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1 Pulmonary and Critical Care Divisions, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115; 2 Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut 06877; 3 Respiratory Research Group, University of Calgary, Calgary, Alberta, Canada T2N 4N1; 4 Leukosite, Inc., Cambridge, Massachusetts 02142; 5 Physiology Program, Harvard School of Public Health, Boston, Massachusetts 02115; and 6 Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
De Sanctis, George T., Walter W. Wolyniec, Francis H. Y. Green, Shixin Qin, Aiping Jiao, Patricia W. Finn, Thomas Noonan, Anthony A. Joetham, Erwin Gelfand, Claire M. Doerschuk, and Jeffrey M. Drazen. Reduction of allergic airway responses in
P-selectin-deficient mice. J. Appl.
Physiol. 83(3): 681-687, 1997.
P-selectin is an adhesion receptor that has been shown to be important in the
recruitment of eosinophils and lymphocytes in a variety of inflammatory
conditions. Because cellular recruitment is thought to be a critical
event in allergen-induced changes in airway responsiveness, we reasoned that P-selectin-deficient mice would exhibit reduced airway
responsiveness and cellular trafficking noted in wild-type (+/+) mice.
Both (+/+) and P-selectin-deficient (
/) mice
sensitized and challenged with ovalbumin (OVA/OVA) exhibited the
same capacity to produce increased titers of total and OVA-specific
immunoglobulin E. Airway responsiveness to methacholine was
significantly greater in the (+/+) (OVA/OVA) animals than it was in the
respective (/) (OVA/OVA) group or control groups
(P = 0.0016). Bronchoalveolar
lavage fluid from (/) (OVA/OVA) mice contained significantly
fewer eosinophils and lymphocytes compared with the (+/+) (OVA/OVA)
mice (P < 0.05). These results
suggest that the predominant role of P-selectin in OVA-induced
airway hyperresponsiveness is to promote the airway inflammatory
response to allergen inhalation.
asthma; bronchoconstriction; methacholine; ovalbumin; knockout
INTRODUCTION SYSTEMIC SENSITIZATION to ovalbumin (OVA) followed by
repeated exposure to aerosols generated from OVA solutions induces
enhanced airway responsiveness to methacholine and airway inflammation in mice (1, 7-9, 13, 14, 17, 24). Because this combination of
airway inflammation and enhanced responsiveness to methacholine recapitulates two of the defining phenotypical characteristics of human
asthma, such models have been useful in defining the nature of the
inflammatory events leading to altered airway responsiveness (5). In a
sensitized animal, inhalation of antigen initiates a cascade of
molecular events that results in the influx of lymphocytes and
eosinophils from the bloodstream into the airway wall and lumen. One of
the key events in this recruitment is the margination of leukocytes
along the walls of postcapillary venules through rolling of leukocytes
along the endothelium. Among the molecular moieties responsible for the
expression of the rolling phenotype is P-selectin, which is expressed
on endothelial cells. Because rolling is thought to be a required step
early in the process of leukocyte emigration and because airway
inflammation is thought to be critical to the development of airway
hyperresponsiveness, we reasoned that mice homozygous for a targeted
disruption of the P-selectin gene would exhibit a diminished capacity
to manifest airway inflammation and airway hyperresponsiveness when
sensitized and challenged by using protocols known to induce both of
these phenotypical features in normal mice.
To test this hypothesis, we sensitized wild-type (+/+) and
P-selection-deficient ( MATERIALS AND METHODS Animals
/) mice to OVA and challenged them with aerosols generated from either OVA or phosphate-buffered saline (PBS)
solutions. Our data demonstrate that (/) mice are not distinguishable from the (+/+) controls in their capacity to produce an
immunoglobulin E (IgE) response to OVA. In contrast, however, P-selectin deficiency is associated with a diminished induction of
airway hyperresponsiveness, decreased cellular recruitment into the
airways, and decreased secretion of interleukin (IL) 4 into the airways
and air spaces.
/) mice
[originally produced on a mixed SV129/C57BL/6 background (19) and
subsequently backcrossed for >10 generations to C57BL/6J
mice] were purchased from Jackson Laboratory, Bar
Harbor, ME. Mice were 4-5 wk old at entry into the protocol and
were housed in isolation cages under SPF conditions. Blood from
sentinel animals was routinely tested to ensure their SPF status. Mice
were acclimatized for 7-10 days after arrival and were studied at
7-8 wk of age.
Experimental Design
Four groups of mice were studied. The (/) and
(+/+) mice were all sensitized to OVA, as detailed below. Approximately
one-half of the mice with each genotype were subsequently repeatedly
exposed to an aerosol generated from an OVA solution while the
remaining mice were exposed at the same time intervals to aerosols
generated from solutions of phosphate-buffered saline (PBS).
Sensitization and Challenge Protocol
On day 0, all mice were immunized via intraperitoneal injection with 10 µg chicken OVA (Grade III, Sigma Chemical, St. Louis, MO), mixed with 1 µg Al(OH)3 (alum; J. T. Baker Chemical, Phillipsburg, NJ) in 0.2 ml of PBS (13). A booster injection was given on day 7, using the identical reagents. Starting 7 days later, mice were exposed either to aerosolized OVA (6% OVA) dissolved in PBS (pH = 7.4) or PBS alone for 25 min/day for 7 consecutive days. For the aerosol exposures, mice were placed in a plastic chamber (23 × 23 × 11 cm), and the OVA or PBS solution was delivered via an ultrasonic nebulizer (model 5000; DeVilbiss, Somerset, PA) attached to a port in the mouse chamber. All nebulizer solutions were adjusted to pH 7.4. Airflow was supplied to the nebulizer head (at ~1.0 l/min) to generate the aerosol. A series of holes, positioned directly opposite the port of entry for the aerosol, allowed the escape of excess aerosol from the exposure chamber.Determination of Anti-OVA Antibody Serum Titers
Serum total IgE, anti-OVA IgE, and OVA-specific immunoglobulin G1 (IgG1) titers were measured by enzyme-linked immunosorbent assay (ELISA), using previously detailed protocols (12, 25). Antibody titers for OVA-specific IgE as well as OVA-specific IgG1 were calculated by using mouse serum standards. The lower limit of detection for total IgE was 100 pg/ml.Determination of Pulmonary Resistance and Airway Responsiveness
Airway responsiveness was measured as previously described (3, 18). Dose-response curves to methacholine were obtained on the day after the last aerosol OVA exposure by administering sequentially increasing doses of methacholine (33-1,000 µg/kg iv) in a 20- to 35-µl volume. From the relationship between dose administered and pulmonary resistance (RL), the effective dose that would have resulted in a doubling of RL was determined by log-linear interpolation. This dose, referred to as the effective dose required to increase RL to 200% of control values (ED200RL), was used as an index of airway responsiveness. Because the doses of agonist are given in geometrically increasing amounts, it is common to log transform this index.Bronchoalveolar Lavage (BAL)
Cell counts. PBS (2 ml) with 0.6 mM EDTA was instilled into the lung and retrieved by using gentle suction. The lavagate was centrifuged at 2,000 revolutions/min (rpm) for 10 min, the supernatant was separated from the cell pellet, and aliquots were frozen at70°C for
cytokine analysis. The cell pellets were resuspended in Hanks' balanced salt solution (JRH Biosciences, Lenexa, KS), and
slides were prepared by spinning samples at 800 rpm for 10 min
(Cytospin 2; Shandon, Pittsburgh, PA). Total cell counts were made in a hemocytometer, and differentials were prepared by cytospin and stained
with Wright-Giemsa stain. The investigator counting the cells was
blinded to the treatment groups.
Measurement of eosinophil peroxidase (EPO), IL-2, IL-4, and IL-5 in
BAL fluid.
EPO levels in the lavage were measured colorimetrically
by modified techniques previously described by Strath et al. (28). Briefly, 100 µl of sample or standard were pipetted in duplicate into
the wells of a 96-well plate (Cell Wells, Corning, Corning, NY)
followed by 100 µl of assay reaction mixture (pH = 8.4). The plate
was incubated in the dark for 30 min, and then the reaction was
terminated with 50 µl of 4 M
H2SO4
per well. The plate was read by using a microtiter plate reader
(Spectramax model 340, Molecular Devices, Sunnyvale, CA) at 490 nm.
Regression analysis was performed by the SOFTmax Pro analysis software
package. Lavage fluid levels of IL-2, IL-4, and IL-5 were determined
colorimetrically with the use of specific mouse IL-2, IL-4, and IL-5
ELISA kits (TiterZyme; PerSeptive Diagnostics, Cambridge, MA). These
markers were evaluated as fluid-phase indicators of the inflammatory
response to allergen that could potentially differ in the (/)
mice.
Flow Cytometry
Immunofluorescence staining of peripheral blood and BAL cells was carried out with the use of directly conjugated monoclonal antibodies (MAb). Lymphocytes were detected by gating, using linear settings on both side and forward scattering. The following conjugated anti-murine MAb were purchased from Pharmigen, San Diego, CA: anti-CD3-fluorescein isothiocyanate, anti-CD4-phycoerythrin (PE), anti-CD8-PE, anti-CD25-PE, and anti-B220-PE. The staining was detected on a fluorescence-activated cell sorter (FACScan; Becton-Dickinson, San Jose, CA).Histological Evaluation
Mice were removed from the plethysmograph while they were under surgical anesthesia, and they were killed by cervical dislocation. Blood was collected by cardiac puncture. The lungs were removed from the thoracic cavity and inflated with pH-balanced 4% formaldehyde fixative (pH = 7.4). A sagittal block of the whole left lung was dehydrated and embedded in paraffin, and 5-µm sections were stained with hematoxylin and eosin and then examined by light microscopy.Statistical Analysis
Computations were performed with the JMP 3.1.5 (SAS Institute, Cary, NC) statistical package. A Tukey-Kramer honestly significant difference test was used to assess differences between all four treatment groups. For nonparametric data, differences between groups were analyzed by using the Wilcoxon rank sum test. When appropriate, results are expressed as means ± SE, and unless otherwise stated, results were considered statistically significant at the P < 0.05 level.RESULTS
Antibody Titers in
(+/+) and
(/) Mice
/) mice (Fig. 1, Table
1). In animals with either
genotype, OVA challenge of sensitized mice was associated with an
increase in both IgE and OVA-specific IgE. However, there were no
significant differences between the (+/+) and (/) mice when
either total or OVA-specific IgE levels were respectively compared
after OVA sensitization and challenge. There were no significant
differences in OVA-specific IgG1 levels
between (+/+) and (/) mice, data not shown.
/) mice. All animals were sensitized with OVA given
intraperitoneally in alum and received either phosphate-buffered saline
[PBS; (OVA/PBS)] or OVA (OVA/OVA) aerosol challenge. For
each condition, there was a significant increase in IgE level (total or
OVA-specific) associated with OVA challenge compared with PBS
challenge. See MATERIALS AND METHODS
for details. There were no significant differences in either total or
OVA-specific IgE between (+/+) and (/) mice, either with
(OVA/OVA) or without (OVA/PBS) OVA aerosol exposure. ELISA,
enzyme-linked immunosorbent assay. See MATERIALS AND
METHODS for details.
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Airway Responsiveness Modified by Allergen Sensitization and
Challenge in
(+/+) and
(/) Mice
/) mice, the log
ED200RL
was 2.32 ± 0.06 (n = 15) when
animals were challenged with PBS and 2.16 ± 0.05 (n = 17) when animals were challenged
with OVA. This difference in log
ED200RL was not statistically significant (Fig. 2).
In contrast, airway responsiveness to methacholine was significantly
enhanced in (+/+) mice sensitized and challenged with OVA compared with
airway responsiveness in (+/+) mice that had been sensitized and
challenged with PBS (P = 0.0005; Fig.
2). Specifically, the log
ED200RL
in (+/+) mice challenged with OVA was 1.86 ± 0.06 (n = 11), whereas in (+/+) mice
challenged with PBS it was 2.27 ± 0.06 (n = 12). Therefore, challenge with antigen in (+/+) mice resulted in a 2.6-fold increase in
airway responsiveness to methacholine, whereas, in the (/) mice,
OVA challenge was associated with a statistically insignificant 1.4-fold increase in airway responsiveness to methacholine.
/) and (+/+) mice. The (+/+) mice sensitized and
challenged with OVA were significantly (P = 0.001) more responsive
to methacholine challenge than were other treatment groups. There were
no other significant differences in log
ED200RL
among the 3 other groups.
BAL Cell Composition
Cell counts, differential, and lymphocyte subsets. OVA challenge in both (+/+) and (/) sensitized
mice was associated with a significant
(P = 0.02) increase in cell number compared with the challenge with PBS (Table
2). The absolute number of cells retrieved
by BAL after OVA challenge in the (+/+) mice was >3.9-fold greater
than the number of cells retrieved from the (/) mice
(P = 0.014). The differential counts
of the cells obtained by BAL are provided in Table 1. OVA challenge, compared with PBS challenge, resulted in a significant increase in the
percentage of neutrophils and eosinophils present in the BAL fluid of
both (+/+) and (/) mice. Similarly, OVA challenge resulted in an
increase in the percentage of lymphocytes in the BAL fluid compared
with PBS challenge in both the (+/+) and the (/) mice. Although
the percentage of lymphocytes was significantly higher in the (/)
mice than in the (+/+) mice (P = 0.0086), because the total cell counts were more than sixfold less in
the (/) mice, the absolute number of lymphocytes in the BAL of
the (/) mice was about fourfold less than it was in the
(+/+) mice. As expected, the percentage of macrophages in the BAL
decreased significantly with OVA challenge in both (+/+) and (/)
mice (Table 1). Among the various groups studied, there were no
significant differences in the peripheral leukocyte differential counts
(data not shown). Flow cytometric analysis of the BAL gated on
scatter patterns typically found in lymphocytes was used to provide an index of the phenotype of the lymphocytes found in the BAL fluid (Table
3).
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in the BAL fluid after OVA challenge were not
significantly different between the (/) and (+/+) groups of mice
(Table 4). Furthermore, in the (+/+) mice,
OVA challenge compared with PBS challenge was not associated with a
change in the concentration of IL-5 or tumor necrosis factor- in the
BAL. In contrast, OVA challenge of the (+/+) mice was associated with a
significantly (P = 0.027) higher
concentration of IL-4 in the lavage fluid than was observed in (+/+)
mice challenged with PBS. A similar difference in IL-4 concentrations
was not observed in (/) mice when comparing cohorts challenged
with PBS vs. OVA (P = 0.883). In
(/) mice, OVA challenge was not associated with significantly
increased concentrations of EPO in the BAL, whereas OVA challenge in
the (+/+) mice was associated with a significant increase in EPO levels (P = 0.0008). The concentration of EPO
in the BAL was significantly (P = 0.012) less after OVA challenge in (/) compared with (+/+) mice.
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Histological Findings
Histological sections taken from the lungs of both (+/+) and (/) mice sensitized to OVA but challenged with PBS were
normal in appearance. The lungs from the (+/+) mice challenged with OVA showed a focal inflammatory cell infiltrate throughout the lung. The
infiltrates were centered on terminal bronchioles as well as alveolar
ducts and around small blood vessels, especially arterioles and
venules. Lymphocytes and eosinophils were present in the perivascular and periairway interstitium. These cells were seen marginating and
emigrating through the walls of small vessels. In the adjacent air
spaces, in addition to the lymphocytes and eosinophils, giant cells of
foreign body type were a prominent feature. Apart from the inflammatory
infiltrates, no morphological changes in the smooth muscle or
epithelium were observed in the airways. In contrast, the lungs of
(/) mice sensitized to OVA and challenged with OVA showed
similar, but attenuated, inflammatory cell changes. In particular,
fewer cells were seen marginating along the luminal aspects of vessel
walls, and there were fewer inflammatory cells within the walls
themselves. In these animals, the cellular infiltrate did not extend to
the peribronchiolar region.
DISCUSSION
OVA sensitization of mice followed by repeated aerosol
challenge is a well-established method of creating a lesion that mimics a number of the phenotypical changes that are observed in human asthma,
namely airway hyperresponsiveness and an inflammatory infiltrate in the
airway consisting of eosinophils and lymphocytes (1, 7-9, 13, 14,
17, 24). Because recruitment of cells from the vasculature is a
necessary step in the inflammatory process, we reasoned that (/)
mice could have a diminished capacity either to respond to antigen
initially or to recruit cells to the airways. We further
reasoned that if either or both of these changes in immune response
occurred after aerosol OVA challenge, (/) mice would demonstrate
either absence of or attenuation of many of the "asthmalike"
phenotypical features that are manifest in this model. Our data show
that, even though (/) mice have an equivalent capacity to
manifest an IgE response to OVA compared with their (+/+) counterparts,
(/) mice have significantly less airway hyperresponsiveness and
airway inflammation when compared with (+/+) mice. These findings
indicate that the predominant role of P-selectin in allergic airway
responses is downstream from the processes that lead to IgE antibody
production, and the role of P-selectin is to promote the airway
inflammatory reaction in response to antigen inhalation.
P-selectin is an endothelial cell receptor for a series of
(1,3)-fucosylated oligosaccharides found on granulocytes and certain activated lymphocytes (26, 34). When circulating inflammatory cells
express an appropriate ligand for P-selectin, a low-affinity attachment
state occurs that results in leukocyte rolling along the vascular
endothelium. This initial event leads to inflammatory cell recruitment
from the vasculature (see Refs. 11, 20, 33 for reviews). Of particular
importance with respect to the present study is that recruitment of
eosinophils and lymphocytes from the vasculature has been shown to be,
in part, a P-selectin-dependent process (4, 29, 31, 32). Deficiency of
P-selectin could, therefore, result in defects in eosinophil migration
to the tissues or in antigen recognition. Finally, it is now
established that P-selectin functions as more than an adhesion
molecule, the sole function of which is to engage leukocytes in the
rolling process; in addition, P-selectin mediates transduction of
proinflammatory signals on interaction with its ligand (2, 6,
35). Based on these known properties of P-selectin, we
postulated that mice deficient in P-selectin through targeted deletion
(19) would display diminished physiological and inflammatory responses
to OVA sensitization and challenge. Our data showed that the (/) mice were 1) not different from
(+/+) mice with respect to their IgE response,
2) failed to manifest a significant
increase in airway hyperresponsiveness in response to allergen
challenge, 3) had decreased
eosinophil and T-lymphocyte recruitment into the airways, and
4) had diminished IL-4 recovery from
the airway. These data indicate that P-selectin contributes to the
magnitude of allergic phenotypical changes in the mouse but is not
solely responsible for the occurrence of these changes.
The sensitization and challenge procedures employed in this study have
been shown to increase levels of total and OVA-specific IgE as well as
OVA-specific IgG1 in BALB/c mice (25). The BALB/c mouse is
known to be a high IgE responder when sensitized to OVA in this manner (12) and is, therefore, highly likely to develop an IgE
response with the protocols used. However, we were able to replicate
these findings in both C57BL/6J (+/+) and (/) mice (Fig. 1, Table
1). These data indicate that antigen uptake, presentation, and
processing, as well as interactions between the antigen-presenting cells and lymphocytes, do not require P-selectin. Therefore, the consequences of P-selectin deficiency in this model are localized to
the inflammatory-effector reactions that lead to airway
hyperresponsiveness.
With respect to lymphocyte recruitment during the aerosol exposure to
OVA, P-selectin likely contributed to the accumulation of
CD3+/IL-2R+
cells found in the BAL fluid, as (/) mice had fewer of such cells
compared with the (+/+) mice after OVA challenge. One might have
predicted that, with fewer lymphocytes and less IL-4, (/) mice
would produce less IgE, because IL-4 is known to serve as the isotype
switch for IgE production (15, 27). Therefore, either small amounts of
IL-4 are adequate to achieve IgE switching or the diminished IL-4
observed in the BAL fluid does not reflect the IL-4 levels at the locus
where the commitment to IgE production occurs.
With respect to eosinophil recruitment, it has been shown by others
that (/) mice have increased circulating white blood cell counts
(19). Although we do not have data on circulating leukocyte numbers, we
did demonstrate that there were no differences in the differential
leukocyte counts. Even with what was likely to be an increased number
of circulating eosinophils, (/) mice did not as effectively
recruit these cells from the circulation in response to OVA challenge
as did (+/+) mice. It has been shown in some models (7), but not
others (1), that eosinophilic infiltration in the airways is a
critical step in developing airway hyperresponsiveness in mice. Because
C57BL/6J mice are the genetic background of the mice in which
eosinophils have been shown to be critical, and this is the background
strain of the (/) mice used in this study, our data support the
concept that the observed decrease in eosinophil accumulation
contributed to the decreased capacity to develop airway
hyperresponsiveness after antigen challenge. Interestingly, even though
there was >90% decrease in eosinophil recruitment, airway
responsiveness was only diminished by a factor of about two. This
observation is consistent with the hypothesis that there are other cell
types contributing to expression of this phenotypical characteristic or
that small numbers of eosinophils are sufficient to partially modify
airway responsiveness.
We find it most interesting that, among the findings in this study, P-selectin deficiency was associated with a failure to manifest a significant increase in airway responsiveness. Given that eosinophils and lymphocytes can be recruited from the circulation by interaction between a number of molecular adhesion ligands and receptors, our data indicate that these molecular adhesion events are not extensively reduplicated with respect to allergic inflammation. Thus allergic inflammation differs from other acute inflammatory events, such as the recruitment of granulocytes from the pulmonary circulation during Pseudomonas-induced pneumonia or cobra venom factor-induced increases in neutrophil-mediated permeability changes in which isolated P-selectin deficiency is not associated with a decreased neutrophil response (21, 23). Modifying the expression of P-selectin has the potential to modify the airway microenvironment that subsequently leads to airway hyperresponsiveness.
ACKNOWLEDGEMENTS
The authors acknowledge the technical expertise provided by the Foothills Hospital Pathology Laboratory, Calgary, Alberta, Canada, for processing the tissue samples. The analysis of lung resistance was performed by using software provided by Andrew Jackson (Biomedical Engineering at Boston University). The authors also thank Gerry Gleich (Mayo Clinic) for providing EPO standards.
FOOTNOTES
Address for reprint requests: J. M. Drazen, Pulmonary Div., Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115.
Received 20 December 1996; accepted in final form 22 April 1997.
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