1 Division of Cell Biology, Department of Pediatrics, and 3 Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado 80206; and 2 Mayo Clinic Scottsdale, Scottsdale, Arizona 85259
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ABSTRACT |
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Different strains of mice exhibit different degrees of airway hyperresponsiveness after sensitization to and airway challenge with ovalbumin. Antibody responses in BALB/c mice far exceeded those in C57BL/6 mice; in contrast, although responsiveness to methacholine was much higher in the BALB/c mice, the number of eosinophils in the bronchoalveolar lavage fluid was higher in C57BL/6 animals. Sensitized and challenged BALB/c mice developed increases in lung resistance and decreases in dynamic compliance after methacholine or 5-hydroxytryptamine inhalation. C57BL/6 mice only exhibited significant levels of responsiveness when dynamic compliance was monitored in response to inhaled 5-hydroxytryptamine. Eosinophils accumulated in the peribronchial and peripheral lung tissue in BALB/c mice but were distributed diffusely in the peripheral lung tissue of C57BL/6 mice. Thus, in addition to differences in antibody responses and cholinergic agonist reactivity, differences in the responses of large and small airways may reflect the selective distribution of eosinophils in lung tissue.
strain variability
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INTRODUCTION |
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TO DEFINE THE PATHOGENESIS of airway hyperresponsiveness (AHR), the hallmark of bronchial asthma, a number of investigators have turned to animal models to gain further insight (20, 23, 36). Murine models of allergen-induced AHR have been developed that demonstrate important roles for T helper type 2 cell (Th2)-like responses, antibodies (IgE/IgG1), adhesion molecules, viral infection, and inflammatory cells, particularly eosinophils (7, 11, 12, 25, 28-30, 37). There is also a known strain dependency for the development of AHR (4, 22, 24, 36, 38) as well as specific antibody responses to allergens (34). Two strains of mice, BALB/c and C57BL/6, are frequently used in these models, but they exhibit quite different levels of airway responsiveness despite identical sensitization and challenge protocols. BALB/c mice are thought to represent a relatively hyperresponsive strain compared with C57BL/6 mice. In addition, BALB/c mice produce high levels of antigen-specific IgE and develop a significant airway eosinophilia. C57BL/6 mice are thought to represent a low Th2 responder strain because of low levels of antigen-specific IgE and airway responsiveness in response to allergen challenge (38).
To further delineate the differences between these two strains of mice, we examined the relationship between eosinophilic inflammation and specific aspects of airway responsiveness. Sensitized and challenged mice were exposed to different inhaled bronchoconstrictors, and changes in lung resistance (RL) and dynamic compliance (Cdyn) were monitored. In parallel, both the number and the localization of eosinophils in the lungs were examined. In these studies, differences in airway responsiveness to the inhaled bronchoconstrictors were associated with differences in eosinophil localization to the large and small (peripheral) airways.
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MATERIALS AND METHODS |
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Animals. Female BALB/c and C57BL/6 mice from 8 to 12 wk of age were obtained from Jackson Laboratories (Bar Harbor, ME). The animals were maintained on an ovalbumin (Ova)-free diet. Experiments were conducted under a protocol approved by the Institutional Animal Care and Use Committee of the National Jewish Medical and Research Center.
Sensitization and airway challenge. Groups of mice (four mice per group per experiment) received the following treatments: 1) no treatment, 2) sensitization to Ova alone, and 3) sensitization to Ova with alum plus an aerosolized airway challenge with nebulized Ova. Mice were sensitized with an intraperitoneal injection of 20 µg of Ova (grade V, Sigma, St. Louis, MO) emulsified in 2.25 mg of alum (Imject Alum; Pierce, Rockford, IL) in a total volume of 100 µl on days 1 and 14. Mice were challenged via the airways with Ova (1% in saline) for 20 min on days 28, 29, and 30 by ultrasonic nebulization and were assessed 48 h after the last Ova exposure. Based on preliminary studies, this time point was selected because previous studies had shown the maximum shift in AHR and the greatest degree of eosinophilia in both strains of mice at this time (11, 12).
Measurements of anti-Ova antibody. Serum levels of Ova-specific IgE and IgG1 were measured by ELISA as previously described (26). The antibody titers of the samples were related to pooled standards that were generated in the laboratory and are expressed as ELISA units per milliliter (EU/ml) (26).
Determination of airway responsiveness. Airway responsiveness was assessed as a change in airway function after challenge with aerosolized methacholine (MCh; Sigma) or serotonin [5-hydroxytryptamine (5-HT); Sigma]. In a small group of animals, histamine was also used. Anesthetized, tracheostomized mice were mechanically ventilated, and lung function was assessed with methods similar to those described previously (23, 31). Briefly, the mice were anesthetized with an intraperitoneal injection of pentobarbital sodium (70-90 mg/kg). When an appropriate plane of anesthesia was achieved, a stainless steel 18-gauge tube was inserted as a tracheostomy cannula and tied in place. The tracheostomy tube was passed through a hole in the whole body plethysmograph. A four-way connector was attached to the tracheostomy tube, with two ports connected to the inspiratory and expiratory sides of a ventilator (model 683, Harvard Apparatus, South Natick, MA). Ventilation was achieved at 160 breaths/min and a tidal volume of 0.15 ml with a positive end-expiratory pressure of 2-4 cmH2O.
The Plexiglas chamber containing the mouse was continuous with a 1.0-liter glass bottle filled with copper gauze to obtain isothermal gas conditions during measurements of volume. Transpulmonary pressure was detected by a differential pressure transducer, with one side connected to the fourth port of the four-way connector and the other side connected to a second port on the plethysmograph. Changes in lung volume were measured by detecting pressure changes in the plethysmographic chamber through a port in the connecting tube with a differential pressure transducer and were then referenced to a second copper gauze-filled 1.0-liter glass bottle. Flow was measured by digital differentiation of the volume signal. RL and Cdyn were continuously computed (Labview, National Instruments) by fitting flow, volume, and pressure to an equation of motion that used a regressive least squares algorithm. The aerosolized bronchoconstrictor agents were administered through bypass tubing via an ultrasonic nebulizer placed between the expiratory port of the ventilator and the four-way connector. The aerosolized agents MCh, 5-HT, and histamine were administered for 10 s with a tidal volume of 0.5 ml and a frequency of 60 breaths/min (or similar) (31). The data of RL and Cdyn were continuously collected for up to 3 min. Maximum values of RL and minimum values of Cdyn were taken to express changes in airway function. Based on these data, conductance and elastance values were calculated and compared and showed similar differences between the two strains of mice.Bronchoalveolar lavage. Immediately after assessment of AHR, lungs were lavaged via the tracheal tube with Hanks' balanced salt solution (1 × 1 ml at 37°C). The volume of collected bronchoalveolar (BAL) fluid was measured in each sample, and the number of leukocytes was counted (Coulter Counter, Coulter, Hialeah, FL). Differential cell counts were performed by counting at least 300 cells on cytocentrifuged preparations (Cytospin 2; Shandon, Runcorn, UK). Slides were stained with Leukostat (Fisher Diagnostics) and differentiated by standard hematological procedures.
Immunohistochemistry studies. Lungs were inflated through the trachea with 1 ml of 10% formalin and fixed in 10% formalin by immersion. Cells containing eosinophilic major basic protein (MBP) were identified by immunohistochemical staining as previously described (11). Blocks of the lung tissue were cut around the main bronchus and embedded in paraffin blocks. Tissue sections (5 µm) were affixed to glass slides, and the slides were deparaffinized and incubated in normal rabbit serum for 2 h at 37°C. The slides were then stained with either rabbit anti-mouse MBP or with normal rabbit preimmune control serum and incubated overnight at 48°C. After being washed and incubated in 1% chromotrope 2R (HARLECO, Gibbstown, NJ) for 30 min, the slides were placed in fluorescein-labeled goat anti-rabbit IgG for 30 min at 37°C. The slides were examined with a Zeiss microscope equipped with a fluorescein filter system as described (11). The number of eosinophils in 0.06-mm2 sections from the submucosal tissue around the major airways or peripheral (nonairway) tissue was analyzed with the IPLab2 software (Signal Analytics, Vienna, VA) (11).
Statistical analysis. All results are expressed as means ± SE except for Ova-specific Ig levels, which are expressed as means and 95% confidence limits. Analysis of variance was used to determine the levels of difference among all groups. Pairs of groups were compared with unpaired two-tailed Student's t-test. The P value for significance was set at 0.05.
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RESULTS |
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Antibody responses after Ova sensitization and challenge.
As shown in Table 1, serum levels of
anti-Ova IgE and IgG1 were significantly increased in BALB/c mice
sensitized and challenged to Ova (P = 0.011 and
P < 0.0001, respectively). Anti-Ova IgE or IgG1 was
not detectable in nonsensitized mice. In sensitized and challenged
C57BL/6 mice, the levels of anti-Ova antibodies were considerably lower
compared with those in BALB/c animals (P = 0.024 and
P < 0.0001, respectively).
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Eosinophils in BAL fluid.
BAL fluid was collected and cells were counted in individual mice. As
shown in Table 2, in sensitized C57BL/6
mice, eosinophil accumulation in BAL fluid markedly increased when the
animals were challenged with Ova. This increase exceeded the increase in eosinophil numbers observed in the BAL fluid from sensitized and
challenged BALB/c mice. The total number of cells recovered also
increased after sensitization and challenge in C57BL/6 mice. In neither
C57BL/6 nor BALB/c mice were eosinophils identified in the BAL fluid,
nor were the total cell counts elevated in nonsensitized (data not
shown) or nonexposed animals.
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Airway responsiveness.
Baseline values were defined in all three groups of mice from both
strains before MCh administration (Fig.
1). There was little difference in
baseline RL in any of the mice regardless of strain or treatment differences. In contrast, baseline values for Cdyn in
C57BL/6 mice were significantly lower than those in BALB/c mice
regardless of treatment status.
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Correlation of airway responsiveness and eosinophil number in BAL
fluid.
To explore the potential relationship between eosinophil numbers in the
airways and allergen-induced AHR, regression analyses were performed.
BAL fluid eosinophil counts were regressed against airway
responsiveness, expressed as provocative concentration (PC) that
produced a 150% change (PC150) in RL
(Fig. 4) or a 50% change
(PC50) in Cdyn (Fig. 5). The
BALB/c strain showed significant correlations between BAL fluid
eosinophil numbers for either MCh-induced (R2 = 0.83, P < 0.02) or
5-HT-induced (R2 = 0.40, P < 0.01) changes in RL. On the other hand, no correlations were demonstrated for either MCh-induced
(R2 = 0.017, P = 0.11) or
5-HT-induced (R2 = 0.11, P = 0.43) changes in RL in the C57BL/6 mice. When Cdyn was
used as the end point (Fig. 5), in the BALB/c strain, a significant correlation for both MCh (P < 0.01) and 5-HT
(P < 0.001) was again demonstrated. However, for the
C57BL/6 mice, changes in eosinophil number were only related to changes
in Cdyn in response to inhaled 5-HT (P = 0.047).
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Localization of eosinophils in lung tissue.
To investigate potential mechanisms underlying the differences in
airway responsiveness between these two murine strains, lung
sections were analyzed for eosinophil distribution. Formalin-fixed, paraffin-embedded lung sections were stained for eosinophils with anti-MBP antibody. In sensitized and challenged animals, a
significantly increased number of eosinophils was observed in the lung
sections (Fig. 6). Control mice showed
few if any MBP-positive cells in the lung tissue. In C57BL/6 mice,
the distribution of eosinophils was relatively homogeneous in the
peripheral tissue but was notably absent to a large extent around the
airways; in BALB/c mice, the eosinophils accumulated in both the
peribronchial and the peripheral tissue. To quantify these
differences, eosinophil number in either the peribronchial or
peripheral lung tissue was counted in standardized areas. This
quantitative approach confirmed the different patterns of eosinophil
distribution in the lungs from sensitized and challenged C57BL/6
and BALB/c mice (Fig. 7). In C57BL/6
mice, the number of eosinophils was 167 ± 16/mm2 in
the peribronchial tissue and 275 ± 14/mm2 in
the peripheral tissue; in BALB/c mice, we detected 332 ± 22 eosinophils/mm2 in the peribronchial tissue and 129 ± 7 eosinophils/mm2 in peripheral tissue.
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DISCUSSION |
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Lung inflammation and bronchial hyperreactivity are two distinct features of asthma. Indeed, in humans as well as in laboratory animals such as monkeys, guinea pigs, rats, sheep, pigs, dogs, and mice, eosinophils are the most prominent proinflammatory cell type in the airways and lung tissue (35). In many of these species, correlations have been drawn between the number of eosinophils or level of eosinophil-derived cationic proteins in the airways and altered airway responsiveness to bronchoconstrictive agents administered intravenously or by inhalation (3, 11, 30, 35). In mice, in addition to eosinophils, other critical components of the allergic response in the lung have been defined, including specific IgE and IgG antibodies, various cytokines and chemokines, and adhesion molecules. The strength of these associations with the development of allergic AHR has been explored in genetically manipulated mice in which specific genes have been deleted or overexpressed. Recently, difficulties in reliably demonstrating AHR in the mouse model have been overcome. Nevertheless, optimal conditions for the induction of AHR have not been studied in a systematic fashion. This is especially important because, not surprisingly, different strains of mice may respond to antigen challenge in very different ways; the inflammatory response may be quite variable, and cytokine production and profile may also vary. Another possibility is that the target tissues (e.g., airway smooth muscle) may respond differently to the same inflammatory signals. In this regard, it is well recognized that the development and extent of the response to bronchoconstrictive agents is strain dependent (3, 4, 20, 22, 38).
However, the underlying mechanism for this strain dependency is not simple genetic variability nor is it unidimensional in pathogenesis. Levitt and colleagues (21, 22) have demonstrated how genetic background has an impact on the expression of nonspecific airway responsiveness to acetylcholine and 5-HT. With the use of an airway pressure-time index and intravenous injection of the bronchoconstrictor agents, BALB/c mice were shown to be intermediate responders, whereas C57BL/6 mice were poor responders to either agonist. Interestingly, DeSanctis et al. (5) demonstrated a role for T lymphocytes in enhancing genetically determined airway responsiveness. They showed that hyporesponsive C57BL/6 mice treated with cells from a hyperresponder strain (A/J) increased MCh responsiveness.
BALB/c mice are widely used to study induced AHR because they generate high titers of Ova-specific IgE and IgG1, eosinophilia in the BAL fluid, and AHR to intravenous or inhaled MCh and/or acetylcholine (3, 12, 25, 38). C57BL/6 mice are generally recognized as hyporesponders based on their poor IgE response to Ova and low response to bronchoconstrictors (3, 38); this strain also appears to produce fewer Th2-like cytokines (14, 38). Preliminary studies established that 48 h after the last challenge, both AHR and the number of BAL fluid eosinophils reached their peak. Nevertheless, the number of BAL fluid eosinophils was higher in the C57BL/6 mice compared with that in BALB/c mice. These findings are similar to those reported by others (38). Because the absence of IgE or antibodies of any isotype does not appear to affect the development of AHR after intraperitoneal sensitization and repeated airway challenge (13), we examined other possibilities to explain the differences in airway responsiveness in these two strains of mice. Among these possibilities were that 1) the strains differed in their response to different agonists, i.e., one agonist might prove to be superior to another despite genetic variability; 2) the parameter of lung function monitored may be critical because the airways are known to be profoundly heterogeneous in their responsiveness; or 3) if eosinophils are linked to AHR, their anatomic localization may be important in dictating the nature and extent of airway responsiveness. In addition, interpretation of the results in many of the previous studies (3, 21, 38) may have been affected by the fact that only a single bronchoconstrictor was used, and often it was administered intravenously.
In the present study, we focused on airway responsiveness to inhaled agonists. We showed that the mice failed to respond to histamine challenge even after sensitization and allergen challenge. This is similar to the results of Martin et al. (23) after intravenous histamine. However, the two strains of mice did show different levels of baseline airway responsiveness (for Cdyn) as well as different degrees of enhanced cholinergic responsiveness after sensitization and challenge. In all of the parameters monitored, BALB/c mice were more responsive to the inhaled bronchoconstrictive agents than the C57BL/6 mice. Nonetheless, in C57BL/6 mice, it appeared that 5-HT triggered a significant fall in Cdyn after sensitization and challenge that exceeded all other parameters. In each of the conditions in which airway responsiveness was significantly affected, BAL fluid eosinophil number correlated significantly with the alteration in specific lung function.
To further explore potential mechanisms underlying these differences in airway function in addition to eosinophil number, tissue localization of eosinophils was analyzed. Sensitization and challenge of mice of both strains elicited a robust response in the BAL fluid, with 50% or more of the total cells identified as eosinophils 48 h after the last Ova challenge. The number of eosinophils in the BAL fluid of C57BL/6 mice exceeded the number in similarly sensitized and challenged BALB/c mice. This was interesting given that BALB/c mice reportedly generate significantly more interleukin-5 than C57BL/6 mice under these conditions (14, 38). To identify eosinophils in the tissue, lung sections were stained with a MBP antibody that has proven valuable for staining these cells in tissue as well as for quantitation and localization (11). The pattern of eosinophil distribution in the two strains was strikingly different; in BALB/c mice, the eosinophils were primarily observed in the peribronchial regions, whereas in the C57BL/6 mice, the eosinophils were primarily detected in the parenchyma or peripheral lung tissue around the smallest airways or alveoli.
The reasons for this differential localization are not readily
apparent. One implication of these findings is that in response to
allergen sensitization and challenge, different profiles of chemokines
develop, affecting leukocyte recruitment to distinct inflammatory
sites. Among the chemokines that may directly affect the pattern of
eosinophil accumulation are eotaxin, regulated on activation normal T
cells expressed and secreted (RANTES), macrophage inflammatory
protein-1, and monocyte chemoattractant protein-5 (8, 15, 16,
27). The effects may also be indirect, mediated by
differential expression, for example, of monocyte chemoattractant
protein-1, which is clearly modulated during allergic lung inflammation
(9). Studies are currently underway to examine chemokine
expression and localization in these two informative strains of mice.
Furthermore, in the absence of in situ markers of eosinophil
activation, it is unclear how the pattern of eosinophil distribution in
the lung affects readouts of airway responsiveness in response to
different inhaled bronchoconstrictors. This is suggested in the current
study by the observation that even with the large eosinophilia observed
in the C57BL/6 strain, the changes in lung function were poorly
correlated to airway eosinophilia.
A commonly held notion is that resistance changes (RL) relate to the narrowing of airways, particularly the more central airways, whereas compliance changes, particularly Cdyn, relate to peripheral airway function (2, 6). More current thinking suggests that airway resistance, which is the pressure drop in phase with airflow, represents airway narrowing and is both a smaller overall component and a small component of the response to bronchoactive agents. On the other hand, the pressure drops that are out of phase with airflow relate to the viscoelastic properties of the parenchymal structures, which are often a larger component. Given the low frequency of ventilation, the degree of tissue resistance measured by the technique used in the current study is likely to be considerable (33). The mechanisms responsible for peripheral lung disease are unclear at present but could include loss of interdependence, ventilation inhomogeneities, and microatelectasis. Cdyn represents pressure losses in phase with volume changes and would likely be influenced by elastic recoil, which is especially important because it has been shown that there are considerable differences in elastic recoil between strains of mice (32). Furthermore, the airway closure and reopening that occurs with volume increases suggests increases in elastic recoil pressure that are potentially a result of surfactant alterations caused by protein extravasation that deactivates the surface-active effects of surfactant proteins (1). Further work will be required to discern between these equally likely possibilities. Hence genetic variability in the relative contributions of these physiological mechanisms might relate to the decreased Cdyn observed in C57BL/6 mice. If so, this may relate to the small changes in RL values in C57BL/6 mice as well as to the lack of correlation with eosinophil number. The preferential accumulation of eosinophils in the peripheral tissue in C57BL/6 mice may be reflected in the more robust changes in Cdyn after allergen sensitization and challenge. As a result, eosinophil localization may complement and explain genetic variability in bronchoconstrictor responsiveness in different strains of mice after sensitization and challenge.
It is of interest that differential localization of eosinophils has been related to stages of human asthma. Kraft et al. (19) suggested that eosinophils in the alveolar tissue play an important role in the development of chronic stable asthma, whereas Haley et al. (10) demonstrated that eosinophils in peripheral airways may relate to asthma severity. In addition, Kaminsky et al. (17, 18) have shown that the peripheral airways of the lungs of patients with very mild asthma have increased resistance to airflow as well as a higher reactivity. These studies in asthmatic patients and the differences described in airway responsiveness that correlate with eosinophil number and localization in the two mouse strains emphasize the need for further understanding of the control of eosinophil recruitment to distinct anatomic sites, which, together with genetic variation in bronchoconstrictor responses, dictate the level of responsiveness in central and peripheral airways after allergen challenge of sensitized hosts.
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ACKNOWLEDGEMENTS |
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We thank Diana Nabighian for help in preparation of this manuscript.
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FOOTNOTES |
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This work was supported in part by National Heart, Lung, and Blood Institute Grants HL-36577 and HL-61005.
Address for reprint requests and other correspondence: E. W. Gelfand, 1400 Jackson St., Denver, CO 80206 (E-mail: gelfande{at}njc.org).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 7 February 2000; accepted in final form 29 January 2001.
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