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HIGHLIGHTED TOPICS
Airway Hyperresponsiveness: From Molecules to
Bedside
Department of Physiology, University of Massachusetts Medical School, Worcester, Massachusetts 01655
Submitted 14 March 2003 ; accepted in final form 16 May 2003
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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hyperreactivity; asthma; acetylcholine; halothane; confocal microscopy
Mice have often been proposed as an experimental animal-model system in which to explore airway reactivity. As a result, measurements of airway reactivity in live animals have been made in a variety of inbred mice (6, 7, 15). Similar approaches have been performed in rats (25). In the initial studies that examined nine different mouse strains (individuals anesthetized with the volatile anesthetic halothane), it was found, based on lung function tests, that in response to intravenous ACh the mouse strain A/J was the most hyper- reactive in its airway response. The Balb/C strain had an intermediate or normal response, whereas the C3H/ HeJ mouse strain was found to be the least reactive (or hyporeactive relative to the Balb/C strain) (15). A similar classification for these mouse strains was found in response to 5-HT (16). Consequently, these mouse strains provide a unique opportunity to correlate the cellular events within SMCs with changes in airway reactivity.
To take advantage of these mouse models, we have refined the preparation of
lung slices to correlate changes in airway caliber with measurements of
Ca2+ signaling in single-airway SMCs
(1,
2). Thick lung slices have been
used by a variety of groups (5,
17,
22), but these precluded the
observation of the Ca2+ dynamics of single cells. With thinner
(
75 µm) lung slice preparations and confocal microscopy, we have found
that ACh (1) and ATP
(2) induce Ca2+
oscillations in airway SMCs. Furthermore, the extent and maintenance of the
airway contraction appeared to be determined by the frequency and persistence
of the Ca2+ oscillations. Consequently, we have investigated here
the Ca2+ signaling of airway SMCs in mouse strains that
exhibit a range of airway reactivity.
By directly measuring changes in airway caliber in response to ACh in three different mouse strains, we have found that the C3H/HeJ mouse showed the greatest degree of airway reactivity, whereas the Balb/C and A/J mice were similar, but less, in their response. However, the ACh-induced Ca2+ signaling, including the initial Ca2+ transient and the frequency of the subsequent Ca2+ oscillations in each mouse strain, was very similar. The order of the airway hyperreactivity differs from previous studies, and one explanation may be the presence of halothane, a volatile anesthetic, which in the previous studies mitigated the ACh responses. From these results, we conclude that the mechanism responsible for airway hyperreactivity in different mouse strains may be associated with the Ca2+ sensitivity of the contractile apparatus of the SMCs rather than with the Ca2+ signaling elements.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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Lung slices. Lung slices were prepared as previously described
(1). Briefly, male mice from
three different inbred strains (Balb/C from Charles River Breeding Labs,
Needham, MA; C3H/HeJ and A/J from Jackson Laboratory, Bar Harbor, ME; 42-77
days old) were killed by intraperitoneal injection of Nembutal. This protocol
was approved by the University of Massachusetts Medial School Institutional
Animal Care and Use Committee. The chest wall was removed and the trachea was
cannulated by using an intravenous catheter (20G Intima, Becton Dickinson,
Sandy, UT), and the lungs were inflated with 2% agarose-sHBSS at 37°C
(1 ml). To ensure that the airways were free to contract and not subject
to luminal resistance, 0.1-0.2 ml of air was subsequently injected to flush
the agarose-sHBSS out of the airways and into the alveoli. To stiffen the soft
lung tissue for sectioning, the agarose was gelled by placing the mouse
preparation at 4°C. The lungs were removed, and slices of 75 µm
thickness were cut with an EMS-4000 tissue slicer (Electron Microscopy
Sciences, Fort Washington, PA). The slices were maintained by floating them in
DMEM supplemented with 10% FBS and antibiotics and antimycotics at 37°C in
10% CO2 for up to 5 days.
Measurement of airway contraction. Lung slices were placed on a cover glass within a custom-made Plexiglas chamber and held in position by a piece of nylon mesh (CMN-300-B, Small Parts, Miami Lakes, FL). Phase-contrast images were recorded with a digital charge-coupled device camera (TM-6710, Pulnix America, Sunnyvale, CA), a digital camera interface (Road Runner, BitFlow, Woburn, MA), and image acquisition software (Video Savant, IO Industries, London, ON, Canada). Frames were captured in time lapse (33-ms exposure, 1 frame/s), and the cross-sectional area of the airway was measured with respect to time, by pixel summing, with the use of the image analysis software Scion (Scion, Frederick, MD; free download available at www.scioncorp.com).
Throughout this paper, we refer to a decrease in the cross-sectional area as airway contraction. The contraction velocity of an airway was calculated as the percent decrease in cross-sectional area with respect to time (%s-1) in the first 10 s after the addition of ACh. This time was chosen because the contraction was found to be approximately linear in the first 10 s.
Measurements of [Ca2+]i. The changes in the [Ca2+]i were monitored with confocal microscopy as previously described in detail (1). Briefly, lung slices were loaded with the calcium indicator dye Oregon green [20 µM for 1 h, Molecular Probes, Eugene, OR (1)] in sHBSS containing 0.2% Pluronic (Pluronic F-127, Calbiochem, La Jolla, CA), 100 µM sulfobromophthalein, and 3 mg/ml ascorbic acid (antioxidant to reduce bleaching). After they were washed in sHBSS (containing 100 µM sulfobromophthalein and 3 mg/ml ascorbic acid) to allow for complete deesterification of the dye, the lung slices were examined with a custom-built confocal microscope (23) based on an inverted microscope with a x40, 1.3 numerical aperture, oil-immersion objective (Nikon). Excitation light was provided at 488 nm by an argon laser, and the emitted fluorescence (>510 nm) was monitored. Individual images were captured with exposure times of 33 ms and recorded at 0.5-s intervals (time lapse of 2 images/s).
Regions of interest (ROIs) of 8.4 x 8.4 µm (10 x 10 pixels) were defined near the middle of single SMCs, and the average fluorescence intensities of each ROI were obtained. To compensate for the initial contraction-induced movements of the SMCs, the pixel location of the ROI was interactively reassigned or tracked by the investigator with the use of a custom-written macro (within Scion software). The images were played frame by frame to determine and assign the ROI position for analysis. The use of a multiple pixel area (10 x 10 pixels) compensates for slight misalignments. Pixel tracking was not required after the maximum contraction was achieved when the Ca2+ oscillations still persisted.
A bleach-correction factor was calculated for each individual cell, from the bleaching rate that occurred during the period of 15-30 s before the addition of drugs. Data from individual cells were corrected with the appropriate bleach- correction factor before a rolling average of three frames was calculated. Final fluorescence values were expressed as a fluorescence ratio (F/F0) normalized to the initial fluorescence (F0).
Drug application. ACh and halothane were dissolved in sHBSS, and a 10x concentrated solution was added (15 µl) to the bath solution (135 µl) in which the final working concentration was obtained by dilution. All experiments were conducted at room temperature.
Statistics. Statistical analysis was performed with the oneway ANOVA and the Kruskal-Wallis ANOVA on ranks (all pairwise multiple comparison procedures = Student-Newman-Keuls method). Values are given as means ± SE. A P value of <0.05 was considered to be statistically significant.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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The addition of ACh initially induced the airways of all the various mouse
strains to contract. Subsequently, in the continued presence of ACh, the
contraction stabilized such that the lumen of the airway was maintained at a
reduced size (Fig. 2,
A-C). This ACh- induced contraction of the
airways (ranging from 10 nM to 10 µM) was concentration dependent in each
mouse strain examined (Fig.
2D). However, the magnitude and rate of the airway
contraction varied between mouse strains. For example, a concentration of 100
nM ACh (or higher) induced a maximal contraction (a reduction of 40% of
starting area, P < 0.05) of the airways of C3H/HeJ mice
(Fig. 2C). By
contrast, the same concentration of ACh induced a significantly smaller
contraction in A/J (20% of starting area) and Balb/C (14%) mice
airways. It is important to note that airway resistance is proportional to the
inverse of the airway radius to the fourth power (Poiseuille's rule;
R 
1/r4). Consequently, a small decrease in
airway diameter can lead to large changes in resistance. We calculate that a
decrease in the area of 40% results in a 2.7x increase in airway
resistance. The smaller changes in airway area observed in A/J and Balb/C mice
still represent significant increases in airway resistance of 1.56x and
1.36x, respectively. A concentration of 500 nM (or higher) ACh was
required to induce a maximal contraction in A/J ( 25%) and Balb/C mice
(20%) (Fig.
2D).
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The initial rate of airway contraction was also faster in C3H/HeJ mice (1.9 ± 0.5%s-1, mean ± SE, n = 8 mice, P < 0.05) compared with A/J mice (1.1 ± 0.4%s-1, n = 8 mice) and Balb/C mice (0.5 ± 0.1%s-1, n = 8 mice, Fig. 3A). However, the period between the time of the addition of 1 µM ACh and the time at which the maximum contraction was reached showed no interstrain differences (257 ± 34 s for C3H/HeJ mice, 249 ± 23 s for A/J mice, and 253 ± 17 s for Balb/C mice, n = 8 mice, Fig. 3B).
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Influence of halothane on airway contractility. To test whether halothane, a volatile anesthetic that had been previously administered to mice to perform in vivo measurements of bronchial hyperreactivity (15), could have impaired the contractile response to ACh, airways in lung slices of C3H/HeJ mice were exposed to halothane before exposure to 100 nM ACh (Fig. 4A). In these experiments, we found that halothane itself initially induced a transient airway contraction that was followed by relaxation. However, more importantly, with subsequent exposure to ACh and in the presence of halothane, the airway contractile response was significantly reduced compared with the reduction in lumen size without the pretreatment with halothane (Fig. 4B). The effectiveness of halothane at antagonizing the ACh response was concentration dependent; 0.17 mM halothane reduced the contraction to 81.3 ± 20.3%, whereas 1.7 mM halothane reduced the contraction response to ACh to 7.6 ± 3.9% (n = 5 slices, P < 0.05, Fig. 4B).
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ACh-induced Ca2+ signaling in airway SMCs. To correlate the Ca2+ signaling in the SMCs with the airway contractile response, lungs slices were loaded with the Ca2+ indicator dye Oregon green and examined with confocal microscopy. With this technique, the SMCs surrounding the airways were readily identified. The use of a small ROI and confocal microscopy ensured that the fluorescence changes monitored arose from a narrow plane centered on the middle of the SMC (Fig. 5). Although the optical sectioning achieved with confocal microscopy was sufficient to exclude fluorescence from other cells within the lung slice, the optical section was not sufficiently thin to discriminate fluorescence emanating from different locations within individual SMCs. In addition, to compensate for the contractile movement of SMC, the position of the ROI was carefully tracked and manually adjusted, frame by frame, to remain in the same relative location within the SMC. Although this procedure does not fully compensate for changes in path length, Ca2+ oscillations can still be clearly observed because these are associated with relative changes in fluorescence.
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In all three mouse strains examined, the Ca2+ response of the SMCs to ACh consisted of an initial transient increase in [Ca2+]i followed by a series of Ca2+ oscillations (Figs. 5 and 6). In keeping with our previous studies (1), no evidence was observed to suggest that the Ca2+ oscillations within each SMC were coordinated with the response of adjacent cells.
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The initial Ca2+ transient (the %difference between
the F/F0 measured immediately before and at maximum value of the
Ca2+ transient) was concentration dependent from 1 nM to
10 µM, but no differences between mouse strains could be observed
(Fig. 7A). Similarly,
the frequency of the Ca2+ oscillations induced by ACh
showed a concentration dependency. The Ca2+ oscillations
increased from a rate of 10 min-1 in response to 10
nM ACh to 20 min-1 in response to 100 nM ACh
(Fig. 7b). This
increase in the Ca2+ oscillation rate corresponds to the
same concentration range for increases in airway contraction. The
Ca2+ oscillation frequency reached a maximum at
concentrations >100 nM. However, there appeared to be no difference between
the concentration-response curves for the frequencies of the
Ca2+ oscillations between mouse strains.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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The mouse strains used for this study were chosen based on previous studies that ordered the hyperreactivity of mouse airways (15). The A/J mouse was reported to have the most hyperreactive airways, whereas the C3H/HeJ mouse was reported to have the least reactive airways. Consequently, we chose to examine these two mouse strains, rather than conducting a full survey of all mouse strains because they represented the two extremes of airway hyperreactivity and might therefore be expected to show the greatest differences in their cellular responses. The Balb/C mouse showed a "normal" response, (greater than A/J but less than C3H/HeJ) and has been the subject of our earlier studies, making it an ideal choice for the control response.
In this study, we found that the in vitro airway reactivity could be graded in the order C3H/HeJ > A/J = Balb/C. However, this is in contrast to studies reporting an in vivo order of A/J > Balb/C > C3H/HeJ (6, 7, 15). This is an important difference, and there are several possible explanations. A major consideration is that, in the study of Levitt and Mitzner (15), the volatile anesthetic halothane was used to anesthetize mice to successfully perform lung function tests. However, Pabelick et al. (19) subsequently reported that halothane could interfere with the Ca2+ signaling in airway SMCs by emptying the Ca2+ stores within the sarcoplasmic reticulum. Similarly, we have previously shown that halothane abolishes Ca2+ oscillations induced by ACh and induces airway relaxation (1). More importantly, we have found in this study that the prior exposure of the lung slices to halothane significantly attenuated the airway response to ACh. We therefore propose that the use of halothane in the earlier in vivo studies probably impaired the efficacy of the ACh to induce contraction, and that this may explain why the order of airway reactivity originally reported differs to the order reported here.
A second potential complication in all of the in vivo studies on airway reactivity is that the agonist used [ACh or methacholine (MCh)] was administered intravenously and therefore exhibited its effects indirectly through the systemic circulation. The physiological consequences of this approach are not clear but may include alterations in pulmonary blood flow and lung compliance. In this respect, the use of lung slices may have the advantage that the agonist has direct access to the SMCs.
A difference between in vivo and in vitro studies has also been reported by Duguet et al. (7). In this study, it was found that the in vivo airway responsiveness to intravenous MCh was in the order of A/J > Balb/C > C3H/HeJ and matched that of Levitt and Mitzner (15). By contrast, the in vitro response, measured with the use of lung slices, revealed that sensitivity to MCh was greater in C3H/HeJ than in A/J mice (7) even though there was no difference between the mouse strains with respect to the maximal contraction achieved. However, Duguet et al. also found that the velocity of the SMC shortening during contraction was higher in A/J than in C3H/HeJ mice. Because the order of the velocity of shortening matched the order of the in vivo classification, Duguet et al. proposed this parameter to be the most relevant in measuring hyperreactivity.
In our study, using ACh, we have found that the order of the contractile velocity matches the order of the maximal airway contraction (i.e., C3H/HeJ > A/J mice = Balb/C). Thus both shortening velocity and maximal contraction are increased in the C3H/HeJ and both are likely to contribute to hyperreactivity. A reason for these different findings may be that there is a variation in the subtype selectivity of the muscarinic receptors in response to MCh, a chemical analog of ACh (27). MCh is frequently used in clinical tests because it is less readily metabolized and therefore it may produce saturating effects. The ability of the airways to reach the same maximal contraction, although at different rates, is consistent with this idea.
Another explanation for the differences between studies is the thickness of the slices used for the in vitro experiments (0.5-1 mm compared with 75 µm thick in this study) and the concentrations of agarose used to stiffen the lung tissue for the cutting process (1% compared with 2% in our study). Although the absence of agarose in the airway lumen discounts the possibility that the airway cannot fully contract, aga- rose in the alveoli is likely to affect the elastic recoil forces of the slices that tend to resist SMC contraction. However, because we have used the same technique for three different mouse strains, it is reasonable to suggest that the recoil forces would be affected similarly in each case. Therefore, a change in the agarose concentration might be expected to change the absolute degree of contraction of each mouse. However, by comparing the response of three mouse strains in one study, we can conclude that the differences in contractility are the result of differences between mouse strains rather than due to differences in technique. A change in agarose concentration would not be expected to change the order of reactivity.
A difference in airway SMC mass between the mouse strains may also explain the differences in airway hyperreactivity. However, Duguet et al. (7) reported that A/J and C3H/HeJ mice had a similar quantity of tracheal SMCs and myosin content. Thus an increased SMC mass does not seem to be an explanation. As mentioned above, the compliance of the lung tissue of C3H/HeJ mice could be higher than that of other mice, and this would result in a greater reduction of airway caliber for the same contractile force exhibited by the airway SMCs. A survey of lung compliance between mouse strains may address this issue, but this is beyond the scope of this study.
Although it is clear that we consistently found differences in the contractile responses of the airways, we were unable to identify any major differences in the basic Ca2+ signaling responses of the SMCs between mouse strains. Both the initial transient increase in Ca2+ and the initiation of the Ca2+ oscillations were similar in all three strains. Furthermore, the concentration response of the increase in Ca2+ oscillation frequency with ACh was not significantly different.
Although there appeared to be no differences between the Ca2+ responses of the different mouse strains, these results remain important because some basic conclusions about Ca2+ signaling in airway SMCs can be drawn from these data. The increase in the frequency of the Ca2+ oscillations correlates with the increase in airway contraction (compare Fig. 2D with Fig. 7B) in all three strains. This supports the hypothesis that the sustained airway contraction is determined by the frequency of the Ca2+ oscillations (1, 2). The results also emphasize the difference between the smooth dynamics of the contractile response of the airway compared with the oscillatory response for [Ca2+]i of the SMCs. This is particularly evident during steady-state contraction, where Ca2+ oscillations occur without additional changes in airway area. The implication of this correlation is that, during ACh stimulation, the contractile state of the SMC does not simply reflect the Ca2+ concentration of the cytosol. This supports the idea that the contractile machinery of the SMCs serves to time average or integrate the Ca2+ oscillations. During the initial contraction, there is an additional component to the Ca2+ response: an initial transient Ca2+ increase. We have previously suggested that the initial Ca2+ transient serves to initiate contraction, whereas the Ca2+ oscillations serve to maintain the contracted state (1).
An additional factor contributing to the contractile dynamics of the airway is that the airway is a multicellular structure and shortening of several SMCs leads to airway constriction. Perhaps, contrary to the initial impression, this compound architecture actually emphasizes the advantages of studying airways in slices to elucidate pulmonary physiology. For example, the effective amount of contraction displayed by a SMC in response to an agonist can only be determined if the extrinsic resistant forces to shortening, i.e., connective tissue, are present. Similarly, relaxation can only be evaluated if the SMC can be stretched. Furthermore, the contribution of each SMC to airway constriction can only be evaluated if the airway is intact. With respect to Ca2+ signaling, confocal microscopy clearly shows that a contracted airway has several SMCs displaying asynchronous Ca2+ oscillations, but the individual SMCs do not display "twitching" in association with their Ca2+ oscillations. Thus, with the lung slice, the in situ responses of individual cells acting cooperatively can be studied.
The similarity of the Ca2+ responses between SMCs in different mouse strains also suggests that the elements and dynamics of the Ca2+ signaling machinery of airway SMCs, for example, muscarinic receptors, IP3 production, IP3 receptors, and internal Ca2+ stores, are also similar. As a result, the idea that a differential compartmentalization of the Ca2+ stores is an explanation for the differences in hyperreactivity of mouse strains seems less likely (21).
In contrast to our results, Tao et al. (25) found increased Ca2+ mobilization in airway SMCs from hyperreactive rats. In their study, SMCs were isolated from the trachea rather than from lower airways and Ca2+ measurements were performed on cultured SMCs. This may be problematic because it has been shown that the response of cultured airway SMCs to stimulation of muscarinic receptors is altered (10, 28). Additionally, the use of different species (rat vs. mouse) and agonists (5-HT vs. ACh) complicates direct comparison of the results.
The fact that airway contractility is increased in C3H/HeJ mice but the Ca2+ signaling in the SMCs appears to be similar to that in other mice leads us to the conclusion that an increased Ca2+ sensitivity of the contractile apparatus in SMCs of hyperreactive mice could also account for stronger airway contraction. Jiang et al. (14) found that the sensitization of dog airways increased the myosin light-chain kinase content and therefore myosin light-chain phosphorylation in the bronchial SMCs. Although intrinsic hyperreactivity rather than sensitization was assessed in our study, this may be a mechanism for how similar Ca2+ signals induce stronger contraction.
In summary, we have correlated airway reactivity to ACh in three different mouse strains with ACh-induced Ca2+ signaling. Although differences in airway reactivity could be demonstrated, no difference in the Ca2+ signaling, including the initial Ca2+ transient and the frequency of the subsequent Ca2+ oscillations, could be detected. As a result, we hypothesize that the mechanism responsible for airway hyperreactivity in different mouse strains resides with the Ca2+ sensitivity of the contractile apparatus of the SMCs rather than with the Ca2+ signaling itself. In addition, we believe these results are important as they underscore the need for a better understanding of in vivo vs. in vitro responses and emphasize the need for caution in the use of these hyperreactive mouse models.
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DISCLOSURES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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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.
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REFERENCES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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)
contracted to a greater extent than those of A/J (
) and Balb/C (
)
mice. Each point represents the mean ± SE of 5-10 experiments performed
in 5-10 different airways of 5-10 different lung slices. The mean
cross-sectional area of the airways used in these experiments was 36,123
± 2,292 µm2 (mean ± SE, n = 137).
*P < 0.05 vs. corresponding experimental groups of A/J and Balb/C
strains.
