histamine release.
Interestingly, whole lung homogenates from the CCR2 knockout mice
contained significantly higher levels of MCP-1 than their littermates
post-allergen challenge (1.40 ± 0.2 ng/ml vs 0.66 ±
0.11ng/ml, respectively, p = 0.005, n =
6 mice), presumably reflecting the fact that the protein is not
utilized by the CCR2 receptor. The CCR2-/- animals
demonstrated similar levels of peribronchial eosinophil accumulation
compared with wild-type mice, at 24 h post-allergen challenge
(648 ± 132 vs 765 ± 183 eosinophils/100 high power fields,
respectively). Thus, airway hyperreactivity during an allergic response
may be controlled through neutralization of MCP-1 or elimination of its
receptor, CCR2.
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, MCP-1 again induced airway
hyperreactivity in littermate control mice that express CCR2. However,
in the CCR2-/- mice, a significant decrease in the airway
hyperreactive response was observed. Altogether, these studies identify
MCP-1 and CCR2 as critical components of the allergic airway responses
that lead to altered physiological function.
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Previous results have clearly demonstrated a role for leukotrienes
in induction of prolonged changes in airway hyperreactivity in animal
models. Because direct MCP-1 instillations induced prolonged
hyperreactivity in nonallergic animals, we began to investigate whether
MCP-1 directly induced the release of LTC4 in the
airways of mice. The results in Fig. 9
illustrate that in animals given MCP-1 down the airway, a significant
increase of LTC4 could be detected in the BAL
fluid from the mice (Fig. 9A). Likewise, when pulmonary mast
cells were treated with MCP-1 in in vitro assays, a significant level
of LTC4 could be detected (Fig. 9B).
Finally, when we examined LTC4 levels in allergic
mice treated with anti-MCP-1, a significant decrease in
LTC4 levels compared with control Ab-treated
animals was observed (Fig. 10).
Altogether, these data suggest that MCP-1 initiates and maintains
airway hyperreactivity in the airway partially through a
leukotriene-mediated mechanism.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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or eotaxin, induces a bronchial
hyperreactivity response in normal mice, suggests an alternative
mechanism that does not directly involve the eosinophil. The additional
evidence that the CCR2-/- mice have an attenuated airway
hyperreactive response during allergen challenge or after direct
instillation of MCP-1 implicates a CCR2-mediated mechanism. Consistent
with previous in vitro and in vivo data, the CCR2-/- mice
had a decreased mononuclear cell influx into the BAL with no apparent
decrease in eosinophil accumulation. Therefore, MCP-1-mediated
mechanisms were not associated with eosinophil biology. Neutralization of MCP-1 during the allergic airway response decreased histamine in the BAL, whereas instillation of rMCP-1 into the airway of normal mice caused an increase in histamine release. Mast cell degranulation causes the release of a number of preformed mediators and those synthesized de novo (44). Our observations that MCP-1 is a potent histamine-releasing factor from pulmonary mast cells in vitro is consistent the work from other groups (31, 32, 33, 34). However, the ability of MCP-1 to activate pulmonary but not bone marrow mast cells may reflect important maturational differences between these two populations of mast cells and possibly the expression of CCR2 (studies in progress). Further studies in our laboratory indicate that isolated pulmonary murine mast cells constitutively express CCR2 mRNA (data not shown). The apparent disparity in the ability of ligands for this receptor that were tested in this study (MCP-1, -3, and -5) to induce hyperreactivity is not entirely clear but may reflect differing affinities at the level of the receptor or in the manner the ligand signals the mast cell. Alternatively, the ability to bind to multiple receptors, as in the case of MCP-3, may alter the CCR2 signaling and thus regulate the mast cell activation or induce an alternative signal pathway (45). It is interesting that increased levels of LTC4 were measured in the BAL after instillation of MCP-1 into normal mice. The leukotrienes are potent, long lasting bronchoconstrictors (46), and their release may account for the longevity of the change in lung function observed after MCP-1 instillation. MCP-1 was originally identified as a monocyte chemoattractant and activating factor (47), and future studies will also examine the ability of MCP-1 to induce mediator and cytokine release by macrophages that ultimately influence airway function. Finally, we are investigating the possibility that MCP-1 might directly induce hyperreactivity via activation of smooth muscle cells surrounding the airways, because vascular smooth muscle expresses CCR2 (48). Whatever the mechanism, the differential effect is striking.
In our cockroach Ag model, we have observed that levels of MCP-1 are significantly elevated 8 h postchallenge, and it follows that the inhibition of hyperreactivity and histamine release in those mice pretreated with anti-MCP-1 Abs was maximal at this time point. Interestingly, Abs against MCP-1 attenuated the airway hyperreactivity at 1 h post-allergen challenge, even though MCP-1 levels were not elevated in whole lung homogenates at this time point. However, studies by Baghestanian et al. (49) indicate that MCP-1 is released from IgE-stimulated mast cells themselves, suggesting that local concentrations of this chemokine might be important very early in the allergic response. The primary source of MCP-1 during allergic inflammation is not clear, although a number of investigators have shown that the alveolar macrophage, pulmonary fibroblast, epithelium, and endothelium are also involved in its production (50, 51, 52, 53, 54, 55, 56). Several studies have now demonstrated that Th2-type cytokines (IL-4, IL-13) induce MCP-1 from multiple structural cell populations (57, 58) and may enhance mononuclear cell recruitment and mast cell activation in the allergic lung. In addition, eosinophils appear to be a significant source of MCP-1 (59). One can easily imagine a model in which activated eosinophils recruited to the airway interact and activate surrounding cell populations, including mast cells, via their ability to produce and release MCP-1.
The role of MCP-1 in human asthmatic responses is not entirely clear, however several studies have demonstrated that MCP-1 is up-regulated during these responses. The expression of MCP-1 protein in bronchial tissue from asthmatic compared with nonasthmatic patients was significantly increased, in that >50% vs <8% of the bronchial epithelial cells stained positive, respectively (52). In subsequent studies, investigators have demonstrated increased production of MCP-1 protein in allergic asthmatic patients compared with nonasthmatic subjects (38, 60). However, to date, few studies have attempted to identify whether MCP-1 has a detrimental role in allergic asthma. The fact that MCP-1 can induce LTC4-mediated pathways make an important link between chemokine biology and arachidonic acid metabolites traditionally viewed as bronchoconstrictor mediators. The data from these studies may help to define a contributory role of MCP-1 in the exacerbation of allergic asthmatic responses and further suggest one possible mechanism of action within this response. Given the information provided in this and other studies, MCP-1 and CCR2 may represent suitable targets for therapeutic intervention of asthmatic responses. Altogether, these data outline how several mediator systems can be interrelated during the progression of allergic airway responses.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Nicholas W. Lukacs, Department of Pathology, University of Michigan Medical School, 1301 Catherine Street, Ann Arbor MI 48109-0602. E-mail address:
3 Abbreviations used in this paper: BAL, bronchoalveolar lavage; LTC4, leukotriene C4; MCP-1, monocyte chemotactic protein-1; MIP-1, macrophage inflammatory protein-1; NRS; normal rabbit serum; SCF, stem cell factor.
Received for publication November 17, 1998. Accepted for publication June 9, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. J. Immunol. 160:3869., and MCP-1 into asthmatic airways following endobronchial allergen challenge. Am. J. Respir. Crit. Care Med 156:1377. and Stat6 phosphorylation. Immunology 91:450.[Medline]
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H. Zhong, L. Belardinelli, T. Maa, I. Feoktistov, I. Biaggioni, and D. Zeng A2B Adenosine Receptors Increase Cytokine Release by Bronchial Smooth Muscle Cells Am. J. Respir. Cell Mol. Biol., January 1, 2004; 30(1): 118 - 125. [Abstract] [Full Text] [PDF]
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C. R. Brown, V. A. Blaho, and C. M. Loiacono Susceptibility to Experimental Lyme Arthritis Correlates with KC and Monocyte Chemoattractant Protein-1 Production in Joints and Requires Neutrophil Recruitment Via CXCR2 J. Immunol., July 15, 2003; 171(2): 893 - 901. [Abstract] [Full Text] [PDF]
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H. Zhong, S. G. Shlykov, J. G. Molina, B. M. Sanborn, M. A. Jacobson, S. L. Tilley, and M. R. Blackburn Activation of Murine Lung Mast Cells by the Adenosine A3 Receptor J. Immunol., July 1, 2003; 171(1): 338 - 345. [Abstract] [Full Text] [PDF]
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K. Raman, M. H. Kaplan, C. M. Hogaboam, A. Berlin, and N. W. Lukacs STAT4 Signal Pathways Regulate Inflammation and Airway Physiology Changes in Allergic Airway Inflammation Locally Via Alteration of Chemokines J. Immunol., April 1, 2003; 170(7): 3859 - 3865. [Abstract] [Full Text] [PDF]
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B. B. Vargaftig and M. Singer Leukotrienes, IL-13, and chemokines cooperate to induce BHR and mucus in allergic mouse lungs Am J Physiol Lung Cell Mol Physiol, February 1, 2003; 284(2): L260 - L269. [Abstract] [Full Text] [PDF]
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S. H. P. Oliveira, D. D. Taub, J. Nagel, R. Smith, C. M. Hogaboam, A. Berlin, and N. W. Lukacs Stem cell factor induces eosinophil activation and degranulation: mediator release and gene array analysis Blood, December 15, 2002; 100(13): 4291 - 4297. [Abstract] [Full Text] [PDF]
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N. Omata, M. Yasutomi, A. Yamada, H. Iwasaki, M. Mayumi, and Y. Ohshima Monocyte Chemoattractant Protein-1 Selectively Inhibits the Acquisition of CD40 Ligand-Dependent IL-12-Producing Capacity of Monocyte-Derived Dendritic Cells and Modulates Th1 Immune Response J. Immunol., November 1, 2002; 169(9): 4861 - 4866. [Abstract] [Full Text] [PDF]
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N. W. Lukacs, A. John, A. Berlin, D. C. Bullard, R. Knibbs, and L. M. Stoolman E- and P-Selectins Are Essential for the Development of Cockroach Allergen-Induced Airway Responses J. Immunol., August 15, 2002; 169(4): 2120 - 2125. [Abstract] [Full Text] [PDF]
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 T. S. Olson and K. Ley Chemokines and chemokine receptors in leukocyte trafficking Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2002; 283(1): R7 - R28. [Abstract] [Full Text] [PDF]
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T. R. Traynor, A. C. Herring, M. E. Dorf, W. A. Kuziel, G. B. Toews, and G. B. Huffnagle Differential Roles of CC Chemokine Ligand 2/Monocyte Chemotactic Protein-1 and CCR2 in the Development of T1 Immunity J. Immunol., May 1, 2002; 168(9): 4659 - 4666. [Abstract] [Full Text] [PDF]
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D. S. Southam, M. Dolovich, P. M. O'Byrne, and M. D. Inman Distribution of intranasal instillations in mice: effects of volume, time, body position, and anesthesia Am J Physiol Lung Cell Mol Physiol, April 1, 2002; 282(4): L833 - L839. [Abstract] [Full Text] [PDF]
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N. W. Lukacs, A. Berlin, D. Schols, R. T. Skerlj, and G. J. Bridger AMD3100, a CxCR4 Antagonist, Attenuates Allergic Lung Inflammation and Airway Hyperreactivity Am. J. Pathol., April 1, 2002; 160(4): 1353 - 1360. [Abstract] [Full Text] [PDF]
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Z. Zhu, B. Ma, T. Zheng, R. J. Homer, C. G. Lee, I. F. Charo, P. Noble, and J. A. Elias IL-13-Induced Chemokine Responses in the Lung: Role of CCR2 in the Pathogenesis of IL-13-Induced Inflammation and Remodeling J. Immunol., March 15, 2002; 168(6): 2953 - 2962. [Abstract] [Full Text] [PDF]
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J. H. Lee, N. Kaminski, G. Dolganov, G. Grunig, L. Koth, C. Solomon, D. J. Erle, and D. Sheppard Interleukin-13 Induces Dramatically Different Transcriptional Programs in Three Human Airway Cell Types Am. J. Respir. Cell Mol. Biol., October 1, 2001; 25(4): 474 - 485. [Abstract] [Full Text] [PDF]
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J. Ahamed, B. Haribabu, and H. Ali Cutting Edge: Differential Regulation of Chemoattractant Receptor-Induced Degranulation and Chemokine Production by Receptor Phosphorylation J. Immunol., October 1, 2001; 167(7): 3559 - 3563. [Abstract] [Full Text] [PDF]
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N. W. Lukacs, K. K. Tekkanat, A. Berlin, C. M. Hogaboam, A. Miller, H. Evanoff, P. Lincoln, and H. Maassab Respiratory Syncytial Virus Predisposes Mice to Augmented Allergic Airway Responses Via IL-13-Mediated Mechanisms J. Immunol., July 15, 2001; 167(2): 1060 - 1065. [Abstract] [Full Text] [PDF]
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 P.J. Barnes Cytokine modulators as novel therapies for airway disease Eur. Respir. J., July 2, 2001; 18(34_suppl): 67S - 77s. [Abstract] [Full Text] [PDF]
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S. H. P. Oliveira, C. M. Hogaboam, A. Berlin, and N. W. Lukacs SCF-induced airway hyperreactivity is dependent on leukotriene production Am J Physiol Lung Cell Mol Physiol, June 1, 2001; 280(6): L1242 - L1249. [Abstract] [Full Text] [PDF]
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Y. Kim, S.-s. J. Sung, W. A. Kuziel, S. Feldman, S. M. Fu, and C. E. Rose Jr Enhanced Airway Th2 Response After Allergen Challenge in Mice Deficient in CC Chemokine Receptor-2 (CCR2) J. Immunol., April 15, 2001; 166(8): 5183 - 5192. [Abstract] [Full Text] [PDF]
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M. Mack, J. Cihak, C. Simonis, B. Luckow, A. E. I. Proudfoot, H. Bruhl, M. Frink, H.-J. Anders, V. Vielhauer, J. Pfirstinger, et al. Expression and Characterization of the Chemokine Receptors CCR2 and CCR5 in Mice J. Immunol., April 1, 2001; 166(7): 4697 - 4704. [Abstract] [Full Text] [PDF]
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N. W. Lukacs, M. M. Glovsky, and P. A. Ward Complement-dependent immune complex-induced bronchial inflammation and hyperreactivity Am J Physiol Lung Cell Mol Physiol, March 1, 2001; 280(3): L512 - L518. [Abstract] [Full Text] [PDF]
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K. K. Tekkanat, H. F. Maassab, D. S. Cho, J. J. Lai, A. John, A. Berlin, M. H. Kaplan, and N. W. Lukacs IL-13-Induced Airway Hyperreactivity During Respiratory Syncytial Virus Infection Is STAT6 Dependent J. Immunol., March 1, 2001; 166(5): 3542 - 3548. [Abstract] [Full Text] [PDF]
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S. W. Chensue, N. W. Lukacs, T.-Y. Yang, X. Shang, K. A. Frait, S. L. Kunkel, T. Kung, M. T. Wiekowski, J. A. Hedrick, D. N. Cook, et al. Aberrant In Vivo T Helper Type 2 Cell Response and Impaired Eosinophil Recruitment in CC Chemokine Receptor 8 Knockout Mice J. Exp. Med., February 26, 2001; 193(5): 573 - 584. [Abstract] [Full Text] [PDF]
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K. Blease, B. Mehrad, N. W. Lukacs, S. L. Kunkel, T. J. Standiford, and C. M. Hogaboam Antifungal and Airway Remodeling Roles for Murine Monocyte Chemoattractant Protein-1/CCL2 During Pulmonary Exposure to Asperigillus fumigatus Conidia J. Immunol., February 1, 2001; 166(3): 1832 - 1842. [Abstract] [Full Text] [PDF]
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J. A. MacLean, G. T. De Sanctis, K. G. Ackerman, J. M. Drazen, A. Sauty, E. DeHaan, F. H. Y. Green, I. F. Charo, and A. D. Luster CC Chemokine Receptor-2 Is Not Essential for the Development of Antigen-Induced Pulmonary Eosinophilia and Airway Hyperresponsiveness J. Immunol., December 1, 2000; 165(11): 6568 - 6575. [Abstract] [Full Text] [PDF]
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B. , G. , W. , and W. CC Chemokine Receptor 2 Is Critical for Induction of Experimental Autoimmune J. Exp. Med., September 18, 2000; 192(6): 899 - 906. [Abstract] [Full Text] [PDF]
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K. Dabbagh, Y. Xiao, C. Smith, P. Stepick-Biek, S. G. Kim, W. J. E. Lamm, D. H. Liggitt, and D. B. Lewis Local Blockade of Allergic Airway Hyperreactivity and Inflammation by the Poxvirus-Derived Pan-CC-Chemokine Inhibitor vCCI J. Immunol., September 15, 2000; 165(6): 3418 - 3422. [Abstract] [Full Text] [PDF]
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 P. M. Murphy, M. Baggiolini, I. F. Charo, C. A. Hebert, R. Horuk, K. Matsushima, L. H. Miller, J. J. Oppenheim, and C. A. Power International Union of Pharmacology. XXII. Nomenclature for Chemokine Receptors Pharmacol. Rev., March 1, 2000; 52(1): 145 - 176. [Abstract] [Full Text] [PDF]
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A. Matsukawa, C. M. Hogaboam, N. W. Lukacs, P. M. Lincoln, R. M. Strieter, and S. L. Kunkel Endogenous Monocyte Chemoattractant Protein-1 (MCP-1) Protects Mice in a Model of Acute Septic Peritonitis: Cross-Talk Between MCP-1 and Leukotriene B4 J. Immunol., December 1, 1999; 163(11): 6148 - 6154. [Abstract] [Full Text] [PDF]
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 T. Mirzadegan, F. Diehl, B. Ebi, S. Bhakta, I. Polsky, D. McCarley, M. Mulkins, G. S. Weatherhead, J.-M. Lapierre, J. Dankwardt, et al. Identification of the Binding Site for a Novel Class of CCR2b Chemokine Receptor Antagonists. BINDING TO A COMMON CHEMOKINE RECEPTOR MOTIF WITHIN THE HELICAL BUNDLE J. Biol. Chem., August 11, 2000; 275(33): 25562 - 25571. [Abstract] [Full Text] [PDF]
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