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Departments of
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Pathology and
Internal Medicine, Division of Pulmonary and Critical Care, University of Michigan Medical School, Ann Arbor, MI 48109
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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being an important eosinophil attractant
during the primary stage and eotaxin during the secondary rechallenge
stage. The development of these models allows the evaluation of
mediators involved in both stages of cockroach allergen challenge, as
well as the testing of specific therapeutic
modalities. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In order to elucidate the specific responses that are associated with cockroach Ag sensitivity, our laboratory has developed a murine model of cockroach allergen-induced hyperreactive airway inflammation and we have begun to assess specific mechanisms that are involved in different stages of this response. Previous data in guinea pigs have shown that aerosolized cockroach Ag can be utilized to induce airway inflammation and alter airway physiology (7). Development of mouse models of allergic airway inflammation with altered physiology will allow better characterization and identification of inflammatory molecules to be targeted for therapy during the responses. In addition, the use of mouse models allows access to a wide range of reagents and genetically altered animals for the investigation of specific responses and molecules.
The data in the present study establishes a murine model for
examining specific stages of inflammatory responses induced by
cockroach allergen characterized by a significant eosinophilic influx
and concurrent airway hyperreactivity. In addition, we have established
models of primary challenge and secondary rechallenge stage allergic
exacerbations, which elicit different responses in the absence or
presence of preexisting eosinophilic inflammation, respectively. In
order to elucidate the mechanisms that mediate these two distinct
stages, we have investigated the role of selected CC chemokines.
Chemokines are a large family of inducible proteins classified into two
main subfamilies based on the position of cysteine residues
(8). The CC chemokines have been extensively studied in
association with allergic inflammation by virtue of their preferential
recruitment of eosinophils, monocytes, basophils, and a variety of T
cell subsets. We report the differential role of eotaxin and
MIP-1,3 two potent murine eosinophil
attractants (9, 10), in the primary vs rechallenge stages
of cockroach Ag-induced allergic airway inflammation. The
identification of mediators pivotal to the development of airway
inflammation and hyperreactivity to this allergen may aid our
understanding of the pathology of asthma and serve as a preclinical
model for testing reagents.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female C57/BL6 mice were purchased from either The Jackson Laboratory, (Bar Harbor, ME) or Charles River Breeding Laboratories (Wilmington, MA) and were maintained under standard pathogen-free conditions. All materials were obtained from Sigma Chemical Company (St. Louis, MO) unless otherwise indicated.
Sensitization and induction of the airway response
Normal C57/BL6 mice were immunized with 10 µg of cockroach
allergen (Bayer, Elkhart, IN) in IFA on day 0. In order to localize the
response to the lung, the mice were given an intranasal administration
of 10 µg of cockroach allergen in 10 µl of diluent, on day 14. This
initial intranasal Ag induced little cellular infiltrate into the lungs
of the mice upon histological examination. Mice were then challenged 6
days later (referred to hereafter as primary challenge response) by
intratracheal administration of 10 µg of cockroach allergen in 50
µl of sterile PBS or with PBS alone (vehicle). The magnitude of
leukocyte recruitment in both the vehicle control and cockroach
allergen-challenged mice was examined histologically. Only the
cockroach allergen-challenged mice displayed a significant inflammatory
response that included mononuclear cell and eosinophil infiltration.
Some mice were given a second intratracheal injection of either
cockroach allergen (10 µg in 50 µl) or diluent control and
subsequently analyzed (secondary rechallenge response). In separate
studies, the effect of anti-murine MIP-1 and anti-murine
eotaxin polyclonal Abs on cockroach Ag-induced responses were assessed
by giving sensitized mice an i.p. dose of the Ab (0.5 ml, titers of
106/ml) at 1 h prior to each Ag challenge. Normal
rabbit serum (NRS) was used as a control. Polyclonal Abs had previously
been demonstrated to block the chemotaxis of murine eosinophils
in vitro (data not shown).
Morphometric analysis of airway and peribronchial eosinophil accumulation
To assess migration of eosinophils into the airway, we subjected the mice to a 1 ml bronchoalveolar lavage (BAL) with PBS containing 25 nM EDTA at various time points postchallenge. The cells were then dispersed using a cytospin (Shandon Scientific, Runcorn, UK) 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.
Lungs from mice immunized and challenged with cockroach allergen or vehicle were preserved with 4% paraformaldehyde at various time points postchallenge. The fixed lungs were embedded in paraffin and multiple 3-µm sections cut and then differentially stained with Wright-Giemsa for the identification of eosinophils and viewed at 1000x. The individual eosinophils were counted from 100 high powered fields (hpf) per lung at each time point using multiple step sections of lung. The eosinophils counted were only in the peribronchial region; this assured the enumeration of only those eosinophils within or immediately adjacent to an airway. The inflammation observed in this model was completely associated with the airway with little or no alveolitis.
Quantitation of chemokines by ELISA
The levels of chemokine protein in whole lung homogenate were
measured by specific ELISA using a modification of a double-ligand
method as previously described (11). Briefly, lung tissue
was homogenized on ice using a tissue-tearer (Biospec Products, Racine,
WI) for 30 s in 1 ml of PBS containing 0.05% Triton X-100. The
resulting supernatant was isolated following centrifugation
(10,000 x g). To measure MIP-1 and eotaxin-1
(hereafter referred to as "eotaxin") levels in this supernatant,
flat-bottom 96-well microtiter plates (Nunc Immunoplate 1 96-F,
Roskilde, Denmark) were coated with 50 µl/well of rabbit
anti-MIP-1 or anti-eotaxin 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 of 3 M H2SO4 solution and the
plates were read at 490 nm in an ELISA reader. Standards were 0.5 log
dilutions of murine rMIP-1 or eotaxin from 1 pg/ml to 100 ng/ml.
ELISAs for these chemokines did not cross-react with each other, JE,
MARC, murine MCP-5, IL-6 or murine TNF.
Measurement of eosinophil peroxidase (EPO)
Cell-free BAL supernatants were analyzed for EPO as a marker of eosinophil degranulation. A total of 50 µl of each BAL sample were mixed with 100 µl of substrate (0.2 mg/ml o-phenylenediamine in Tris, pH 8, containing 0.1% Triton and 0.02% H2O2) in 96-well microtiter plates (Nunc-Immunoplates I 96-F). The reaction was allowed to progress for 30 min before quenching with 50 µl of 4 M sulfuric acid. Plates were read at 490 nm using an ELISA reader.
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 (12).
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-expiatory pressure 2.5 to 3.0 cm
H2O) and the tail vein was cannulated with a 27-gauge
needle for injection of the methacholine challenge. The plethysmograph
was sealed and readings were monitored by computer. Since 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 = cm
H2O/ml/s) at two time points from the volume curve, based
upon a percentage of the inspiratory volume. Once the mouse was hooked
up to the box it was ventilated for 5 min prior to acquiring readings.
Once baseline levels were stabilized and initial readings were taken, a
methacholine challenge was given via the cannulated tail vein. After
determining a dose-response curve (0.001 to 0.5 mg), an optimal dose
was chosen (0.1 mg of methacholine), which was used throughout the rest
of the experiments in this study. After the methacholine challenge, the
response was monitored and the peak airway resistance was recorded as a
measure of airway hyperreactivity.
Statistics
Statistical significance was determined by ANOVA with p values <0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The sensitization of mice with cockroach allergen
systematically over a 14-day period was accomplished by immunization
with cockroach allergen in IFA. Localization of the response to the
airway was mediated by a single intranasal administration at day 14,
followed by an intratracheal primary challenge at day 20. Histological
analysis of the ensuing inflammation demonstrated a significant influx
of leukocytes around the airways (Fig. 1, A to
C). This peribronchial
inflammation consisted of mononuclear cells (monocytes and lymphocytes)
and eosinophils at all time points examined. Subsequent studies focused
on the effect of cockroach allergen rechallenge on airway inflammatory
responses. An increased severity of this peribronchial eosinophilia was
observed during the secondary rechallenge vs primary cockroach Ag
intratracheal administration at each time point examined (Fig. 1,
D to F). Quantitation of the kinetics of this
inflammation indicated that eosinophils were elevated around the
airways at 8 h after primary challenge compared with
vehicle-challenged controls and continued to intensify, peaking between
24 and 48 h and declining by 72 h postchallenge (Fig. 2
). However, following secondary allergen
rechallenge, the number and rate of eosinophil accumulation rose
steeply, increasing sixfold over primary challenge levels by 24 h
(1581 ± 641 vs 261 ± 40 cell/100 hpf, respectively). We
also characterized the influx of eosinophils into the airway by BAL
leukocyte analysis. The eosinophil influx into the airway was detected
at 8 h after primary allergen challenge (9 ± 2.5% of total
BAL leukocytes, using n = 6 animals), persisted at
24 h (16.2 ± 2.4%), and peaked by 48 h postchallenge
(34.6 ± 8%). No time-dependent changes in eosinophil
accumulation were observed in the BAL in cockroach Ag-sensitized,
vehicle-challenged mice (3.5 ± 0.6% at 24 h after
primary challenge). Secondary rechallenge with cockroach Ag further
increased the proportion of eosinophils in the BAL, accounting for
40 ± 7% of total leukocytes (n = 8 animals) at
24 h, and 80 ± 2.2% by 48 h. This response would
appear to by synergistic rather than simply additive of two primary
challenge responses. Altogether, these data demonstrate that a primary
allergen challenge of sensitized mice elicits a peribronchial
inflammatory response, characterized by significant eosinophil
accumulation. However, subsequent challenges with the same Ag greatly
increase the rate and severity of this inflammation.
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The assessment of reversible airway hyperreactivity responses is a
clinically relevant marker of asthmatic airway disease.
Allergen-challenged mice were examined for changes in airway physiology
at various time points (8, 24, and 48 h) after primary challenge,
(Fig. 3). Vehicle-challenged control mice
had virtually no increase in airway resistance, as compared with
background resistance, when given i.v. methacholine. In contrast,
cockroach allergen-sensitized mice demonstrated significant increases
in airway resistance at 8 and 24 h after cockroach Ag challenge
upon methacholine administration. By 48 h after allergen
challenge, the airway resistance changes had diminished.
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). At
24 h after secondary rechallenge (72 h after primary challenge),
the airway resistance response was significantly increased compared
with those animals that received vehicle upon secondary rechallenge
(7.5 ± 0.8 vs 3.5 ± 1.2, respectively). Furthermore, the
airway hyperreactivity response was greater in the rechallenged animals
compared with the primary stage, at similar time points postchallenge
(Fig. 3). Interestingly, unlike the primary challenge, airway
resistance continued to increase by 48 h during the secondary
rechallenge response. Since a concurrent increase in the severity of
the airway inflammation was observed in the rechallenge vs primary
responses, these studies indicate that airway physiological responses
correlate with the intensity of the inflammation within the airway, in
this model.
The role of the MIP-1 and eotaxin in primary and rechallenge
allergen exacerbations
The chemokines eotaxin and MIP-1 have been demonstrated to be
potent eosinophil chemoattractants (9, 10) and we wished
to assess their role in our model. Analysis of whole lung homogenates
by specific ELISA revealed that levels of both chemokines were maximal
at 8 h after primary challenge. However, levels of eotaxin, but
not MIP-1, were significantly higher in the secondary rechallenge
compared with the primary challenge lungs (Fig. 4).
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prior to cockroach Ag challenge decreased the peribronchial
eosinophilia at 24 h following primary challenge, but were
ineffective at inhibiting the infiltration after secondary allergen
rechallenge (Fig. 5A). In
contrast, Abs to eotaxin inhibited eosinophilia by 60% in the
secondary rechallenge but not primary stage (Fig. 5B).
Interestingly, no significant differences were observed in peripheral
blood eosinophil numbers following pretreatment with anti-MIP-1
prior to primary Ag challenge or anti-eotaxin prior to secondary
rechallenge compared with NRS controls. Furthermore, Abs raised against
eotaxin (but not MIP-1) were able to significantly attenuate airway
hyperresponsiveness during the secondary rechallenge response compared
with normal rabbit serum controls. Neither Ab significantly effected
hyperresponsiveness during the primary challenge (Fig. 6).
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). At this time point, however, BALs
from animals rechallenged with cockroach Ag contained significantly
more EPO than those that had undergone primary challenge alone.
Furthermore, the rechallenge EPO levels could be attenuated by
pretreatment of the mice with anti-eotaxin, but not
anti-MIP-1, Abs before each challenge (Fig. 8).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and eotaxin. Only anti-eotaxin Abs were able to
significantly affect changes in airway physiology associated with the
secondary rechallenge response. Prior to primary cockroach allergen
challenge, there is little inflammation present in the airways of these
allergic mice and a significant increase in both mononuclear cells
(monocytes and lymphocytes) and eosinophils occurs after the allergen
challenge. When these animals are again rechallenged at this time with
a second allergen stimulation, there is a resurgence of eosinophil
accumulation in the BAL, which occurs more quickly and is associated
with increased airway hyperreactivity. Our results suggest that the
response elicited by sensitized subjects toward a single Ag exposure
appears to resolve comparatively rapidly. However, persistent/repeated
exposures in close succession appear to increase the extent and rate of
the eosinophilia around the asthmatic airway, leading to prolonged
airway hyperreactivity. Therefore, the more inflammation that is
present prior to allergen challenge, the more severe the subsequent
response. Several animal models of allergic airway inflammation, including those that have utilized parasitic Ags (14), OVA (15), and plant extracts (16) as allergens, have characterized many of the basic processes that occur during allergic airway responses. Animal models have delineated and described very important mechanisms of activation, however, they have either utilized a primary allergen exacerbation or have given repeated doses of the allergen over an extended period of time to the animal. In both cases very little information has been described comparing and contrasting the responses that are elicited in these two different stages (primary vs rechallenge) of allergic models.
Our murine model of cockroach antigen-induced allergic airway
inflammation demonstrates key differences in the roles played by
MIP-1 and eotaxin following primary and rechallenge exacerbations of
this clinically relevant Ag. We have previously demonstrated that
MIP-1 is a key murine eosinophil chemoattractant in a murine model
of parasite Ag (Schistosoma mansoni egg Ag)-induced allergic
inflammation (10), and it would appear that this chemokine
plays a similar role following primary cockroach Ag challenge. However,
physiological studies demonstrate that MIP-1 plays a minimal role in
airway hyperreactivity in either allergic airway model. In contrast,
eotaxin appears to be an important eosinophil attractant in the
secondary rechallenge but not the primary response. This latter
chemokine has also been characterized as a potent murine eosinophil
attractant in both in vitro and in vivo experimental settings
(10, 17, 18). However, our results are the first to
demonstrate a role of endogenous eotaxin in airway physiological
changes after allergen challenge.
The observations of differential chemokine roles could be explained by
a number of interrelated mechanisms. First, although temporal increases
in chemokine levels in whole lung homogenates are similar for both
eotaxin and MIP-1, the compartmentalized production by particular
cell types and the timing of this production may be pivotal in
determining the principle chemokine at work. For example, MIP-1 is
produced by macrophage populations while the epithelium is an important
source of eotaxin (19), thus enabling eosinophils to
migrate into the interstitial compartment and accumulate around the
airways. In additional studies in our laboratory, we have examined
eosinophil degranulation in vitro and observed that eotaxin, but not
MIP-1, can induce murine eosinophil degranulation (data not shown).
Since a number of investigators have demonstrated a direct correlation
between eosinophil degranulation and airway function (20, 21), this may explain the ability of anti-eotaxin Abs to
attenuate hyperreactivity only during the secondary rechallenge phase,
when eosinophils are already present in the airway. Conceivably,
however, it is possible that some component of the observed
deterioration in lung function following secondary rechallenge may also
be due to increased physical congestion of the airways through an
increased inflammation.
Second, the relative contributions of different chemokines may reflect
changes in the temporal expression of their receptors. Murine MIP-1
binds both murine eosinophil chemokine receptors, CCR1 and, to a lesser
extent, CCR3, while eotaxin binds only to CCR3 (17, 22, 23). It is tempting to speculate whether events that promote the
preferential binding of MIP-1 to CCR1 might occur in the primary
phase, but shift to eotaxin and CCR3 following secondary allergen
rechallenge. This latter aspect would be heightened by the significant
increase in eotaxin, but not MIP-1, during the secondary rechallenge
response.
Finally, other groups (24, 25) have demonstrated that eotaxin is a potent local recruiter of eosinophils, but IL-5 is required to induce the systemic release of eosinophils from the bone marrow. Our observations would be compatible with this process in which a Th2-type response is implicated, and IL-5 is likely present to induce the systemic release of sufficient eosinophils, which can be subsequently recruited into the lung. In addition, IL-5 has been demonstrated to be an important priming agent for eosinophils toward other chemokines (26), although it remains to be established as to whether this cytokine potentiates the chemoattractant/degranulation activity of eotaxin. The net result of the above mechanisms is a greater number of leukocytes participating in the allergen-induced inflammatory response during the secondary rechallenge, resulting in severe airway inflammation. This was demonstrated by greater numbers of eosinophils migrating into the airway as well as the exacerbation of the hyperreactivity in the secondary rechallenge response compared with the primary stage allergen challenge.
The data presented in these studies have outlined a novel murine model for a clinically relevant and environmentally detrimental allergen from cockroaches. In addition, two distinct stages of disease have been examined, a primary allergen challenge stage, which elicits a response in the absence of significant inflammation, and a rechallenge stage, which induces a greater airway hyperreactive response in the presence of intense inflammation. It appears that the increased hyperreactivity responses during repeated allergen exposure is dependent upon eotaxin production, eosinophil accumulation, and degranulation. These studies further demonstrate the complexity of the allergic airway response and chemokine biology.
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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: MIP-1, macrophage inflammatory protein-1; BAL, bronchoalveolar lavage; EPO, eosinophil peroxidase; hpf, high power fields; NRS, normal rabbit serum.
Received for publication April 20, 1998. Accepted for publication August 20, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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influences eosinophil recruitment in antigen-specific airway inflammation. Eur. J. Immunol. 25:245.[Medline]
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 S. H. P. Oliveira, S. Lira, C. Martinez-A, M. Wiekowski, L. Sullivan, and N. W. Lukacs Increased responsiveness of murine eosinophils to MIP-1{beta} (CCL4) and TCA-3 (CCL1) is mediated by their specific receptors, CCR5 and CCR8 J. Leukoc. Biol., June 1, 2002; 71(6): 1019 - 1025. [Abstract] [Full Text] [PDF]
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M. T. Borchers, T. Ansay, R. DeSalle, B. L. Daugherty, H. Shen, M. Metzger, N. A. Lee, and J. J. Lee In vitro assessment of chemokine receptor-ligand interactions mediating mouse eosinophil migration J. Leukoc. Biol., June 1, 2002; 71(6): 1033 - 1041. [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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S. S. Cheng, N. W. Lukacs, and S. L. Kunkel Eotaxin/CCL11 Suppresses IL-8/CXCL8 Secretion from Human Dermal Microvascular Endothelial Cells J. Immunol., March 15, 2002; 168(6): 2887 - 2894. [Abstract] [Full Text] [PDF]
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H. F. Rosenberg and J. B. Domachowske Eosinophils, eosinophil ribonucleases, and their role in host defense against respiratory virus pathogens J. Leukoc. Biol., November 1, 2001; 70(5): 691 - 698. [Abstract] [Full Text] [PDF]
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L.-C. Chen, Z. Zhang, A. C. Myers, and S.-K. Huang Cutting Edge: Altered Pulmonary Eosinophilic Inflammation in Mice Deficient for Clara Cell Secretory 10-kDa Protein J. Immunol., September 15, 2001; 167(6): 3025 - 3028. [Abstract] [Full Text] [PDF]
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J. Kim, A. C. Merry, J. A. Nemzek, G. L. Bolgos, J. Siddiqui, and D. G. Remick Eotaxin Represents the Principal Eosinophil Chemoattractant in a Novel Murine Asthma Model Induced by House Dust Containing Cockroach Allergens J. Immunol., September 1, 2001; 167(5): 2808 - 2815. [Abstract] [Full Text] [PDF]
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 N. W. Lukacs, D. M. Prosser, M. Wiekowski, S. A. Lira, and D. N. Cook Requirement for the Chemokine Receptor Ccr6 in Allergic Pulmonary Inflammation J. Exp. Med., August 20, 2001; 194(4): 551 - 556. [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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 J.C. Kips Cytokines in asthma Eur. Respir. J., July 2, 2001; 18(34_suppl): 24S - 33s. [Abstract] [Full Text] [PDF]
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R.-F. Guo, A. B. Lentsch, R. L. Warner, M. Huber-Lang, J. V. Sarma, T. Hlaing, M. M. Shi, N. W. Lukacs, and P. A. Ward Regulatory Effects of Eotaxin on Acute Lung Inflammatory Injury J. Immunol., April 15, 2001; 166(8): 5208 - 5218. [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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N. Zimmermann, S. P. Hogan, A. Mishra, E. B. Brandt, T. R. Bodette, S. M. Pope, F. D. Finkelman, and M. E. Rothenberg Murine Eotaxin-2: A Constitutive Eosinophil Chemokine Induced by Allergen Challenge and IL-4 Overexpression J. Immunol., November 15, 2000; 165(10): 5839 - 5846. [Abstract] [Full Text] [PDF]
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A. E. Dixon, J. B. Mandac, D. K. Madtes, P. J. Martin, and J. G. Clark Chemokine expression in Th1 cell-induced lung injury: prominence of IFN-gamma -inducible chemokines Am J Physiol Lung Cell Mol Physiol, September 1, 2000; 279(3): L592 - L599. [Abstract] [Full Text] [PDF]
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J. B. Domachowske, C. A. Bonville, J.-L. Gao, P. M. Murphy, A. J. Easton, and H. F. Rosenberg The Chemokine Macrophage-Inflammatory Protein-1{alpha} and Its Receptor CCR1 Control Pulmonary Inflammation and Antiviral Host Defense in Paramyxovirus Infection J. Immunol., September 1, 2000; 165(5): 2677 - 2682. [Abstract] [Full Text] [PDF]
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A. Trifilieff, Y. Fujitani, F. Mentz, B. Dugas, M. Fuentes, and C. Bertrand Inducible Nitric Oxide Synthase Inhibitors Suppress Airway Inflammation in Mice Through Down-Regulation of Chemokine Expression J. Immunol., August 1, 2000; 165(3): 1526 - 1533. [Abstract] [Full Text] [PDF]
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K. Blease, B. Mehrad, T. J. Standiford, N. W. Lukacs, S. L. Kunkel, S. W. Chensue, B. Lu, C. J. Gerard, and C. M. Hogaboam Airway Remodeling Is Absent in CCR1-/- Mice During Chronic Fungal Allergic Airway Disease J. Immunol., August 1, 2000; 165(3): 1564 - 1572. [Abstract] [Full Text] [PDF]
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A. Panoskaltsis-Mortari, R. M. Strieter, J. R. Hermanson, K. V. Fegeding, W. J. Murphy, C. L. Farrell, D. L. Lacey, and B. R. Blazar Induction of monocyte- and T-cell-attracting chemokines in the lung during the generation of idiopathic pneumonia syndrome following allogeneic murine bone marrow transplantation Blood, August 1, 2000; 96(3): 834 - 839. [Abstract] [Full Text] [PDF]
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C. M. Hogaboam, K. Blease, B. Mehrad, M. L. Steinhauser, T. J. Standiford, S. L. Kunkel, and N. W. Lukacs Chronic Airway Hyperreactivity, Goblet Cell Hyperplasia, and Peribronchial Fibrosis during Allergic Airway Disease Induced by Aspergillus fumigatus Am. J. Pathol., February 1, 2000; 156(2): 723 - 732. [Abstract] [Full Text] [PDF]
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E. Campbell, S. L. Kunkel, R. M. Strieter, and N. W. Lukacs Differential Roles of IL-18 in Allergic Airway Disease: Induction of Eotaxin by Resident Cell Populations Exacerbates Eosinophil Accumulation J. Immunol., January 15, 2000; 164(2): 1096 - 1102. [Abstract] [Full Text] [PDF]
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A. E. I. Proudfoot, R. Buser, F. Borlat, S. Alouani, D. Soler, R. E. Offord, J.-M. Schroder, C. A. Power, and T. N. C. Wells Amino-terminally Modified RANTES Analogues Demonstrate Differential Effects on RANTES Receptors J. Biol. Chem., November 5, 1999; 274(45): 32478 - 32485. [Abstract] [Full Text] [PDF]
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M. E. Rothenberg Eotaxin . An Essential Mediator of Eosinophil Trafficking into Mucosal Tissues Am. J. Respir. Cell Mol. Biol., September 1, 1999; 21(3): 291 - 295. [Full Text]
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H. Ochi, W. M. Hirani, Q. Yuan, D. S. Friend, K. F. Austen, and J. A. Boyce T Helper Cell Type 2 Cytokine-Mediated Comitogenic Responses and Ccr3 Expression during Differentiation of Human Mast Cells in Vitro J. Exp. Med., July 19, 1999; 190(2): 267 - 280. [Abstract] [Full Text] [PDF]
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C. M. Hogaboam, C. S. Gallinat, D. D. Taub, R. M. Strieter, S. L. Kunkel, and N. W. Lukacs Immunomodulatory Role of C10 Chemokine in a Murine Model of Allergic Bronchopulmonary Aspergillosis J. Immunol., May 15, 1999; 162(10): 6071 - 6079. [Abstract] [Full Text] [PDF]
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