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Division of Biochemistry and Molecular Biology and
Division of Immunology and Cell Biology, John Curtin School of Medical Research, Australian National University, Canberra, Australia; and
Division of Pulmonary Medicine, Allergy, and Clinical Immunology, Department of Pediatrics, Children’s Hospital Medical Center, Cincinnati, OH 45227
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The trafficking of eosinophils to the airways is a complex process that may be regulated by a multiplicity of cytokines, chemokines, adhesion molecules, and lipid mediators (2, 17, 18). Collectively, these molecules form a coordinate network that regulates eosinophil development, release from the bone marrow, accumulation, effector function, and survival in tissues. Once recruited to tissues, eosinophils receive signals that promote degranulation and the secretion of cytokines. Investigations in vitro also indicate the potential role of various cytokines, lipid mediators, and Igs as triggers for the induction of degranulation (3, 19, 20). Of the inflammatory mediators postulated to contribute to the regulation of eosinophil trafficking and degranulation, only IL-5 and eotaxin have been identified to selectively regulate eosinophil function.
Investigations suggest that eotaxin plays an integral role in the baseline homing of eosinophils to mucosal tissues and during the early phase of eosinophil recruitment following allergen challenge (21, 22, 23, 24, 25). Eotaxin may also regulate the mobilization of eosinophils and their precursors into the blood (23, 25, 26). IL-5 regulates the growth, differentiation, and activation of eosinophils, and has been strongly implicated in the etiology of asthma (27, 28, 29, 30, 31, 32). Studies with IL-5-deficient (IL-5-/-) mice indicate that this cytokine provides an essential signal for the induction of blood and pronounced tissue eosinophilia that is observed during allergic lung inflammation (33). A limited number of studies suggest that eotaxin and IL-5 cooperate to regulate eosinophil trafficking at baseline and during allergic inflammation (34, 35, 36). The accumulation of eosinophils into the skin of guinea pigs and mice in response to eotaxin is amplified by the i.v. administration of IL-5 (34, 35). Furthermore, eotaxin-induced recruitment of eosinophils into the skin and lungs is only consistently observed in transgenic mice that constitutively express elevated levels of IL-5 and have a pronounced blood eosinophilia (36). In addition to regulating eosinophil trafficking, both IL-5 and eotaxin have also been implicated in the mechanism leading to the activation of eosinophils (30, 37). However, the physiological significance of these in vitro degranulation studies to the fundamental processes initiating eosinophil degranulation in the airways and subsequent induction of AHR has not been defined.
In asthma, IL-5 levels are often elevated in the lung and blood, suggesting that this cytokine has the potential to regulate eosinophil function in both compartments (29). Although IL-5 and eotaxin cooperate to selectively regulate tissue eosinophilia, the role of these cytokines in regulating blood and airways eosinophilia, eosinophil degranulation, and AHR when expressed in the lung has not been fully determined. In this investigation, we have employed a transgene approach to selectively identify the roles played by IL-5 and eotaxin in eosinophil recruitment and degranulation and the development of AHR. By gene transfer of eotaxin and/or IL-5 to the airways of naive mice, we have investigated the effect of transient expression of these molecules on the level of blood and airways eosinophils and their activation status in the lung. Furthermore, we determine whether IL-5 and eotaxin provide key signals for the induction of AHR to cholinergic stimuli. In addition, we have also employed our transgene model in naive mice to selectively examine the effect of Ag inhalation on eosinophil degranulation and AHR in the presence of eotaxin and IL-5.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 mice (male, 6–8 wk old) and strain-matched IL-5-deficient mice (38) were supplied by Pathogen Free facilities at the John Curtin School of Medical Research, Australian National University (Canberra, Australia).
Construction of recombinant vaccinia viruses
A recombinant vaccinia virus (VV) containing murine eotaxin cDNA (VV-HA-eotaxin) under the control of the P7.5 VV promoter was generated as previously described (39, 40). Briefly, VV-HA-eotaxin was constructed from VV-HA-PR8, which carries the hemagglutinin (HA) gene of the influenza virus A/PR/8/34 and the thymidine kinase (TK) gene of the HSV in the HindIII sites of the J and F regions, respectively. Recombinant virus was purified using marker rescue of the TK gene under methotrexate selection. VV-HA-IL-5 and the control virus (VV-HA-TK) were previously constructed (39). Expression of encoded IL-5 (39) and eotaxin (unpublished data (eosinophil-specific migration assays)) by VV-HA-IL-5 and VV-HA-eotaxin was confirmed by specific bioassay in vitro.
Analysis of viral growth in vivo
Mice were given an intranasal (i.n.) inoculum of 1 x 107 PFU of VV-HA-eotaxin, VV-HA-IL-5, or VV-HA-TK, or a co-inoculum of 0.5 x 107 PFU each of VV-HA-eotaxin and VV-HA-IL-5. At 1–5, 7, and 9 days after viral inoculation, mice were sacrificed by cervical dislocation and the lungs removed under sterile conditions. Lung viral titers were determined by titration on 143B cell monolayers (39).
Application of recombinant VV constructs: two regimes employing VV constructs were designed
Regime A.
Mice were given i.n. 1 x 107 PFU of
VV-HA-eotaxin, VV-HA-IL-5, or VV-HA-TK, or a co-inoculum of 0.5 x
107 PFU each of VV-HA-eotaxin and VV-HA-IL-5
(Fig. 1
a, day 1). Four days
later (peak viral titer, day 5), IL-5 (200 pmol/kg) or control vehicle
(100 µl of 0.1% BSA/PBS, pH 7.4) was injected i.v. (Fig. 1a). Leukocyte levels in the bronchoalveolar lavage fluid
(BALF) were determined on day 6 (24 h after i.v. IL-5) after washing
the lungs with 2 x 1 ml of HBSS (33) (Fig. 1a).
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b). On day 4, VV-HA-eotaxin
and VV-HA-IL-5 (0.5 x 107 PFU/virus) or
VV-HA-TK (1 x 107 PFU) was administered
i.n. Four days after viral inoculation (day 8), IL-5 (200 pmol/kg) or
control vehicle (100 µl of PBS/0.1% BSA, pH 7.4) was injected i.v.
On day 9 or 11, leukocyte numbers and levels of MBP in the BALF and
histology were analyzed. The induction of a late-phase AHR to
ß-methylcholine was determined on day 11 (Fig. 1b).
Responses in saline-treated mice were characterized
simultaneously. The effect of eotaxin and/or IL-5 expression on the induction of blood and airways eosinophilia
Mice were treated as described in regime A. In addition, blood smears were taken daily postviral inoculations, and the percentage of eosinophils in the total circulating leukocyte population was determined by differential staining (33). Blood samples were also taken before, and at 30 min i.v. postinjection to confirm the induction of blood eosinophilia by IL-5. Blood eosinophil levels were determined using the method of Discombe (41).
The effect of the coexpression of eotaxin and IL-5 in the airways on eosinophil degranulation and the induction of AHR
VV-HA-eotaxin and VV-HA-IL-5 or VV-HA-TK was administered i.n., and IL-5 or control vehicle was injected i.v., as described in regime A. On day 8, the airways were analyzed for the induction of a late-phase AHR to ß-methylcholine and for the presence of eosinophils and morphological changes. Leukocyte infiltration into the BALF and the presence of extracellular MBP in BALF supernatants were also determined.
The effect of Ag inhalation on eosinophil degranulation and AHR in the presence of eotaxin and IL-5
Mice were treated as described in regime B. In addition, groups of IL-5-/- mice were also exposed to viral constructs and i.v. treatments, and challenged with saline or OVA.
Determining the role of CD4+ T cells in the induction of eosinophil degranulation and AHR
Mice were treated as described in regime B. In addition, on days 1 and 6, 1 mg of anti-CD4 mAb (clone GK1.5) or of rat isotype control IgG mAb (clone GL113) was injected i.p. We have previously shown that this treatment regime results in the depletion of CD4+ T cells in the spleen and peribronchial lymph nodes during the course of OVA inhalation and inhibits the development of CD4+ Th2 cell-dependent allergic disease of the lung (42).
Induction of allergic airways inflammation and AHR
To compare airways reactivity after IL-5 and eotaxin gene transfer experiments with that which occurs in models of allergic lung disease, mice were sensitized by i.p. injection with 50 µg OVA/1 mg Alhydrogel (CSL, Parkville, Australia) in 0.9% sterile saline on days -24 and -12. Nonsensitized mice received 1 mg of Alhydrogel in 0.9% saline (33). From day 1, both groups of mice were aeroallergen challenged (OVA), and AHR was measured as described in regime B. Comparisons were made between controls that were positive (OVA sensitized and aerosol) or negative (saline i.p. and OVA aerosol) for the development of AHR.
Detection of free MBP in BALF
BALF was centrifuged (350 x g, 4°C) for 5 min. Aliquots of supernatant were removed and analyzed by immunoblot for the presence of MBP, as previously described (42).
The analysis of histological sections and leukocyte populations in the blood and BALF
Transverse sections (
4 mm wide) of lung were cut from the
left lobe and fixed in 10% neutral buffered Formalin for a minimum of
24 h. Samples were then processed by the Histology Unit (John
Curtin School of Medical Research, Australian National University).
Leukocytes in the blood, BALF, and lung were identified by
morphological criteria after differential staining with
Giemsa-May-Grunwald (33, 42). Routinely, 300–400 cells
were counted per slide.
Measurement of AHR
AHR was measured with a bronchospasm transducer (Ugo Basil 7020), which was coupled to a Lab Mac/8 analysis station (AdInstruments, Sydney, Australia), as previously described (33). Changes in respiratory overflow volume were determined during cumulative i.v. administration of ß-methylcholine. The increase in respiratory overflow volume provoked by ß-methylcholine is represented as a percentage of maximal airways occlusion.
Materials
Mouse rIL-5 was expressed and purified from the baculovirus expression system (43), and protein levels were estimated by OD at 280 nm and Bio-Rad (Richmond, CA) protein assay using gamma-globulin as the standard.
Statistical analysis
The significance of differences between experimental groups was analyzed using Student’s unpaired t test. Differences in means were considered significant if p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The kinetics of viral growth and clearance in the lung were
similar for VV-HA-eotaxin and VV-HA-TK when inoculated with 1 x
107 PFU (Fig. 2a). Viral titers peaked 4 to
5 days after administration (106 PFU/lung) and
subsequently declined to undetectable levels
(<102 PFU/lung) by day 9. Growth and clearance
of VV-HA-eotaxin or VV-HA-TK (Fig. 2a) in the lung were also
similar to co-inoculation with VV-HA-eotaxin and VV-HA-IL-5 (0.5
x 107 PFU/virus) (Fig. 2b) and to
that previously reported for VV-HA-IL-5 (at 1 x
107 PFU) (39). Thus, vaccinia growth
and clearance from the lung were not affected by the expression of IL-5
or eotaxin, alone or in combination, and the kinetics were similar to
the control virus (Fig. 2).
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Exposure of the lung to VV-HA-eotaxin or VV-HA-IL-5 or in
combination (eotaxin + IL-5) induced a pronounced and selective airways
eosinophilia that peaked 6 days after administration (regime A, Fig. 3). Furthermore, VV-HA-eotaxin and
VV-HA-IL-5 were equipotent at inducing airways eosinophilia. The level
of eosinophils in the BALF in the presence of VV-HA-TK (control) was
similar to that observed in nontreated mice (<0.2 x
103 eosinophils/ml BALF). Notably, airways
eosinophilia induced by eotaxin and/or IL-5 was significantly
amplified by the i.v. administration of IL-5 on the day of peak viral
titers (Fig. 3). The coexpression of eotaxin and IL-5 in conjunction
with i.v. IL-5 treatment induced the most potent and sustained airways
eosinophilia. The numbers of neutrophils, lymphocytes, and macrophages
in the BALF were not significantly different between groups treated
with viral constructs (results not shown; moreover, the levels of these
cells in BALF from VV-HA-eotaxin, VV-HA-IL-5, VV-HA-TK, or coexpression
studies on day 6 were not significantly different from those shown for
day 8, 48 h later (see Fig. 5a)). Intravenous IL-5
induces a pronounced blood eosinophilia that peaks rapidly (30 min) and
declines to baseline levels over 5 h (results not shown), as
previously reported (34). Eosinophils (albeit slowly
declining in numbers) localized to the airways for more than 7 days
(>103 eosinophils/ml BALF 7 days after i.v. IL-5
treatment). Notably, the expression of IL-5 or eotaxin or both
cytokines in the lung failed to significantly increase blood eosinophil
levels (results not shown).
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B). Eosinophils were also
observed migrating through the vasculature (not shown). Similar results
were obtained with the expression of eotaxin or IL-5 alone (results not
shown). Eosinophils in the peribronchial regions were predominantly
localized to areas associated with the airways smooth muscle (ASM)
layer. In marked contrast to VV-HA-eotaxin- and/or VV-HA-IL-5-treated
airways, eosinophils were detected infrequently in the lungs exposed to
VV-HA-TK (Fig. 4A). Eosinophilia induced by eotaxin and IL-5
did not result in morphological changes (epithelial cell shedding,
goblet cell hyperplasia, or increased mucus production) to the
respiratory epithelium (Fig. 4B). Collectively, these
results show that eotaxin and IL-5 operate mechanisms both
independently and cooperatively within the lung to promote eosinophil
chemotaxis and localization to the airways.
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Although coexpression of eotaxin and IL-5 selectively induced a
significant BALF and airways eosinophilia (Fig. 3, day 6, and Fig. 5a, day 8), they did not
induce a late-phase AHR to the cholinergic agonist ß-methylcholine
(Fig. 5b, only data for day 8 shown). Furthermore, no MBP
was detected in cell-free extracts of BALF taken from the airways
expressing eotaxin and IL-5 on day 6 or 8 (Table I). As a control for the development of
these features of allergic disease, responses after VV-HA-eotaxin and
VV-HA-IL-5 treatment were compared with those observed in an
established model of allergic airways disease. Intraperitoneal
sensitization and subsequent induction of allergic airways disease by
OVA inhalation (BALF inflammatory cell numbers not shown) resulted in
the development of marked AHR (Fig. 5b, positive control)
and the detection of a strong signal for MBP on immunoblots of
cell-free BALF (Table I). Furthermore, baseline airways reactivity in
VV-HA-eotaxin- and VV-HA-IL-5-treated lung was similar to that observed
in the absence of airways eosinophilia in VV-HA-TK-treated and negative
control mice. Thus, although eotaxin and IL-5 expression regulated
eosinophilia within the lung compartment, signals elicited by these
cytokines did not induce eosinophil degranulation or AHR. Furthermore,
exposure of the airways to viral constructs did not affect baseline
airways reactivity.
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Next, the airways of naive mice expressing eotaxin and IL-5 (and
control groups) were exposed to OVA or saline to determine whether
signals associated with Ag inhalation could activate airways
eosinophils and induce immunopathological responses associated with
allergic disease of the lung (regime B). OVA inhalation over a 7-
to10-day period does not induce eosinophilia, AHR, or allergic
pathological lesions to the respiratory epithelium (33, 34, 44). OVA inhalation (Fig. 1b) did not significantly
affect the levels of eosinophils, lymphocytes, or neutrophils in the
BALF in the presence of VV-HA-IL-5 and VV-HA-eotaxin or VV-HA-TK (Fig. 6a, only results for day 11
shown). However, macrophage numbers in the BALF were significantly
higher in both of the groups treated with viral constructs
(p < 0.05) following OVA inhalation, when
compared with saline-exposed controls (Fig. 6a, day 11).
Strikingly, in the airways expressing eotaxin and IL-5, OVA inhalation
resulted in the induction of eosinophil degranulation (free MBP in the
BALF) (Table I) and AHR to ß-methylcholine (Fig. 6b). The
eotaxin/IL-5-regulated airways eosinophilia did not predispose to the
development of these immunopathological features of allergy in the
saline-treated group (Fig. 6 and Table I) or with VV-HA-IL-5 and
VV-HA-eotaxin alone (Fig. 5). Similarly, these features were not
observed in the airways exposed to VV-HA-TK and OVA (Fig. 6 and Table I). Notably, AHR in the model of allergic lung disease (positive
control) that was induced by i.p. sensitization and aerosol challenge
with OVA was more pronounced in comparison with that observed in the
airways of naive mice when eotaxin and IL-5 were expressed in the
presence of OVA (Fig. 6b). OVA inhalation and/or viral
constructs (Fig. 6b) did not effect basal AHR. Although
eotaxin and IL-5 expression induced eosinophil degranulation and AHR in
the presence of OVA, no pronounced morphological changes to the airways
were observed (histology not shown). Furthermore, the eosinophils that
were present in the airways were consistently and predominantly
localized to regions associated with ASM. These results strongly
suggest that signals elicited during Ag inhalation in the lung can
result in degranulation of airways eosinophils and predispose to the
development of enhanced bronchial reactivity.
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Eosinophil degranulation and the development of AHR in the lungs expressing eotaxin and IL-5 in the presence of OVA are CD4+ T cell dependent
The development of the immunopathological processes associated
with allergic airways disease has been shown to be exclusively
regulated by CD4+ T cells in mouse models
(42). To determine the role of CD4+
T cells in the induction of AHR and eosinophil degranulation in the
presence of OVA inhalation and VV-HA-IL-5 and VV-HA-eotaxin,
anti-CD4 mAb or isotype control was administered i.p. Anti-CD4 mAb
(or isotype control) treatment did not affect individual leukocyte
levels in the BALF (Fig. 7a).
However, anti-CD4 mAb (but not isotype control) inhibited
eosinophil degranulation (Table I) and the development of AHR (Fig. 7b). Numbers of leukocytes in the BALF after VV-HA-TK and
OVA treatments in the presence of anti-CD4 mAb or isotype control
were similar (results not shown) and not significantly different from
the data shown for VV-HA-TK + OVA (Fig. 7a). AHR was also
measured after VV-HA-TK and OVA treatment in the presence of
anti-CD4 (GK1.5) (Fig. 7b) or control Ab (GL113) (not
shown), and responses were not significantly different between these
groups.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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When compartmentalized to tissues, the role of IL-5 in eosinophil chemotaxis is controversial (22, 24, 25, 33, 34, 45). In particular, after gene transfer of IL-5 by adenoviral vectors to IL-5-/- mice, it was postulated that IL-5 in the circulation and not lung production of this cytokine was essential for promoting blood and airways eosinophilia after sensitization and aeroallergen challenge (44). The potent chemotactic signal elicited by IL-5 and eotaxin in our investigation also failed to induce a pronounced airways or blood eosinophilia in naive IL-5-/- (but not in wild-type) mice. However, we have previously shown that transient expression of IL-5 in the lungs of allergic mice deficient in this cytokine reconstitutes both blood and airways eosinophilia after allergen inhalation (33). This and other investigations indicate that additional factors released from the site of Ag challenge are required to amplify the IL-5 signal to generate both airways eosinophilia and allergic responses (33, 34, 44). Attempts to induce eosinophil trafficking in IL-5-/- mice are compounded by the extremely low circulating and tissue levels of eosinophils. It is likely that IL-5 expression in the lung of IL-5-/- mice with adenoviral or VV vectors was not sufficient to reconstitute basal levels of eosinophils and thus promote trafficking of this leukocyte to the airways (44 and this study). Furthermore, it is possible that other factors (such as eotaxin) within the lung that are required to augment the IL-5 signal for the induction of eosinophilia were not sufficiently induced by the sensitization and Ag inhalation protocol employed (44). Our data show that when expressed in the lung of wild-type mice, IL-5 elicits a chemotactic signal (directed migration to the airways) for eosinophils and that this response occurs in the absence of a peripheral blood eosinophilia. Thus, IL-5 operates mechanisms within the lung and in the circulation to regulate eosinophilia, and these mechanisms may potentially operate in asthma (29). Furthermore, eotaxin and IL-5 act in synergy to specifically coordinate blood and tissue eosinophilia (26, 34).
Although eotaxin and IL-5 selectively regulate eosinophil migration, the signals elicited by these cytokines failed to promote the release of MBP, predispose to morphological changes of the airways wall, or enhance airways reactivity to cholinergic stimuli. These results are in marked contrast to the constitutive overexpression of IL-5 in the airways of transgenic mice in which morphological changes to the respiratory epithelium and AHR were observed (46). Sustained exposure of eosinophils to IL-5 induces degranulation, and this process may underlie the pathophysiological changes observed in the airways of these and other studies performed in IL-5 transgenic mice (46, 47). Our model of airways eosinophilia was designed to mimic the transient expression of IL-5 and eotaxin that is observed after allergen inhalation and acute exacerbation of asthma and to avoid the pathophysiological features associated with chronic exposure to these cytokines. Our results support data that eosinophils alone in the airways are not sufficient to induce AHR (48, 49) and suggest that other factors linked with allergic inflammation in association with IL-5 and eotaxin trigger degranulation and AHR.
To determine whether factors elicited by Ag inhalation in the lung predisposed to eosinophil degranulation and AHR, we exposed the airways of naive mice to OVA in the presence of an airways eosinophilia induced by eotaxin and IL-5. Strikingly, immunological processes associated with Ag inhalation resulted in signals that induced eosinophil degranulation (release of MBP) and enhanced airways reactivity to cholinergic stimuli. Importantly, OVA inhalation alone did not induce a blood or airways eosinophilia or significantly amplify eosinophil numbers in these compartments in the presence of IL-5 and eotaxin; thus, induction of these immunopathological features of allergy was only associated with airways eosinophils and IL-5 and eotaxin expression. Notably, expression of IL-5 and eotaxin in the airways of naive IL-5-/- mice failed to promote airways eosinophilia or AHR in response to Ag inhalation. These results strongly suggest that the eosinophil and not these cytokines alone predisposed to the development of AHR. In asthmatics, eosinophils are often resident in the airways mucosa even at quiescent periods, and their contribution to the induction of the asthma after allergen inhalation is unknown (1, 3). Our data suggest that latent eosinophils that are localized to the airways wall can become activated after Ag provocation and mediate AHR.
Notably, the mechanism for the induction of eosinophil degranulation and AHR was dependent on CD4+ T cells. Furthermore, we have preliminary data that suggest OVA inhalation does not predispose to eosinophil degranulation or AHR in MHC-II-deficient mice after IL-5 and eotaxin gene transfer (not shown). Thus, our results suggest that Ag uptake and processing by professional APC in the lung result in the expansion of CD4+ T cells, which subsequently trigger airways eosinophils to degranulate. The mechanism for the induction of CD4+ T cell-mediated AHR in this model is yet to be defined. However, a direct correlation between the presence of MBP in the BALF, localization of eosinophils to the ASM band, and the induction of AHR was observed. Notably, in our investigation, AHR occurred independently of pronounced morphological changes to the respiratory epithelium. Thus, MBP may induce AHR by directly acting on smooth muscle as well as through its cytotoxic properties upon the respiratory epithelium (9, 10, 50). It is tempting to speculate that IL-13 liberated from CD4+ T cells may play a key role in eosinophil activation and/or the induction of AHR (51, 52).
Although it is likely that AHR was mediated through CD4+ T cell-regulated eosinophil degranulation, it should be noted that there is potential for bidirectional signaling between these two leukocytes. Eosinophils express MHC class II molecules (53, 54) and secrete a range of proinflammatory cytokines and chemokines that are CD4+ T cell growth factors and chemoattractants (1, 2, 3, 55). GM-CSF expression in the lung and the subsequent recruitment of eosinophils to the airways have also been shown to increase local Ag-presenting capacity to OVA inhalation in naive mice and promote T cell-mediated features of allergy (56). It should be noted that depletion of CD4+ T cells may also have complex effects in terms of both immune responsiveness as well as eosinophils activation. Importantly, we show that CD4+ T cells play a central role in the degranulation of airways eosinophils. Furthermore, CD4+ T cells and eosinophils may collaborate to directly modulate AHR.
In this investigation, we provide new insights into the mechanisms that regulate the selective recruitment and degranulation of airways eosinophils and induce the development of AHR. Collectively, our results show that IL-5 and eotaxin act in synergy to provide elemental signals within the lung for the recruitment of eosinophils to the airways. Importantly, IL-5 not only regulates eosinophil migration from the bone marrow, but also eosinophilia within the lung. Moreover, we demonstrate that CD4+ T cells play a key role in the release of MBP from eosinophils and in the subsequent induction of AHR during Ag inhalation. Targeting both IL-5- and eotaxin-regulated eosinophilia in the lung and the bone marrow compartments may be required to effectively resolve chronic lesions and AHR in asthma.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Paul S. Foster, Division of Biochemistry and Molecular Biology, John Curtin School of Medical Research, Australian National University, Canberra, ACT 0200, Australia. E-mail address:
3 Abbreviations used in this paper: AHR, airways hyperreactivity; ASM, airways smooth muscle; BALF, bronchoalveolar lavage fluid; HA, hemagglutinin; i.n., intranasal; MBP, major basic protein; TK, thymidine kinase; VV, vaccinia virus.
Received for publication September 7, 1999. Accepted for publication December 8, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RII induce eosinophil degranulation. J. Clin. Invest. 95:2813.
4 integrin-dependent eotaxin induction of bronchial hyperresponsiveness and eosinophil migration in interleukin-5 transgenic mice. Am. J. Respir. Cell Mol. Biol. 20:992. expression. J. Immunol. 150:2554.[Abstract]
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 A. Hoshino, T. Tsuji, J. Matsuzaki, T. Jinushi, S. Ashino, T. Teramura, K. Chamoto, Y. Tanaka, Y. Asakura, T. Sakurai, et al. STAT6-mediated signaling in Th2-dependent allergic asthma: critical role for the development of eosinophilia, airway hyper-responsiveness and mucus hypersecretion, distinct from its role in Th2 differentiation Int. Immunol., October 1, 2004; 16(10): 1497 - 1505. [Abstract] [Full Text] [PDF]
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M. S. Thomas, S. L. Kunkel, and N. W. Lukacs Regulation of Cockroach Antigen-Induced Allergic Airway Hyperreactivity by the CXCR3 Ligand CXCL9 J. Immunol., July 1, 2004; 173(1): 615 - 623. [Abstract] [Full Text] [PDF]
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 T. R. Johnson, M. N. Teng, P. L. Collins, and B. S. Graham Respiratory Syncytial Virus (RSV) G Glycoprotein Is Not Necessary for Vaccine-Enhanced Disease Induced by Immunization with Formalin-Inactivated RSV J. Virol., June 1, 2004; 78(11): 6024 - 6032. [Abstract] [Full Text] [PDF]
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K. Clark, L. Simson, N. Newcombe, A. M. L. Koskinen, J. Mattes, N. A. Lee, J. J. Lee, L. A. Dent, K. I. Matthaei, and P. S. Foster Eosinophil degranulation in the allergic lung of mice primarily occurs in the airway lumen J. Leukoc. Biol., June 1, 2004; 75(6): 1001 - 1009. [Abstract] [Full Text] [PDF]
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U. Atasoy, S. L. Curry, I. Lopez de Silanes, A.-B. Shyu, V. Casolaro, M. Gorospe, and C. Stellato Regulation of Eotaxin Gene Expression by TNF-{alpha} and IL-4 Through mRNA Stabilization: Involvement of the RNA-Binding Protein HuR J. Immunol., October 15, 2003; 171(8): 4369 - 4378. [Abstract] [Full Text] [PDF]
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 M. A. Carey, D. R. Germolec, J. A. Bradbury, R. A. Gooch, M. P. Moorman, G. P. Flake, R. Langenbach, and D. C. Zeldin Accentuated T Helper Type 2 Airway Response after Allergen Challenge in Cyclooxygenase-1-/- but Not Cyclooxygenase-2-/- Mice Am. J. Respir. Crit. Care Med., June 1, 2003; 167(11): 1509 - 1515. [Abstract] [Full Text] [PDF]
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 C. Buttner, A. Lun, T. Splettstoesser, G. Kunkel, and H. Renz Monoclonal anti-interleukin-5 treatment suppresses eosinophil but not T-cell functions Eur. Respir. J., May 1, 2003; 21(5): 799 - 803. [Abstract] [Full Text] [PDF]
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A. Holub, J. Byrnes, S. Anderson, L. Dzaidzio, N. Hogg, and A. Huttenlocher Ligand density modulates eosinophil signaling and migration J. Leukoc. Biol., May 1, 2003; 73(5): 657 - 664. [Abstract] [Full Text] [PDF]
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G. Wohlleben, J. Muller, U. Tatsch, C. Hambrecht, U. Herz, H. Renz, E. Schmitt, H. Moll, and K. J. Erb Influenza A Virus Infection Inhibits the Efficient Recruitment of Th2 Cells into the Airways and the Development of Airway Eosinophilia J. Immunol., May 1, 2003; 170(9): 4601 - 4611. [Abstract] [Full Text] [PDF]
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P. C. Reading, J. A. Symons, and G. L. Smith A Soluble Chemokine-Binding Protein from Vaccinia Virus Reduces Virus Virulence and the Inflammatory Response to Infection J. Immunol., February 1, 2003; 170(3): 1435 - 1442. [Abstract] [Full Text] [PDF]
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B. Lamkhioued, S. G. Abdelilah, Q. Hamid, N. Mansour, G. Delespesse, and P. M. Renzi The CCR3 Receptor Is Involved in Eosinophil Differentiation and Is Up-Regulated by Th2 Cytokines in CD34+ Progenitor Cells J. Immunol., January 1, 2003; 170(1): 537 - 547. [Abstract] [Full Text] [PDF]
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W. N. Rom, M. Weiden, R. Garcia, T. A. Yie, P. Vathesatogkit, D. B. Tse, G. McGuinness, V. Roggli, and D. Prezant Acute Eosinophilic Pneumonia in a New York City Firefighter Exposed to World Trade Center Dust Am. J. Respir. Crit. Care Med., September 15, 2002; 166(6): 797 - 800. [Abstract] [Full Text]
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 K. H. Mohamed, A. I. Abdelhamid, Y. C. G. Lee, K. B. Lane, B. Conner, M. Hawthorne, and R. W. Light Pleural Fluid Levels of Interleukin-5 and Eosinophils Are Closely Correlated* Chest, August 1, 2002; 122(2): 576 - 580. [Abstract] [Full Text] [PDF]
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J. M. Schuh, K. Blease, S. L. Kunkel, and C. M. Hogaboam Eotaxin/CCL11 is involved in acute, but not chronic, allergic airway responses to Aspergillus fumigatus Am J Physiol Lung Cell Mol Physiol, July 1, 2002; 283(1): L198 - L204. [Abstract] [Full Text] [PDF]
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J. B. Domachowske, C. A. Bonville, A. J. Easton, and H. F. Rosenberg Pulmonary eosinophilia in mice devoid of interleukin-5 J. Leukoc. Biol., June 1, 2002; 71(6): 966 - 972. [Abstract] [Full Text] [PDF]
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M. F. Gurish, A. Humbles, H. Tao, S. Finkelstein, J. A. Boyce, C. Gerard, D. S. Friend, and K. F. Austen CCR3 Is Required for Tissue Eosinophilia and Larval Cytotoxicity After Infection with Trichinella spiralis J. Immunol., June 1, 2002; 168(11): 5730 - 5736. [Abstract] [Full Text] [PDF]
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E.-B. Haddad, S. L. Underwood, D. Dabrowski, M. A. Birrell, K. McCluskie, C. H. Battram, M. Pecoraro, M. L. Foster, and M. G. Belvisi Critical Role for T Cells in Sephadex-Induced Airway Inflammation: Pharmacological and Immunological Characterization and Molecular Biomarker Identification J. Immunol., March 15, 2002; 168(6): 3004 - 3016. [Abstract] [Full Text] [PDF]
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J. R. Crosby, H. H. Shen, M. T. Borchers, J. P. Justice, T. Ansay, J. J. Lee, and N. A. Lee Ectopic expression of IL-5 identifies an additional CD4+ T cell mechanism of airway eosinophil recruitment Am J Physiol Lung Cell Mol Physiol, January 1, 2002; 282(1): L99 - L108. [Abstract] [Full Text] [PDF]
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 E L J van Rensen, R G Stirling, J Scheerens, K Staples, P J Sterk, P J Barnes, and K F Chung Evidence for systemic rather than pulmonary effects of interleukin-5 administration in asthma Thorax, December 1, 2001; 56(12): 935 - 940. [Abstract] [Full Text] [PDF]
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J. R. MacKenzie, J. Mattes, L. A. Dent, and P. S. Foster Eosinophils Promote Allergic Disease of the Lung by Regulating CD4+ Th2 Lymphocyte Function J. Immunol., September 15, 2001; 167(6): 3146 - 3155. [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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J. Mattes, M. Yang, A. Siqueira, K. Clark, J. MacKenzie, A. N. J. McKenzie, D. C. Webb, K. I. Matthaei, and P. S. Foster IL-13 Induces Airways Hyperreactivity Independently of the IL-4R{alpha} Chain in the Allergic Lung J. Immunol., August 1, 2001; 167(3): 1683 - 1692. [Abstract] [Full Text] [PDF]
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C. LAMBLIN, F. BOLARD, P. GOSSET, A. TSICOPOULOS, T. PEREZ, J. DARRAS, A. JANIN, A. B. TONNEL, Q. HAMID, and B. WALLAERT Bronchial Interleukin-5 and Eotaxin Expression in Nasal Polyposis . Relationship with (A)symptomatic Bronchial Hyperresponsiveness Am. J. Respir. Crit. Care Med., April 1, 2001; 163(5): 1226 - 1232. [Abstract] [Full Text]
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L. R. Hall, E. Diaconu, R. Patel, and E. Pearlman CXC Chemokine Receptor 2 But Not C-C Chemokine Receptor 1 Expression Is Essential for Neutrophil Recruitment to the Cornea in Helminth-Mediated Keratitis (River Blindness) J. Immunol., March 15, 2001; 166(6): 4035 - 4041. [Abstract] [Full Text] [PDF]
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 M. Malm-Erjefalt, C. G. A. Persson, and J. S. Erjefalt Degranulation Status of Airway Tissue Eosinophils in Mouse Models of Allergic Airway Inflammation Am. J. Respir. Cell Mol. Biol., March 1, 2001; 24(3): 352 - 359. [Abstract] [Full Text] [PDF]
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K. L. Denzler, S. C. Farmer, J. R. Crosby, M. Borchers, G. Cieslewicz, K. A. Larson, S. Cormier-Regard, N. A. Lee, and J. J. Lee Eosinophil Major Basic Protein-1 Does Not Contribute to Allergen-Induced Airway Pathologies in Mouse Models of Asthma J. Immunol., November 15, 2000; 165(10): 5509 - 5517. [Abstract] [Full Text] [PDF]
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