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1 Department of Thoracic and Cardiovascular Surgery2 Department of Pathology3 Department of Physiology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
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Abstract |
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(Received 21 September 2004;
accepted after revision 4 March 2005; first published online 15 March 2005)
Corresponding author T. Nakahari: Department of Physiology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan. Email: takan{at}art.osaka-med.ac.jp
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Introduction |
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It is widely accepted that ATP increases the ciliary beat frequency (CBF) of ciliated epithelia in nose, trachea, oesophagus and oviduct (Wanner et al. 1996). ATP, a purinergic agonist, is reported to increase intracellular Ca2+ concentration ([Ca2+]i) in tracheal ciliary cells (Marino et al. 1999; Zhang & Sanderson, 2003). However, the effects of ATP on ciliary function of the distal airways in lungs are unknown. Our previous reports demonstrated that the CBF can be measured in tracheal slices using video microscopy (Kawakami et al. 2004). We have developed this technique to study the ciliary function of the distal airway epithelia. This method allows us to compare CBF responses in tracheal and distal airway epithelia during ATP stimulation.
There are some morphological differences between the tracheal ciliary cells and the distal airway ciliary cells, such as the number and length of cilia, cellular height and density of ciliary cells (Ishii, 1977; Wanner et al. 1996). However, we have only limited knowledge about differences in CBF regulation between tracheal and distal airway ciliary cells.
The differences in CBF regulation between tracheal and distal airway epithelia appear to be important for independently increasing tracheal CBF or distal airway CBF of patients having respiratory problems. The aim of the present study was to clarify the differences in the ATP-stimulated CBF responses between tracheal and distal airway epithelia.
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Methods |
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The control solution (solution I) contained (mM): NaCl 121, KCl 4.5, MgCl2 1, CaCl2 1.5, NaHCO3 25, NaHepes 5, HHepes 5 and glucose 5 (pH 7.4). To prepare the Ca2+-free solution CaCl2 was replaced in solution I by 1 mM (solution II). All the solutions were aerated with 95% O2–5% CO2 at 37°C. Adenosine 5'-triphosphate (ATP), adenosine 5'-diphosphate (ADP), 2-methylthio ATP (MeSATP), 
,ß-thylene ATP (ßmeATP), 3'-O-(4-benzoyl)benzoyl ATP (BzATP), and uridine 5'-triphosphate (UTP) were from Sigma Chemical (St Louis, MO, USA), acetylcholine (ACh), terbutaline, suramin and thapsigargin were from Wako Pure Chemical (Osaka, Japan) and ionomycin was from Calbiochem-Novabiochem (La Jolla, CA, USA).
Cell preparation
Adult male rats (Slc: Wistar/ST) weighing between 150 and 250 g were purchased from SLC Inc. (Hamamatsu, Japan). The rats were anaesthetized by intraperitoneal injection of pentobarbital sodium (60–70 mg kg–1), followed by injection of heparin (1000 units kg–1). The lungs were transcardially perfused with heparinized Ca2+-free solution (4 units ml–1) (Hosoi et al. 2002, 2004; Shiima-Kinoshita et al. 2004; Kawakami et al. 2004). The trachea, lungs and heart were removed from the animals. The lungs and trachea were then cut into small pieces (5–6 mm x 5–6 mm blocks) and suspended in the control solution (4°C).
The experiments were approved by the Animal Research Committee of Osaka Medical College, and the animals were cared for according to the guidelines of this committee.
Measurement of CBF
Before experiments, a tracheal or lung block was cut into thin pieces by two adherent razor blades, each of which was moved in the opposite direction, and thin slices were placed on a coverslip precoated with Cell-Tak (Becton Dickinson Labware, Bedford, MA, USA) to allow slices to adhere firmly to the coverslip. The coverslip with slices was set in the perfusion chamber, the volume of which was approximately 20 µl, and the rate of perfusion was 200 µl min–1 (Fujiwara et al. 1999; Hosoi et al. 2002, 2004; Shiima-Kinoshita et al. 2004; Kawakami et al. 2004). The chamber was mounted on a differential interference contrast (DIC) microscope (BX50WI, Olympus, Tokyo, Japan) which was connected to a video-enhanced contrast (VEC) system (Argus-20, Hamamatsu Photonics, Hamamatsu, Japan). The CBF of the tracheal or distal airway epithelia in a slice preparation was measured from 60 to 120 video frame images (30 Hz) (Shiima-Kinoshita et al. 2004; Kawakami et al. 2004).
Before the experiments, five CBFs were measured every 30 s for 2.5 min and the averaged values of these five CBFs were used as the basal CBF (CBF0). Changes in CBF were expressed as the CBF ratio (CBFt/CBF0); where CBFt is the CBF at time t after the start of stimulation. One experiment was performed using 5–8 coverslips from two to three animals. Values were expressed as the means ± S.E.M. for n preparations. The statistical significance of differences was assessed by ANOVA. Differences were considered significant at P < 0.05.
Measurement of [Ca2+]i
The tracheal and lung blocks were incubated in solution I containing 2% bovine serum albumin (BSA) and 10 µM acetoxymethyl ester (AM) of fura 2 (Dojindo, Kumamato, Japan) for 60 min at room temperature (22–24°C), and then washed three times with solution I containing 2% BSA. The tracheal blocks were resuspended and stored in the solution I containing 2% BSA at 4°C. Fura 2-loaded tracheal slices were placed on a coverslip precoated with neutralized Cell-Tak. The coverslip with slices was set in a perfusion chamber, which was then mounted on the stage of an inverted microscope (IX70, Olympus, Tokyo, Japan) connected to an image-analysis system (Argus/HiSCa, Hamamatsu Photonics) (Fujiwara et al. 1999; Nakahari et al. 1999, 2002; Yoshida et al. 2003). All the experiments were performed at 37°C. The volume of the perfusion chamber was approximately 80 µl and the rate of perfusion was 500 µl min–1. Fura 2 was excited at 340 nm and 380 nm, and emission was measured at 510 nm, and the fluorescence ratio (F340/F380) was calculated and stored in an image-analysis system (Argus/HiSCa). The calibration curve was obtained from the F340/F380 values of the cell-free Ca2+-calibration solutions containing 10 µM fura 2. Solution III contained (mM): KCl 130, NaCl 20, EGTA 2 and Hepes 10. To prepare the cell-free Ca2+-calibration solutions, an appropriate amount of CaCl2 (0.2–2 mM) calculated using a computer program was added to solution III (Fabiato & Fabiato, 1976). The pH was adjusted to 7.05 by adding KOH (1 M). The dissociation constant of Ca2+ and EGTA used was 214 nM (37°C, pH 7.05) (Konishi et al. 1988). One experiment was performed using 5–6 coverslips, and the F340/F380 values of three cells from two to three coverslips were expressed as means ± S.E.M.
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Results |
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Effects of ATP
Figure 1 shows the effects of ATP on the CBF in tracheal ciliary cells and distal airway ciliary cells. ATP (100 µM) increased CBF biphasically in tracheal ciliary cells; an initial transient phase followed by a sustained phase (Fig. 1A). When ATP was removed from the perfusion solution, CBF decreased immediately. The CBF ratios 1 and 4 min after the addition of ATP (100 µM) were 1.42 ± 0.02 and 1.25 ± 0.06 (n = 5), respectively. ATP (10 µM) induced a similar biphasic increase in CBF. Similar experiments were also performed in distal airway ciliary cells. However, ATP ranging from 0.1 to 100 µM did not induce any increase in the CBF of distal airway ciliary cells (Fig. 1B). The CBF ratio of the initial peak (Fig. 1C) and the sustained phase (Fig. 1D, 4 min after the ATP addition) were plotted against ATP concentration. ATP (100 µM) maximally increased the CBF ratios in the initial peak and the sustained phase in the ciliary cells of tracheal slices. Again, ATP did not increase CBF in the ciliary cells of lung slices.
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Infusion of a Ca2+-free solution (solution II) decreased the CBF gradually to a plateau value in tracheal ciliary cells (CBF ratio at 11 min after the switching to the Ca2+-free solution (solution II) was 0.68 ± 0.06; n = 4) (Fig. 4A). Cells were perfused with solution II for 7 min prior to stimulation with 10 µM ATP. Stimulation with ATP increased CBF rapidly to a peak value and CBF returned to baseline values shortly thereafter in tracheal ciliary cells. The CBF ratios at 1 and 5 min after the ATP stimulation were 1.26 ± 0.08 and 0.85 ± 0.09 (n = 5), respectively (Fig. 4B). Experiments were performed in the presence of Ni2+ (1 mM, an inhibitor of Ca2+ channels). Addition of Ni2+ decreased CBF gradually in tracheal ciliary cells, in a similar manner to solution II (CBF ratio at 7 min after the addition of NaCl2 was 0.77 ± 0.06; n = 5) in tracheal ciliary cells, and then ATP (10 µM) induced a transient increase in the CBF of tracheal ciliary cells (Fig. 4C).
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The tracheal ciliary cells were stimulated with ADP and UTP (Fig. 7A and B). ADP (100 µM) induced a sustained increase in CBF (CBF ratio 1 min after the addition was 1.12 ± 0.07, n = 9). UTP (100 µM) also induced a sustained increase in CBF (CBF ratio 1 min after the addition was 1.34 ± 0.06, n = 6). Thus, the effects of P2Y receptor agonists on tracheal CBF were as follows; UTP = ATP >> ADP.
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Tracheal ciliary cells were stimulated with ßmeATP and BzATP (Fig. 8A and B). ßmeATP (100 µM) induced a rapid increase followed by a gradual decrease in CBF. The CBF ratios 1 and 5 min after the addition were 1.26 ± 0.04 and 1.12 ± 0.06 (n
= 5), respectively. BzATP (100 µM) also induced a rapid increase followed by a gradual decrease in CBF. The CBF ratios 1 and 5 min after the addition were 1.24 ± 0.08 and 1.06 ± 0.08 (n
= 5), respectively. Thus, the effects of P2X receptor agonists on the tracheal CBF were as follows; ATP > ßmeATP = BzATP.
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The [Ca2+]i of ciliary cells were measured using fura 2 (Fig. 9). ATP (10 µM) increased the F340/F380 biphasically in tracheal cells; a transient increase followed by a sustained increase. However, ATP (10 µM) did not induce any increase in F340/F380 in distal airway cells.
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The effects of acetylcholine (Fig. 10) or terbutaline (Fig. 11) were also examined, because both agonists are well known to increase the CBF of tracheal ciliary cells. Acetylcholine (ACh, 100 µM, a muscarinic agonist) increased and sustained the rise in CBF. The CBF ratio at 2.5 min after ACh stimulation was 1.23 ± 0.02 (n = 4) in tracheal cells (Fig. 10A), and Ach did not induce an increase in the CBF of the distal airway cells (Fig. 10B).
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Discussion |
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In unstimulated ciliated cells of tracheal and distal airway epithelia, the CBF was mainly maintained by Ca2+-independent mechanisms, as a reduction of Ca2+ influx by a Ca2+-free solution or Ni2+ decreased CBF by approximately 20%, as previously reported (Kawakami et al. 2004), and [Ca2+]i in the ciliated cells was similar in both tracheal and distal airway epithelia.
In tracheal ciliary cells, ATP increased CBF biphasically; an initial transient increase, followed by a sustained increase, and this was also induced by the addition of ionomycin or thapsigargin. A Ca2+-free solution (solution II) or the addition of Ni2+ eliminated the ATP-induced CBF increase, although it is interesting that the inital transient phase was still maintained. Measurement of the fura 2 fluorescence ratio (F340/F380) demonstrated that ATP increased the [Ca2+]i in tracheal ciliary cells. These results suggest that ATP increases the CBF via [Ca2+]i elevation (Ca2+ release from internal stores followed by Ca2+ entry) in the ATP-stimulated tracheal ciliary cells.
On the other hand, ATP did not induce any CBF increase in distal airway ciliary cells, and measurement of [Ca2+]i demonstrated that ATP does not increase [Ca2+]i in distal airway cells. In single distal airway ciliary cells obtained by elastase treatment (Shiima-Kinoshita et al. 2004), ATP also failed to increase the CBF (data not shown). Ionomycin or thapsigargin did, however, increase the CBF in distal airway cells. This indicates that no [Ca2+]i increase occurred in ATP-stimulated distal airway ciliary cells.
There are two subtypes of ATP receptors (P2X and P2Y) in tracheal epithelial cells (Marino et al. 1999). The P2X receptors induce Ca2+ influx via ATP-gated Ca2+-permeable channels, while the P2Y receptors induce Ca2+ release from stores via inositol 1,4,5-trisphosphate (IP3) (Harden et al. 1995; Ralevic & Burnstock, 1998). As mentioned above, in the absence of extracellular Ca2+, CBF measurements suggest that ATP mobilizes Ca2+ from internal stores in the tracheal ciliary cells. The P2Y agonist studies (order of efficacy, UTP = ATP >> ADP) suggest that P2Y2 exists in tracheal ciliary cells, while the P2X agonist studies (order of efficacy, ATP = MeSATP > ßmeATP = BzATP) suggest that P2X1, P2X2, P2X3 and P2X7 may exist in tracheal ciliary cells. It has been reported already that messenger RNAs for the P2X4, P2X7, P2Y1 and P2Y2 receptors are expressed in rat tracheal epithelial cells (Marino et al. 1999). These observstions indicate that P2X receptor subtypes (P2X1–4 and 7) and P2Y receptor subtypes (P2Y1–2) play an important role in CBF regulation of tracheal eptheium.
On the other hand in distal airway ciliary cells, ATP did not induce an increase in CBF or in [Ca2+]i. There are some reports showing that culture conditions and culture time alter the activity, number or expression of P2 receptors (Turner et al. 1997; Clunes et al. 1998). There are some morphological differences between tracheal ciliary cells and distal airway ciliary cells, such as cell height, number of cilia, length of cilia and the proportion of ciliary cells and goblet cells (Ishii, 1977; Wanner et al. 1996; Rhee et al. 2001). The ciliary cells in the trachea and distal airways may differ in their stages of differentiation, which would cause some difference in the purinergic receptor activity.
ACh failed to increase CBF in distal airway epithelia, although it did increase CBF in tracheal ciliary cells. The slice preparations are unlikely to have affected the CBF responses to agonists, as terbutaline (a ß2-agonist) increased the CBF in both tracheal and distal airway ciliary cells.
ATP and ACh, which lead to the accumulation of [Ca2+]i in many cell types, do not increase the CBF of distal airway epithelia. However terbutaline, which leads to the accumulation of cAMP in many cell types, increases the CBF in both tracheal and distal airway epithelia. Thus, the CBF of the rat distal airway epithelia was mainly under ß2-adrenergic regulation, and not under purinergic or muscarinic regulation.
The physiological role of the differences in CBF regulation between the tracheal and the distal airway epithelia still remains uncertain. Foreign materials, which are trapped within the distal airways, are removed via the trachea. Therefore, activation of CBF in the tracheal epithelial cells is required to remove foreign material originating in the distal airways. Thus, tracheal cells may require various activation mechanisms, as they are exposed to foreign material more frequently than the distal airway epithelium. Mechanical stimulation of tracheal ciliary cells causes an increase in CBF by elevation of [Ca2+]i mediated by ATP receptors (Hansen et al. 1993; Sanderson & Dirksen, 1989). Moreover, Smith et al. (1996) reported that the interactions between cAMP and Ca2+ regulate CBF in the proximal airways. These mechanisms appear to play an important role in the removal of foreign material from the trachea. The Ca2+-mobilizing systems that regulate CBF may develop in tracheal ciliary cells during cellular differentiation. Further studies will be required to clarify the difference between the regulation of tracheal and distal airway cell CBF.
In conclusion, CBF is differently regulated in tracheal and distal airway ciliary cells; the CBF of tracheal ciliary cells is increased by ATP, ACh and terbutaline, while that of distal airway ciliary cells is increased only by terbutaline. These differences may play an important role in removing irritants from distal to proximal airway trees.
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, n
= 3).
