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Department of Medicine, University of Illinois at Chicago, and West Side Department of Veterans Affairs Medical Center, Chicago, Illinois 60612
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Gao, Xiao-pei, Hideyuki Suzuki, Christopher O. Olopade,
Sergei Pakhlevaniants, and Israel Rubinstein. Purified ACE attenuates smokeless tobacco-induced increase in macromolecular efflux
from the oral mucosa. J. Appl.
Physiol. 83(1): 74-81, 1997.
The purpose of this
study was to determine whether purified angiotensin I-converting enzyme
(ACE) attenuates smokeless tobacco extract (STE)-induced increase in
macromolecular efflux from the in situ oral mucosa. By
using intravital microscopy, we found that suffusion of an aqueous
extract of smokeless tobacco elicited significant concentration-dependent leaky site formation and increase in clearance of fluorescein isothiocyanate-labeled dextran (mol mass, 70 kDa) from
the hamster cheek pouch (P < 0.05). Suffusion of purified rabbit lung ACE
significantly attenuated these responses in a concentration-dependent
fashion (P < 0.05). These effects
were specific because purified ACE also significantly attenuated the increase in macromolecular efflux elicited by bradykinin, which is
produced in the cheek pouch during suffusion of STE, but did not
attenuate the increase elicted by adenosine. Moreover,
suffusion of heat-inactivated purified ACE and purified superoxide
dismutase had no significant effects on STE- and
bradykinin-induced responses. Collectively, these data suggest
that exogenous ACE attenuates STE-induced increase in macromolecular
efflux from the in situ oral mucosa, in part, by promoting local
bradykinin catabolism.
inflammation; microcirculation; plasma exudation; bradykinin; angiotensin-I converting enzyme; hamster
INTRODUCTION A LARGE BODY OF CLINICAL EVIDENCE suggests that regular
use of smokeless tobacco is associated with oral mucosa injury and inflammation (2, 4, 5, 14). A characteristic
histopathological manifestation of this process is plasma exudation
from postcapillary venules that leads to interstitial edema and tissue
dysfunction (14). However, the mechanisms underlying this process are
uncertain.
To this end, Gao et al. (12) showed recently that suffusion of an
aqueous extract of smokeless tobacco increases macromolecular efflux
from postcapillary venules in the in situ hamster cheek pouch, and this
response was mediated by local production of bradykinin, a potent
vasoactive peptide (3). They also showed that the extract elicited a
significant decrease in cheek pouch activity of angiotensin
I-converting enzyme (ACE; EC 3.4.15.1), a membrane-bound metalloenzyme
widely distributed in the microcirculation that regulates the
edemagenic effects of bradykinin in the cheek pouch by cleaving and
inactivating the peptide (3, 6, 23, 30). However, the role of tissue
ACE in modulating smokeless tobacco-induced increase in macromolecular
efflux from the oral mucosa is uncertain.
We reasoned that if smokeless tobacco elicits bradykinin production in
the oral mucosa while decreasing tissue ACE activity, and if ACE
regulates the edemagenic effects of bradykinin in the tissue by
cleaving and inactivating the peptide, then pharmacological interventions that would increase ACE activity in the oral mucosa should mitigate the increase in macromolecular efflux elicited by
smokeless tobacco (12, 30). The purpose of this study was to begin to
address this issue by determining whether suffusion of purified ACE
attenuates smokeless tobacco extract-induced increase in macromolecular
efflux from the in situ hamster cheek pouch.
METHODS General Methods
70°C until used.
1 · h1).
A femoral artery was cannulated to obtain arterial blood samples and to
monitor arterial blood pressure, which did not change significantly during the experiments. Body temperature was kept constant
(37-38°C) throughout the experiment by using a heating pad.
To visualize the microcirculation of the cheek pouch, we used methods
previously described in our laboratory (8-12, 23, 28, 30).
Briefly, the left cheek pouch was spread gently over a small plastic
baseplate, and an incision was made in the outer skin to expose the
cheek pouch membrane. The avascular connective tissue layer was
removed, and a plastic chamber was positioned over the baseplate and
secured in place by suturing the skin around the upper chamber. This
chamber contained the suffusion fluid. This arrangement forms a
triple-layered complex: the baseplate, the upper chamber, and the cheek
pouch membrane exposed between the two plates. After these initial
procedures, the hamster was transferred to a heated microscope stage.
The chamber was connected to a reservoir containing warmed bicarbonate
buffer (37-38°C), which allowed continuous suffusion of the
cheek pouch. The buffer was bubbled continuously with 95%
N2-5%
CO2 (pH 7.4). The chamber was also
connected via a three-way valve to an infusion pump (model 341B, Sage
Instruments, Boston, MA) that allowed constant administration of
smokeless tobacco extract and drugs into the suffusate.
Determination of clearance of macromolecules.
The cheek pouch microcirculation was visualized with an Olympus
microscope (Jacobs Instruments, Shawnee Mission, KS) coupled to a 100-W
mercury light source at a magnification of ×40. Fluorescence microscopy was accomplished with the aid of filters that matched the
spectral characteristics of FITC-dextran. An excitation filter (KP-490)
and a heat filter were positioned between the light source and the
objective. A barrier filter (510 nm) was positioned between the
objective and the beam splitter. Macromolecular leakage was determined
by exudation of FITC-dextran, which appeared as fluorescent "spots" or leaky sites around postcapillary venules (8-12,
17, 18, 21, 23, 30). The number of leaky sites was determined by
counting three random microscopic fields at predetermined time intervals during each intervention. The total number of leaky sites was
then averaged and expressed as the number of leaky sites per 0.11 cm2 of cheek pouch, which
corresponds to the area of one microscopic field (9, 10, 12, 30).
In each experiment, clearance of FITC-dextran from the cheek pouch was
also calculated as a second parameter of macromolecular efflux as
previously described in our laboratory (8-10, 12, 30). The
suffusate was collected at 5-min intervals throughout the experiment by
a fraction collector (Cygnet, Isco, Lincoln, NE). Samples were
collected into glass test tubes, and the concentration of FITC-dextran
was determined. Arterial blood samples were collected in heparinized
capillary tubes (70-µl volume; Scientific Products, McGaw Park, IL),
beginning 5 min before and 5, 30, 60, 120, 180, and 240 min after
injection of FITC-dextran. The concentration of FITC-dextran was
determined in all plasma samples. To quantitate the concentration of
FITC-dextran in the plasma and suffusate, a standard curve for
FITC-dextran concentrations vs. percent emission was performed on a
spectrophotofluorometer (Photon Technology International, Princeton,
NJ). The standard was FITC-dextran that was prepared on a weight per
volume basis. With the bicarbonate buffer used as background, a
standard curve was generated for each experiment, and each curve was
subjected to linear regression analysis. The percent emission for
unknown samples (plasma and suffusate) was measured on the
spectrophotofluorometer, and the concentration of FITC-dextran was
calculated from the standard curve. In preliminary experiments, minimal
fluorescence signal (<2% above background) was detected when drugs
were added to the buffer and when plasma and suffusate samples were
examined before the addition of FITC-dextran. Clearance of FITC-dextran
was determined by calculating the ratio of suffusate (ng/ml) to plasma
(mg/ml) concentration of FITC-dextran and multiplying this ratio by the suffusate flow rate (2 ml/min).
Experimental Protocols
Effects of purified ACE on smokeless tobacco extract-induced responses. The purpose of these studies was to determine whether purified ACE attenuates smokeless tobacco extract-induced leaky site formation and increase in clearance of FITC-dextran from the cheek pouch. After buffer was suffused for 30 min (equilibration period), FITC-dextran was injected intravenously, and the number of leaky sites and clearance of FITC-dextran were determined for 30 min. Then, smokeless tobacco extract (0.25%) was suffused for 20 min (12, 23). At least 45 min elapsed between subsequent suffusions of smokeless tobacco extract (12, 23, 28). After suffusion of smokeless tobacco extract was stopped and the number of leaky sites returned to baseline, purified rabbit lung ACE (0.05 or 0.1 unit) was suffused onto the cheek pouch for 30 min before and during a second suffusion of smokeless tobacco extract (0.25%). In another group of animals, the experimental design was similar except that 0.5% smokeless tobacco extract was used. The number of leaky sites and clearance of FITC-dextran were determined during each intervention. In preliminary studies, we determined that repeated suffusions of smokeless tobacco extract (0.25 and 0.5%) before and after suffusion of saline (vehicle) for 30 min were associated with reproducible results. In addition, suffusion of purified ACE (0.05 and 0.1 unit) alone for 30 min and of saline for the entire duration of the experiment was not associated with visible leaky site formation and increase in clearance of FITC-dextran. The concentrations of smokeless tobacco extract and purified ACE used in these studies were based on preliminary studies, previous studies in our laboratory, and a report in the literature (12, 16, 19, 23, 28). Effects of purified ACE on bradykinin-induced responses. Because smokeless tobacco extract elicits bradykinin production in the cheek pouch (12), and because ACE regulates the edemagenic effects of bradykinin in the tissue by cleaving and inactivating the peptide (30), we sought to determine whether purified ACE attenuates leaky site formation and the increase in clearance of FITC-dextran elicited by bradykinin. After buffer was suffused for 30 min (equilibration period), FITC-dextran was injected intravenously, and the number of leaky sites and clearance of FITC-dextran were determined for 30 min. Then, two concentrations of bradykinin (0.5 and 1.0 µM) were suffused for 5 min in a nonsystematic fashion. At least 45 min elapsed between subsequent suffusions of bradykinin (8, 11, 13, 17, 30). After suffusion of bradykinin was stopped and the number of leaky sites returned to baseline, purified ACE (0.05 unit) was suffused for 30 min before and during a second suffusion of bradykinin (0.5 and 1.0 µM). In another group of animals, the experimental design was similar, except that 0.1 unit purified ACE was used. The number of leaky sites and clearance of FITC-dextran were determined during each intervention. In preliminary studies, we determined that repeated suffusions of bradykinin (0.5 and 1.0 µM) before and after suffusion of saline (vehicle) for 30 min were associated with reproducible results. The concentrations of bradykinin used in these studies were based on previous studies in our laboratory and reports in the literature (10, 11, 13, 17, 30). Specificity of purified ACE-induced responses. The purpose of these studies was to determine the specificity of the attenuating effects of purified ACE on smokeless tobacco extract- and bradykinin-induced increase in macromolecular efflux. To accomplish this goal, we used three experimental approaches. First, we determined the effects of purified lung rabbit ACE on adenosine-induced leaky site formation and increase in clearance of FITC-dextran. Adenosine, like bradykinin, increases macromolecular efflux from postcapillary venules in the cheek pouch by specific receptor-mediated mechanism(s) (10, 13, 17, 30). After buffer was suffused for 30 min (equilibration period), FITC-dextran was administered intravenously and the number of leaky sites and clearance of FITC-dextran were determined. Then, adenosine (1.0 µM) was suffused for 5 min. After suffusion of adenosine was stopped and the number of leaky sites returned to baseline, purified ACE (0.1 unit) was suffused for 30 min before and during a second suffusion of adenosine (1.0 µM). At least 45 min elapsed between subsequent suffusions of adenosine (8, 13, 17, 30). The number of leaky sites and clearance of FITC-dextran were determined during each intervention. In preliminary studies, we determined that repeated suffusions of adenosine (1.0 µM) before and after suffusion of saline (vehicle) for 30 min were associated with reproducible results. The concentration of adenosine used in these studies was based on previous studies in our laboratory and a report in the literature (8, 13, 17, 30). Second, we determined whether the effects of purified ACE are dependent on the catalytic sites of the enzyme by determining the effects of heat-inactivated purified ACE on smokeless tobacco extract- and bradykinin-induced responses (6, 23). After buffer was suffused for 30 min (equilibration period), FITC-dextran was injected intravenously and the number of leaky sites and clearance of FITC-dextran were determined for 30 min. Then, smokeless tobacco extract (0.25%) was suffused for 20 min. After suffusion of smokeless tobacco extract was stopped and the number of leaky sites returned to baseline, purified ACE (0.1 unit) that was incubated at 60°C for 15 min was suffused for 30 min before and during a second suffusion of smokeless tobacco extract (0.25%). In another group of animals, bradykinin (0.5 µM) rather than smokeless tobacco extract was suffused for 5 min before and during suffusion of heat-inactivated purified ACE (0.1 unit). The number of leaky sites and clearance of FITC-dextran were determined during each intervention. In preliminary studies, we determined that suffusion of heat-inactivated purified ACE (0.1 unit) alone for 30 min was not associated with visible leaky site formation and increase in clearance of FITC-dextran. Last, we determined whether the effects of purified lung rabbit ACE are enzyme specific by determining the effects of purified superoxide dismutase, an enzyme structurally and functionally unrelated to ACE (7), on smokeless tobacco extract- and bradykinin-induced leaky site formation and increase in clearance of FITC-dextran. After buffer was suffused for 30 min (equilibration period), FITC-dextran was injected intravenously and the number of leaky sites and clearance of FITC-dextran were determined for 30 min. Then, smokeless tobacco extract (0.25%) was suffused for 20 min. After suffusion of smokeless tobacco extract was stopped and the number of leaky sites returned to baseline, purified bovine erythrocyte superoxide dismutase (60 units/ml) was suffused for 30 min before and during a second suffusion of smokeless tobacco extract (0.25%). In another group of animals, bradykinin (0.5 µM) rather than smokeless tobacco extract was suffused for 5 min before and during suffusion of purified bovine erythrocyte superoxide dismutase (60 units/ml). At least 45 min elapsed between subsequent suffusions of smokeless tobacco extract and bradykinin. The number of leaky sites and clearance of FITC-dextran were determined during each intervention. In preliminary studies, we determined that suffusion of purified bovine erythrocyte superoxide dismutase (60 units/ml) alone for 30 min was not associated with visible leaky site formation and increase in clearance of FITC-dextran. The concentration of purified bovine erythrocyte superoxide dismutase used in these studies was based on preliminary studies and a previous report in the literature (7).Drugs
Smokeless tobacco (moist snuff; 1S3) was obtained from the Tobacco and Health Research Institute, University of Kentucky (Lexington, KY). FITC-dextran, purified rabbit lung ACE, bradykinin, adenosine, and purified bovine erythrocyte superoxide dismutase were obtained from Sigma Chemical (St. Louis, MO). Smokeless tobacco extract and drugs were diluted in saline to the desired concentrations on the day of the experiment.Data and Statistical Analyses
When a test compound was suffused over the cheek pouch, we determined the maximal change in the number of leaky sites and clearance of FITC-dextran and used the change as the response to that compound. Data are expressed as means ± SE. Because the number of leaky sites and clearance of FITC-dextran returned to baseline between successive suffusions of test compounds, all vehicle (saline) control data are expressed as a single value for each experimental condition. Statistical analysis was performed by using two-way analysis of variance and the Newman-Keuls test for multiple comparisons. A P value < 0.05 was considered significant.RESULTS
Effects of Purified ACE on Smokeless Tobacco Extract-Induced Responses
Smokeless tobacco extract elicited significant, concentration-dependent leaky site formation and increase in clearance of FITC-dextran (Figs. 1 and 2; n = 4 in each group; P < 0.05). These responses were significantly attenuated by purified ACE in a concentration-dependent fashion (Figs. 1 and 2; P < 0.05). For instance, the number of leaky sites decreased significantly from 9 ± 1/0.11 cm2 during suffusion of smokeless tobacco extract (0.5%) alone to 5 ± 1/0.11 cm2 during suffusion of smokeless tobacco extract (0.5%) and purified ACE (0.1 unit; P < 0.05). Clearance of FITC-dextran decreased significantly from 20.6 ± 2.1 ml/min × 106 during suffusion of
smokeless tobacco extract (0.5%) alone to 14.7 ± 2.2 ml/min × 106 during
suffusion of smokeless tobacco extract (0.5%) and purified ACE (0.1 unit; P < 0.05).
P < 0.05 vs. STE alone.
P < 0.05 vs.
STE alone.
Effects of Purified ACE on Bradykinin-Induced Responses
Bradykinin elicited significant, concentration-dependent leaky site formation and increase in clearance of FITC-dextran (Fig. 3A; n = 4 in each group; P < 0.05). These effects were significantly attenuated by 0.1 unit but not by 0.05 unit purified ACE (Fig. 3A; P < 0.05). The number of leaky sites decreased significantly from 19 ± 3/0.11 cm2 during suffusion of bradykinin (1.0 µM) alone to 9 ± 2/0.11 cm2 during suffusion of bradykinin (1.0 µM) and purified ACE (0.1 unit; P < 0.05). Clearance of FITC-dextran decreased significantly from 37.5 ± 9.0 ml/min × 106 during suffusion of
bradykinin (1.0 µM) alone to 14.1 ± 4.8 ml/min × 106 during suffusion of
bradykinin (1.0 µM) and purified ACE (0.1 unit;
P < 0.05).
P < 0.05 vs.
BK alone.
Specificity of Purified ACE-Induced Responses
Purified ACE (0.1 unit) had no significant effects on adenosine (1.0 µM)-induced leaky site formation and increase in clearance of FITC-dextran (Fig. 3B; n = 4 in each group; P > 0.5). In addition, heat-inactivated purified ACE (0.1 unit) had no significant effects on smokeless tobacco extract (0.25%)- and bradykinin (0.5 µM)-induced leaky site formation and increase in clearance of FITC-dextran (Fig. 3, C and D; n = 4 in each group; P > 0.5). Last, purified superoxide dismutase (60 units/ml) had no significant effects on smokeless tobacco extract (0.25%)- and bradykinin (0.5 µM)- induced leaky site formation and increase in clearance of FITC-dextran (Fig. 4, A and B; n = 4 in each group; P > 0.5).
DISCUSSION
The results of this study show that exogenous ACE attenuates smokeless tobacco extract- and bradykinin-induced increases in macromolecular efflux from the in situ hamster cheek pouch. These effects were specific and dependent on the catalytic sites of the enzyme, because ACE had no significant effects on adenosine-induced increase in macromolecular efflux and because heat-inactivated ACE and superoxide dismutase had no significant effects on smokeless tobacco extract- and bradykinin-induced responses, respectively. Overall, these data suggest that exogenous ACE attenuates smokeless tobacco-induced increase in macromolecular efflux from the in situ oral mucosa, in part, by promoting bradykinin catabolism.
The hamster cheek pouch is an established model to investigate the mechanisms underlying the injurious effects of smokeless tobacco in the in situ oral mucosa (1, 12, 23, 26, 28). For instance, Gao et al. (12) showed recently that smokeless tobacco extract similar to that used in the present study decreases ACE activity in the cheek pouch. These data are consistent with previous studies showing that tissue ACE activity is decreased in inflamed tissues (20, 25). To this end, ACE has been shown to modulate the edemagenic effects of bradykinin, a potent vasoactive mediator produced during exposure to smokeless tobacco extract, in the cheek pouch (12, 23, 30). The results of the present study support and extend these observations by showing that exogenous ACE attenuates smokeless tobacco extract-induced increase in macromolecular efflux from the cheek pouch.
Although the mechanisms underlying this response were not addressed directly in the present study, the concomitant attenuation of exogenous bradykinin-induced increase in macromolecular efflux by purified ACE and the lack of effect of heat-inactivated ACE and superoxide dismutase on smokeless tobacco extract- and bradykinin-induced responses suggest that it was mediated, in part, by bradykinin catabolism (3, 16, 30). Support for our hypothesis comes from the study of Müns et al. (16), who showed that smokeless tobacco extract attenuates ACE activity in oral keratinocytes, thereby amplifying bradykinin-induced cell proliferation. Moreover, for a similar increase in macromolecular efflux elicited by smokeless tobacco extract and bradykinin, only the higher concentration of exogenous ACE used in the present study was effective. These data suggest that the extent of tissue penetration determines, in part, the effectiveness of exogenous ACE in mitigating the edemagenic effects of smokeless tobacco extract and bradykinin in the in situ cheek pouch. Clearly, additional studies are warranted to support or refute this hypothesis.
The salutary effects of exogenous ACE may have been related, in part, to potential interaction(s) of the enzyme with bradykinin B2 receptors in the cheek pouch, thereby hindering ligand-receptor interactions and attenuating macromolecular efflux (3, 27). However, this possibility seems unlikely, because exogenous ACE had no significant effects on adenosine-induced increase in macromolecular efflux, a receptor-mediated phenomenon (10, 13, 17, 30). This observation also implies that the effects of exogenous ACE on smokeless tobacco extract- and bradykinin-induced responses were not related to changes in vasomotor tone and/or venular driving pressure in the cheek pouch (17, 21, 29). Overall, these data suggest that the effects of exogenous ACE on smokeless tobacco extract- and bradykinin-induced responses are specific.
The constituents of smokeless tobacco extract that elicit bradykinin production in the cheek pouch, thereby increasing macromolecular efflux, are difficult to characterize because the chemical composition of smokeless tobacco is complex (15, 22). So far, >3,000 constituents have been identified in smokeless tobacco (22). Nonetheless, Hoffmann et al. (15) determined the concentrations of several major toxic and carcinogenic constituents of smokeless tobacco extract similar to that used in the present study, including nicotine, tannins, and nitrosamines. To this end, Myers et al. (18) showed that suffusion of nicotine, a major constituent of smokeless tobacco (15, 22), had no significant effects on macromolecular efflux from the cheek pouch. Further studies are indicated to identify constituents of smokeless tobacco extract that elicit bradykinin production in the cheek pouch.
In summary, we found that exogenous ACE attenuates smokeless tobacco extract-induced increase in macromolecular efflux from the in situ oral mucosa, in part, by promoting bradykinin catabolism. We suggest that topical application of ACE should be considered in the treatment of oral mucosa inflammation elicited by smokeless tobacco.
ACKNOWLEDGEMENTS
This study was supported, in part, by National Institute of Dental Research (NIDR) Grant DE-10347 and by grants from the American Heart Association of Metropolitan Chicago and the Laerdal Foundation for Acute Medicine. I. Rubinstein is a recipient of NIDR Research Career Development Award DE-00386 and a University of Illinois Scholar Award.
FOOTNOTES
Address for reprint requests: I. Rubinstein, Dept. of Medicine (M/C 787), Univ. of Illinois at Chicago, 840 South Wood St., Chicago, IL 60612-7323.
Received 8 July 1996; accepted in final form 7 March 1997.
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