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Abstract |
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Abstract
Introduction
Materials & Methods
Results
Discussion
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Ozone (O3) is the principal oxidant pollutant in photochemical smog. Repeated exposures to O3 induces inflammation and mucous cell metaplasia in the nasal airways of laboratory animals. Our study was designed to determine the efficacy of a topical anti-inflammatory corticosteroid in preventing O3-induced rhinitis and mucous cell metaplasia in rat nasal epithelium. Male F344 rats were exposed to filtered air (0 ppm O3; air-controls) or 0.5 ppm O3, 8 h/day, for 3 or 5 days. Immediately before and after each exposure, rats received an intranasal instillation (50 µl/nasal passage) of a topical corticosteroid, fluticasone propionate (FP; 25 µg/nasal passage) or its vehicle only (0.01% ethanol in saline). Rats were killed 2 h after the third exposure (3-day exposure) or 3 days after the fifth exposure (5-day exposure) and nasal tissues were processed for light microscopy. Numeric densities of epithelial cells and neutrophils, and the amount of intraepithelial mucosubstances (IM) in the epithelium lining the maxilloturbinates were morphometrically determined. There were no significant differences in any measured parameter in air-exposed rats instilled with FP compared with air-exposed rats instilled with vehicle. Vehicle-treated rats exposed to ozone had neutrophilic rhinitis with 3.3- and 1.6-fold more intraepithelial neutrophils (3-day and 5-day exposure, respectively) and marked mucous cell metaplasia (5-day exposure only) with numerous mucous cells and approximately 60 times more IM in the nasal transitional epithelium compared with vehicle-treated air-controls. FP-treated rats exposed to ozone had minimal nasal inflammation (1.3-fold more intraepithelial neutrophils only after 3-day exposure) and minimal mucous cell metaplasia (5-fold more IM only after 5-day exposure) compared with vehicle-instilled, air-exposed rats. Results of this study indicate that FP-treatment is effective in attenuating not only O3-induced rhinitis (30-60% reduction) but also O3-induced mucous cell metaplasia (85% reduction) in rat nasal transitional epithelium. The cellular and molecular mechanisms involved in FP-induced attenuation of O3-induced nasal lesions remain to be determined.
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Introduction |
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Abstract
Introduction
Materials & Methods
Results
Discussion
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Ozone is the major irritant oxidant gas in photochemical smog. Among the major air pollutants for which National Ambient Air Quality Standards (NAAQS) have been designated under the Clean Air Act, ozone currently presents the most pervasive problem (1). The U.S. Environmental Protection Agency has estimated that in 1991, 69 million people in the United States lived in counties that violated the NAAQS for O3 (2). Recent histopathologic studies of nasal airways of people who live in Mexico City, which has high ambient levels of ozone and other air pollutants, suggest that these residents have substantially more lesions in their nasal mucosa than do people of similar age and gender living in rural Mexico, where there is little air pollution (3).
The acute morphologic response to O3 involves epithelial cell injury, resulting in rapid cell loss and replacement (4). We have previously reported that F344/N rats exposed to 0.8 ppm ozone, 6 h/day for 7 days, developed mucous cell metaplasia (the appearance of mucous secretory cells in an epithelium normally devoid of these cells) in the nasal transitional epithelium (NTE) lining the maxilloturbinates, lateral wall, and lateral aspects of the nasoturbinates in the anterior nasal cavity (5). The appearance of mucous secretory cells in the NTE is always preceded by a transient influx of neutrophils (4, 6), and an increase in NTE cell DNA synthesis (4, 7, 8). The role of neutrophilic inflammation and airway epithelial cell proliferation in the pathogenesis of O3-induced mucous cell metaplasia has yet to be determined.
Many inhaled toxicants induce acute neutrophilic inflammation in rodent airways but do not induce mucous
cell metaplasia. Therefore, ozone, or other agents which
induce mucous cell metaplasia, must trigger a series of cellular events which promote the expression of a mucous
cell phenotype in normally nonsecretory airway epithelial cells. Both airway epithelial cells and neutrophils produce
soluble factors that have been shown to modulate airway
mucous production and secretion. Airway epithelial cell
production of cytokines can be induced directly by exposure to ozone (9). In addition, airway epithelial secretion
of cytokines can amplify inflammatory events in response
to secreted neutrophil products such as tumor necrosis factor 
(TNF-), interleukin-6 (IL-6) and elastase (10). TNF-, IL-1
, and IL-6 have all been reported to induce
airway mucin hypersecretion (10, 14). Neutrophil
elastase has been shown to induce mucous cell metaplasia
in rodent pulmonary airways (18). Recently, TNF-
has been shown to induce the expression of a major airway
mucin gene (MUC-2) (14).
Corticosteroids are potent anti-inflammatory agents.
Corticosteroids have been shown to reduce the goblet cell
hyperplasia induced by tobacco smoke (21), bacterial endotoxin (22), and human neutrophil elastase (23). Fluticasone propionate (FP) is a potent topical anti-inflammatory
corticosteroid with low systemic activity (24). FP has
been shown to attenuate pulmonary inflammation in laboratory rodents (27) and humans (28), and inhibit neutrophil chemotaxis (29), endothelial cell adhesion molecule
expression (30), and cytokine production (26, 31, 32). Due
to the ability of this steroidal agent to decrease neutrophilic inflammation and decrease the expression of cytokines which modulate airway mucin expression (e.g., TNF-,
IL-6) this study was designed to determine the effect of FP
on ozone-induced rhinitis and mucous cell metaplasia in
the nasal airways of rats.
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Materials and Methods |
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Materials & Methods
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Animals, Intranasal Instillations, and Ozone Exposures
A total of 48 male F344/N Hsd rats (Harlan Sprague Dawley, Indianapolis, IN) were used in this study. The rats were randomly assigned to one of 8 experimental groups (n = 6/group) based on their body weight. The group assignments were adjusted to result in mean group body weights that were not significantly different from one another. The body weights ranged from 203 g to 232 g on the day of the first exposure. The rats were individually housed in stainless steel wire mesh cages within 6 m3 stainless steel and glass whole-body inhalation chambers (MPI Research, Mattawan, MI) with free access to food (Certified Rodent Chow #5002; PMI Feeds Inc., St. Louis, MO) and water. The rats were housed and observed for 12 days prior to the first exposure. The chamber temperature and relative humidity were maintained between 71°F and 74°F and 41% to 63%, respectively. The room lights were set on a 12-h light/dark cycle beginning at 6:00 AM.
Beginning on the first day of exposure, all rats received twice-daily intranasal instillations of fluticasone propionate (50 µg/instillation) in 100 µl (50 µl/airway) of saline containing 0.01% ethanol (vehicle) or vehicle alone. Rats were gently held in a supine position such that the nose was pointed up. The tip of a micropipette was placed in close proximity to, but not touching, the external naris. The instillate was slowly delivered as droplets that were aspirated by the rat into the nasal airways. Equal amounts of the instillate (50 µl) were delivered to each naris.
The rats were exposed to nominal ozone concentrations
of 0 ppm (HEPA-filtered air), or 0.5 ppm, 8 h/day, for 3 or
5 consecutive days. Ozone was generated from medical
grade oxygen by U.V. irradiation using an OREC Model
O3V1-O ozone generator (Ozone Research and Equipment Corp., Phoenix, AZ). The concentration of ozone
within the chambers was monitored throughout the exposures with 2 Dasibi 1003 AH ambient air ozone monitors
(Dasibi Environmental Corp., Glendale, CA). The air-sampling probes were placed in the breathing zone of the
rats. The chamber ozone concentration was maintained by
adjusting the intensity of U.V. irradiation. The chamber
ozone concentrations were recorded every 30 min during
the exposure periods. The mean chamber ozone concentrations (± SD) during the 5 days of exposure were
0.022 ± 0.005 ppm (0 ppm O3 
air control) and 0.539 ± 0.026 ppm (0.5 ppm O3).
Necropsy and Tissue Preparation
Rats were killed approximately 2 h after the end of 3 days of exposure or 3 days after the fifth day of exposure. Two hours prior to killing, all rats were injected, intraperitoneally, with bromodeoxyuridine (BrdU; 50 mg/kg body weight) to label cells undergoing DNA synthesis.
Rats were killed by exsanguination following deep anesthesia induced by sodium pentobarbital. Immediately after death, the head of each rat was removed from the carcass, and the nasal airways were flushed retrograde through the nasopharyngeal orifice with 10 ml of zinc-formalin (Anatech, Battle Creek, MI). The eyes, lower jaw, skin, and musculature were removed, and the head was immersed in a large volume of the same fixative for 48 h.
After fixation, the heads were decalcified with 13% formic acid for 4 days and then rinsed in tap water for 4 h. A tissue block was removed from the anterior nasal cavity by making two transverse cuts perpendicular to the hard palate; (1) immediately posterior to the upper incisor teeth and (2) at the level of the incisive papilla (Figure 1). The tissue blocks were embedded in paraffin and 5 micrometer-thick sections were cut from the anterior surface. Nasal tissue sections were histochemically stained with Alcian Blue (pH 2.5)/Periodic Acid Schiff's sequence (AB/PAS) to detect acidic and neutral mucosubstances, with Alcian Blue (pH 2.5)/ hematoxylin and eosin for histopathologic examination, or were immunohistochemically stained (7) to detect BrdU-labeled cells.
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Morphometric Quantitation
The NTE overlying the medial and lateral surfaces of the maxilloturbinates was analyzed. The length of epithelium evaluated per rat ranged from 2.2 mm (only 1 maxilloturbinate present in the tissue section) to 4.9 mm (two maxilloturbinates). The morphometric analyses were performed using a semi-automatic, computerized image analysis system consisting of a light microscope (e.g., Olympus BX-60; Olympus Corp., Lake Success, NY) connected to a high-resolution CCD camera (e.g., VE-1000; Dage-MTI, Inc., Michigan City, IN), a Scion LG-3 digital image-processing board (e.g., Scion Corp., Frederick, MD), a color monitor, and a Power Macintosh 7100/66 computer running the public domain NIH image analysis program (NIH Image; written by Wayne Rasband at the U.S. National Institutes of Health and available on the Internet at http://rsb.info.nih. gov/nih-image/).
The effect of ozone exposure and FP on neutrophilic inflammation was determined by quantitating the number of neutrophils within the surface epithelium (from the basal lamina to the airway lumen) overlying the maxilloturbinates. Nasal tissue sections were examined at a magnification of ×400. Neutrophils were identified by their darkly stained multi-lobed nucleus and pale cytoplasm. The length of basal lamina underlying the surface epithelium was determined using the image analysis system described above. The data for each experimental group were expressed as the mean number of intraepithelial neutrophils/mm basal lamina ± SE of the mean.
The effect of ozone exposure and FP on NTE cell DNA synthesis was determined by counting the number of BrdU-labeled NTE nuclei per mm basal lamina. The data for each experimental group were expressed as the mean number of BrdU-labeled NTE cells/mm basal lamina ± SE of the mean.
The numeric density of NTE cells (i.e., epithelial cells/ mm basal lamina) was determined by counting the total number of epithelial cell nuclear profiles present in the surface epithelium lining both maxilloturbinates and dividing by the total length of the basal lamina underlying the epithelium. The data for each experimental group were expressed as the mean number of epithelial cells/mm basal lamina ± SE of the mean.
The volume density (Vs) of acidic and neutral intraepithelial mucosubstances within the surface epithelium overlying both maxilloturbinates was determined for each rat. In addition, to determine if FP affects the amount of stored mucosubstances in an epithelium that normally contains copious amounts of stored mucins, the volume density of stored mucosubstances in the respiratory epithelium lining the surface of the nasal septum adjacent to the medial surfaces of the maxilloturbinates (mid-septum; Figure 1) was determined for all 5-day exposed rats. The areas of AB/ PAS-positive intraepithelial mucosubstances were calculated from the automatically circumscribed perimeter of the stained material. The method used to estimate the amount of stored mucosubstance per unit area of epithelial basal lamina has been described in detail (5, 33). Data were expressed as the mean volume density (Vs; nl/mm2 basal lamina) of AB/PAS-positive mucosubstances within the epithelium ± SE of the mean.
The numeric density of mucous secretory cells within the surface epithelium overlying the maxilloturbinates was determined for each rat. Only AB/PAS-positive epithelial cells with a nuclear profile were counted. The data were expressed as the mean number of AB/PAS-positive epithelial cells/mm basal lamina ± SE of the mean.
Statistical Analyses
The data were evaluated for potential effects of exposure
duration (3 days versus 5 days), ozone concentration (filtered air versus 0.5 ppm), and intranasal instillate (vehicle
versus FP) using a 3-way analysis of variance (ANOVA).
Significant differences were evaluated using a post-hoc
multiple pairwise comparison procedure (Tukey test) to
identify the source of the variance. Statistical analyses
were performed using a commercial statistical analysis package (SigmaStat; Jandel Scientific Software, San Rafael,
CA). The level of statistical significance was set at P 
0.05.
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Histopathology
No exposure-related lesions were found in the nasal airways of control rats exposed to 0 ppm ozone (filtered air). In all ozone-exposed rats, exposure-related lesions were bilateral (present in both nasal passages) and were restricted to the nasal mucosa, containing NTE, lining the lateral meatus. The mucosa lining the dorsolateral aspect of the maxilloturbinates, the lateral ridge of the nasoturbinates, and the dorsal recesses of the lateral walls were the sites most severely affected by the ozone exposures. The character and severity of the ozone-induced injury were time-dependent. The nasal mucosa containing respiratory epithelium that lines the luminal surfaces of the septum and roof of the proximal nasal cavity and the mucosa containing squamous epithelium that lines the floor of the proximal nasal cavity were not morphologically altered by the ozone exposure. Animals that were killed 2 h after the end of the third day of ozone exposure had a mild, bilateral acute rhinitis. This acute inflammatory response was characterized by margination of neutrophils along the endothelial surfaces of large capacitance blood vessels in the lamina propria with a modest influx of these inflammatory cells in the interstitial tissues between the blood vessels and the surface epithelium. In addition, the surface epithelium was thickened due to NTE cell hyperplasia.
Few neutrophils were present in the nasal mucosa of ozone-exposed rats that were killed 3 d after the fifth day of exposure. The surface epithelium was markedly thickened and hyperplastic. The principal histologic findings in the ozone-exposed rats that were killed after 5 days of exposure was a conspicuous increase in the number of AB/ PAS-positive mucous secretory cells with increased amounts of intraepithelial mucosubstances.
Morphometric Quantitation
Neutrophil influx. The number of neutrophils within the NTE overlying both maxilloturbinates was determined for each animal. Only neutrophils within the surface epithelium (between the basal lamina and the airway lumen) were counted. The data, expressed as the mean number of intraepithelial neutrophils per mm basal lamina ± SE of the mean, are presented in Figure 2.
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The cellular and molecular mechanisms involved in the pathogenesis of ozone-induced mucous cell metaplasia are not currently known. We have previously demonstrated that acute exposure to ozone results in transient neutrophilic inflammation, epithelial cell injury and death, and subsequent cell proliferation in the nonciliated, cuboidal, nasal transitional epithelium of rats (4). These ozone- induced epithelial and inflammatory cell responses precede the appearance of mucous secretory cells in this normally nonsecretory surface epithelium (i.e., mucous cell metaplasia). The cellular events that commit the NTE to undergo this phenotypic alteration occur during the first 3 days of ozone exposure. In 1991, we reported that ozone-induced mucous cell metaplasia and epithelial hyperplasia in the NTE of rats can be induced with only 3 consecutive, 6-h/day-exposures to ozone (34). Seven days after the start of the exposures, rats exposed to ozone for 3 days had mucous cell metaplasia that was indistinguishable from that in rats exposed to the same concentration of ozone for 7 days. The fact that the type and magnitude of the alterations induced by either 3 or 7 days of ozone exposure were similar suggests that the critical cellular and molecular events that initiate the expression of a mucous cell phenotype occur during the first 3 days of exposure. Once initiated, the development of ozone-induced mucous cell metaplasia in the NTE is independent of further ozone exposure.
In the present study, we found that fluticasone propionate, a topical corticosteroid, decreased neutrophilic inflammation and greatly attenuated mucous cell metaplasia without inhibiting nasal epithelial hyperplasia in ozone-exposed rats. We used BrdU (an analog of thymidine) to label NTE cells in the S-phase of the cell cycle. Increased airway epithelial cell DNA synthesis is a sensitive indicator of O3-induced cellular injury (35). Quantitation of epithelial cell numeric density was used to assess treatment-induced effects on NTE cell population dynamics (e.g., both cell loss and cell proliferation). Both section thickness and nuclear volume can affect estimates of numeric density and labeling index by influencing the probability of observing a nuclear profile in a tissue section. In the present study, all tissues were sectioned at approximately the same thickness (5 µm), and there was no discernible change in NTE cell nuclear volume in any experimental group. Therefore, the results of the present study reflect actual treatment-induced epithelial responses.
The method used to determine the volume density of stored intraepithelial mucosubstances has previously been described in detail (33). This method and other stereologic formulas have an underlying assumption that observed changes in the two-dimensional objects measured in the tissue section accurately reflect changes occurring in the three-dimensional cell or tissue. In the present study, O3 induced a significant increase in the area of AB/PAS-stainable mucosubstances within the NTE, and, FP greatly reduced that increase in stored intraepithelial mucosubstances. We also estimated the numeric density of mucous secretory cells by counting all AB/PAS-positive epithelial cells, with a nuclear profile, in the surface epithelium of the maxilloturbinates and dividing by the length of basal lamina underlying that epithelium. This method may underestimate the actual number of mucous secretory cells in the epithelium, because, as the amount of stored product is reduced, the probability of sectioning through and correctly identifying a cell as a mucous secretory cell is reduced. Therefore, the data presented in Figure 8 should be considered a minimum estimate of the number of mucous secretory cells in the NTE.
The ability of FP to inhibit ozone-induced mucous cell metaplasia in nasal airways is similar to an earlier report by Rogers and Jeffery (21) that glucocorticoids inhibit tobacco smoke-induced mucous cell hyperplasia/metaplasia in rat pulmonary airways. Similarly, Lundgren and colleagues (23) used dexamethasone, administered systemically in drinking water, to reduce rat tracheal mucous cell hyperplasia induced by neutrophil lysates or elastase alone. Though it is evident that corticosteroids can attenuate toxicant-induced mucous cell hyperplasia and metaplasia, the cellular and molecular mechanisms by which they exert their action have yet to be determined.
We hypothesize that neutrophil-derived products (i.e., cytokines and proteases) play an essential role in the differentiation of nonsecretory cells into mucous secretory cells following toxicant-induced airway epithelial injury. However, infiltrating neutrophils cannot be solely responsible for this metaplastic response. Many inhaled toxicants induce acute neutrophilic inflammation in rodent airways but do not induce mucous cell metaplasia. Therefore, ozone or other agents which induce mucous cell metaplasia (e.g., chlorine, sulfur dioxide, tobacco smoke, bacterial endotoxin), must initiate a series of cellular events that permit the expression of a mucous cell phenotype in normally nonsecretory airway epithelial cells. But, only if additional stimuli, resulting from the interaction of infiltrating neutrophils and airway epithelial cells, are present.
In the present study, FP reduced the number of intraepithelial neutrophils in ozone-exposed rats. This may be
due to the ability of FP to reduce the expression of adhesion molecules (30), inhibit neutrophil chemotaxis (28),
and inhibit the production of cytokines (IL-1) or chemokines (CINC), chemotactic for neutrophils, by airway
epithelial cells (31, 32, 36). Infiltrating neutrophils secrete
soluble products such as cytokines (TNF-, IL-1, IL-6) (12) and proteases (i.e., elastase and cathepsin G) (13). TNF-, IL-1, and IL-6 have all been reported to induce
airway mucin hypersecretion (14). Neutrophil elastase
has also been shown to induce mucous cell metaplasia in
rodent pulmonary airways (18). Recently, TNF- has
been shown to induce the expression of a major airway
mucin gene (MUC-2) (14) that codes for the core polypeptide of high molecular weight secreted mucins. If neutrophil-derived products are involved in the pathogenesis of toxicant-induced mucous cell metaplasia, then simply reducing the number of neutrophils infiltrating the site of injury may decrease the metaplastic response of the NTE to
ozone exposure. In addition, FP like other corticosteroids
can directly inhibit the expression of TNF-, IL-1, and
IL-6 which may decrease the expression of a mucous cell
phenotype.
Another corticosteroid, dexamethasone, has recently
been shown to suppress mucus production and MUC-2
and MUC-5 gene expression in vitro (37). Therefore, FP
may attenuate ozone-induced mucous cell metaplasia
by directly inhibiting airway mucin gene expression. Although FP inhibited the increase in stored intraepithelial
mucosubstances induced by ozone in the nasal transitional
epithelium lining the maxilloturbinates, it had no effect on
the amount of stored mucosubstances in the adjacent respiratory epithelium lining the nasal septum immediately
adjacent to the maxilloturbinates. This suggests that the
effects of corticosteroids on mucin gene expression in vitro may not reflect what occurs in vivo. Alternatively, there
may be differences in the regulation of mucus production
and mucin gene expression in mucous secretory cells
present in an epithelium which normally contains these
cells (i.e., the respiratory epithelium lining the anterior nasal septum) compared with mucous secretory cells which
arise in a normally nonsecretory epithelium following toxicant-induced epithelial injury (i.e., mucous cell metaplasia). The mechanisms of airway mucin gene expression are
currently unknown, therefore, it is not possible to predict
whether FP acts directly to modulate mucin gene expression, whether it alters the stability of mucin mRNA, or
whether it modulates mucin gene expression indirectly by
altering the expression of another gene product such as
TNF- which can itself induce mucin gene expression.
Increased DNA synthesis and cell proliferation are sensitive indicators of toxicant-induced epithelial injury (4, 35). In this study, we examined the effect of FP on both ozone-induced NTE cell DNA synthesis (BrdU-labeled NTE cells/mm basal lamina) and NTE cell proliferation (NTE cell numeric density). Examining epithelial cell DNA synthesis after a single pulse of BrdU (an analog of thymidine) provides an estimate of toxicant-induced cellular injury, but only during a short (2 h) period of time. Determination of epithelial cell numeric density provides an integrated assessment of both epithelial cell proliferation (i.e., epithelial cells entering the epithelial compartment) and epithelial cell death (i.e., cells lost from the epithelial compartment). At the end of 3 days of ozone exposure, rats instilled with FP had approximately 30% fewer NTE cells undergoing DNA synthesis than did ozone-exposed rats intranasally instilled with the vehicle. However, FP had no effect on ozone-induced nasal epithelial cell hyperplasia. Ozone-exposed rats intranasally instilled with either FP or its vehicle alone had similarly increased numbers of nasal transitional epithelial cells after 3 and 5 days of exposure. If the difference in epithelial DNA synthesis observed at the end of 3 days of exposure was representative of what was occurring after 1 and 2 days of exposure, then fewer NTE cells must have been lost from the surface epithelium overlying the maxilloturbinates of ozone-exposed rats treated with FP compared with ozone-exposed rats instilled with the vehicle. The underlying basis of this observation cannot be determined from the results of the present study. FP may have decreased ozone-induced injury (reflected by fewer cells undergoing DNA synthesis) or increased the survival of sublethally injured epithelial cells (e.g., fewer cells lost as a result of cell death). Alternatively, fewer cells may have been lost from the epithelial compartment because there were fewer infiltrating neutrophils in FP-instilled rats. Infiltrating neutrophils may increase the number of cells lost from an epithelial compartment due to release of reactive oxygen species or proteases. Venaille and colleagues (38) recently demonstrated that neutrophils can detach human amnion epithelial cells from their underlying basement membrane, in vitro, in a dose- and time-dependent manner. They concluded that neutrophil-induced detachment of epithelial cells involves the release of chymotrypsin-like serine proteases, probably in conjunction with reactive oxygen metabolites. Cheek and associates (39) have shown that neutrophils enhance the removal of rat pulmonary epithelial cells injured in vitro by exposure to ambient (0.1 ppm) levels of ozone. Additional studies using rats depleted of circulating neutrophils (to prevent ozone-induced neutrophil influx) are needed to differentiate the effects of infiltrating neutrophils and the direct effect of FP on ozone-induced nasal epithelial injury.
In conclusion, we have demonstrated that fluticasone propionate, a topical corticosteroid, can attenuate not only ozone-induced neutrophilic inflammation but also ozone-induced epithelial alterations in the rat nasal airways. FP inhibited toxicant-induced increases in the amount of stored epithelial mucosubstances and the number of mucous secretory cells in a normally non-secretory epithelium with no apparent effect on mucous production in nasal respiratory epithelium which normally expresses a mucous secretory phenotype. To our knowledge, this is the first report demonstrating that a topical corticosteroid was effective in preventing airway nasal epithelial cell differentiation (i.e., mucous cell metaplasia) induced by a common ambient air pollutant, ozone. Our findings suggest that FP may be a useful prophylactic for ozone-induced nasal airway injury. In addition, FP may be a useful tool to investigate cell or tissue specific regulation of mucin gene expression in airway epithelium. Additional research is needed to determine if inhaled topical steroids can be employed to reduce the overproduction and hypersecretion of airway mucins in humans with other respiratory diseases such as chronic bronchitis, asthma, or cystic fibrosis.
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Abbreviations: analysis of variance, ANOVA; fluticasone propionate, FP; interleukin, IL; intraepithelial mucosubstances, IM; National Ambient Air Quality Standards, NAAQS; nasal transitional epithelium, NTE; tumor necrosis factor, TNF.
(Received in original form January 16, 1997 and in revised form April 16, 1997).
Acknowledgments: The authors gratefully acknowledge the excellent technical assistance provided by Ms. Catherine Bennett of Michigan State University, and the members of the Necropsy and Inhalation Toxicology sections of MPI Research. They also thank Glaxo Wellcome, Inc. for providing fluticasone propionate for use in this study. This research was supported by NHLBI Grant 5RO1-HLS1712 and was conducted with the generous cooperation of MPI Research, which provided the inhalation exposure suite and personnel to perform the intranasal instillations and whole-body exposures, in facilities fully accredited by the American Association for Accreditation of Laboratory Animal Care.
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References |
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