A Comparison with Lipopolysaccharide-induced Mucus Production |
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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
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We produced ovalbumin (OVA)-sensitized rats as an animal model of nasal allergy. Intranasal instillation of OVA induced hypertrophic and metaplastic changes of goblet cells in nasal epithelium of OVA- sensitized rats. Intraepithelial mucosubstance in nasal mucosa increased significantly at 24 h after 3 or 7 d of OVA instillation, accompanied by mucosal infiltration of eosinophils. The effects of H1-antagonist (d-chlorpheniramine malate), H2-antagonist (cimetidine), dexamethasone, indomethacin, cysteinyl leukotrienes (cysLTs)-antagonist (ONO1078), and antirat neutrophil antiserum on OVA-induced changes were examined. Mucus production was significantly inhibited by dexamethasone, and ONO1078, whereas eosinophil infiltration was significantly inhibited by H1-antagonist, dexamethasone, and anti-rat neutrophil antiserum. These results indicate that cysLTs (LTs C4, D4, and E4) may play an important role in antigen-induced mucus production, and that eosinophil infiltration does not relate to mucus production. Intranasal instillation of lipopolysaccharide (LPS) also induced intraepithelial mucus production, and it was significantly inhibited by dexamethasone, indomethacin, and antirat neutrophil antiserum; however, cysLTs antagonist had no effect on LPS-induced change. These results indicate that neutrophil and cyclooxygenase products are important in LPS-induced mucus production, and there are different mechanisms of mucus production between allergic inflammation and LPS stimulation.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Hypertrophic and metaplastic changes of goblet cells associated with mucous hypersecretion are common characteristics of airway inflammation. Many inflammatory stimuli such as inhalative irritants (1, 2), neutrophil products (3), or viral and bacterial infections (6) have been used to study the mechanisms of mucous hypersecretion. In the previous study (7), we induced these pathologic changes in rat nasal epithelium by the intranasal instillation of lipopolysaccharide (LPS); intraepithelial mucosubstance increased significantly at 24 h after 3 d of LPS instillation.
Mucous hypersecretion is an important clinical observation in allergic inflammation of respiratory epithelium such as bronchial asthma because an excessive production of mucus causes plugging in the lower airways that may lead to airway obstruction and progressive respiratory insufficiency. The ovalbumin (OVA)-sensitized animals are commonly used to study the pathophysiologic changes of allergic asthma, including nonspecific airway hyperresponsiveness, airway eosinophilia, bronchocontraction, and plasma extravasation (8); however, little attention has been paid to the mechanism of mucuos hypersecretion. The elevated levels of allergic mediators, the increased infiltration of inflammatory cells, and goblet cell metaplasia are induced in allergic inflammation, but the relationships between allergic mediators, inflammatory cells, and mucous hypersecretion are still unclear.
In the present study, to elucidate the mechanism of mucous hypersecretion in allergic inflammation, we produced a rat model of nasal allergy, and examined (1) whether intranasal challenge of OVA can induce hypertrophic and metaplastic changes of goblet cells and eosinophil infiltration in nasal mucosa of OVA-sensitized rats, (2) the effects of H1- and H2- antagonist on OVA-induced mucus production and eosinophil infiltration, and (3) the effects of dexamethasone, indomethacin, cysteinyl leukotrienes (cysLTs)-antagonist, and antirat neutrophil antiserum on OVA-induced changes compared with LPS-induced mucus production. This model may be useful in the understanding of the role of allergic mediators, and inflammatory cells in mucous hypersecretion of allergic inflammation.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Sensitization with Ovalbumin
Specific pathogen-free male Fisher 344 rats (Japan SLC, Inc., Shizuoka, Japan) 7 to 8 wk of age were used in this study. Ovalbumin (OVA) (Grade V; Sigma Chemical Co., St. Louis, MO) was prepared at 400 µg/ml in saline and precipitated at a 1:1 ratio with Al(OH)3 (20 mg/ml). Rats were immunized by an intraperitoneal injection of 200 µg OVA (1 ml OVA-Al[OH]3 suspension) at Days 1, 2, 3, and 11, following the sensitization procedure of Asakura and coworkers (13) with some modifications (Figure 1). Heat-killed Bordetella pertussis bacilli (1010 in 50 µl saline; Wako Pure Chemical Industries, Ltd., Osaka, Japan) were given by a foot pat injection on Day 1 as an adjuvant. Sham immunizations were done without OVA but in the same manner with saline-Al(OH)3 and B. pertussis.
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Intranasal Challenge with OVA
At Day 19, rats were anesthetized with ether, and 0.1 ml of saline containing 10 mg of OVA was instilled into both airways of nasal cavity for 1, 3, or 7 consecutive days. The instillation methods and tissue preparations were carried out as previously described (14). The instillate was deposited as a bead of fluid on the external nares, which allowed the rats to aspirate it. Sham-challenged rats received 0.1 ml saline in the same manner.
OVA-specific Serum IgE
OVA-specific serum IgE levels were measured with an enzyme-linked immunosorbent assay (ELISA) employing antirat IgE monoclonal antibody (Zymed laboratories Inc., South San Francisco, CA) at the time the rats were killed (24 h after the last nasal challenge). It increased significantly in OVA-sensitized allergic rats (0.12 ± 0.1; optical density, 490 nm), compared with sham-sensitized control animals (0.06 ± 0.1, p < 0.01, n = 6)
Tissue Preparations
At 24 h after the last intranasal challenge, rats were killed with an intraperitoneal overdose of sodium pentobarbital. The head of each rat was removed and fixed in 10% neutral buffered formalin for 3 d, then decalcified in 5% trichloroacetic acid for 5 d. The nasal cavity was transversely sectioned at the level of the incisive papilla of the hard palate. The tissue block was embedded in paraffin.
Morphometry
Paraffin sections 5 µm thick were stained with alcian blue (pH, 2.6)- periodic acid-Schiff (AB-PAS) and hematoxylin. The percent area of AB-PAS-stained mucosubstance in the epithelial surface was determined by an image analyzer (SP 500; Olympus, Tokyo, Japan). The area of nasal epithelium was outlined and the image analyzer determined the area of AB-PAS-stained mucosubstance within this reference area. The percent area of stored mucosubstance in the epithelial surface was calculated over 2 mm (1 mm each side of nasal septum × 2) of the basal lamina at the center of the septal cartilage. The infiltrating eosinophils in nasal mucosa were examined using Hansel staining. The number of eosinophils in nasal septal mucosa was counted over both sides of septal cartilage using an oil immersion objective lens (magnification: ×1,000).
Intranasal Instillation with Lipopolysaccharide
Rats were anesthetized with ether, and 0.1 ml of saline containing 0.1 mg of lipopolysaccharide (LPS) from Escherichia coli 0111:B4 (Sigma Chemical) was instilled for 3 consecutive days. The instillation methods were same as above. Rats were killed and examined at 24 h after the last instillation of LPS.
Treatment with H1-antagonist, H2-antagonist, Dexamethasone, and Indomethacin
Each drug was given by intraperitoneal injection once a day for 4 d, starting 1 day before the first intranasal challenge. In these experiments, rats were examined at 24 h after a third OVA challenge. For the injection, indomethacin (2 mg/kg body weight; Sigma Chemical) was dissolved in 1% sodium bicarbonate. Other drugs were given in the form prescribable for injection: H1-antagonist (d-chlorpheniramine malate, 5 mg/kg body weight) formulated as Polaramine (Schelling Praw, Osaka, Japan), H2-antagonist (cimetidine, 200 mg/kg body weight) as Tagamet (Smith Klein Beecham, Osaka, Japan), and Dexamethasone sodium phosphate (4 mg/kg body weight) as Decadron (Banyu Pharmaceutical Co., Tokyo, Japan).
Treatment with Cysteinyl Leµukotrienes-antagonist, ONO1078
Cysteinyl leukotrienes (cysLTs)-antagonist, ONO1078 (Planlukast), was a kind gift from Ono Pharmaceutical Co., Ltd. (Osaka, Japan) (15). ONO1078 (200 mg/kg body weight) in 0.5% carboxymethyl cellulose sodium salt was given orally at 1 h before the intranasal challenge for 3 d.
Treatment with Antirat Neutrophil Antiserum
To induce depletion of circulating blood neutrophils, rabbit antirat neutrophil antiserum (1 ml/body weight) (Inter-Cell Technologies, Hopewell, NJ) was given by intraperitoneal injection for 3 d, starting 1 d before the first intranasal challenge.
Statistics
All data are expressed as mean ± SD. The difference between variables was analyzed by the Mann-Whitney test. Probability values of p < 0.05 were considered as statistically significant.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Eosinophil Infiltration
OVA-sensitized rats, challenged with OVA on each of 7 consecutive days, showed a significant eosinophil infiltration into nasal septal mucosa at 24 h after the last challenge (Figure 2A). Eosinophil infiltration occurred only in the group that had been both sensitized and challenged with OVA. Control groups (sham-sensitized rats challenged with saline or OVA, and OVA-sensitized rats challenged with saline) showed no eosinophil infiltration. When OVA-sensitized rats were challenged with a single intranasal instillation of OVA, a modest infiltration of eosinophils occurred in the nasal septal mucosa. Eosinophil infiltration peaked at 24 h after 3 d of OVA challenge, and no significant difference was observed after 3 and 7 d of OVA challenge (Figure 3A).
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Intraepithelial Mucus Production
When OVA-sensitized rats were challenged with OVA on each of 7 consecutive days, hypertrophic and metaplastic changes of goblet cells occurred in nasal septal epithelium at 24 h after the last challenge (Figure 4). Only a few goblet cells were observed in control groups (sham-sensitized rats challenged with saline or OVA, and OVA-sensitized rats challenged with saline). There were taller epithelium and moderate hypertrophy of the cytoplasmic component, compared with the epithelium of control animals. Quantitative changes in the percent area of mucosubstance in this epithelium are described in Figure 2B. Intraepithelial mucosubstance increased significantly only in the group that had been both sensitized and challenged with OVA. This intraepithelial mucus production did not occur in OVA-sensitized rats challenged with a single intranasal instillation of OVA. Intraepithelial mucosubstance increased significantly at 24 h after 3 d of OVA challenge in OVA-sensitized rats, and no significant difference was observed after 3 or 7 d of OVA challenge (Figure 3B).
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Effects of Treatment with H1-antagonist and H2-antagonist
Eosinophil infiltration into the nasal septal mucosa at 24 h after a third OVA challenge in OVA-sensitized allergic rats was significantly inhibited by the intraperitoneal injection of H1-antagonist (d-chlorphenilamine malate) (Figure 5A); however, Intraepithelial mucus production was not affected (Figure 5B). H2-antagonist (cimetidine) had no significant effect on the number of infiltrating eosinophils and the amount of intraepithelial mucosubstance.
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Effects of Treatment with Dexamethasone and Indomethacin
Both the eosinophil infiltration into nasal mucosa and the mucus production in nasal epithelium at 24 h after a third OVA challenge in OVA-sensitized allergic rats were significantly inhibited by the intraperitoneal injection of dexamethasone. Dexamethasone also inhibited LPS-induced mucus production at 24 h after 3 d of intranasal instillation (Figure 6). LPS did not induce eosinophil infiltration.
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The intraperitoneal injection of indomethacin had no significant effect on eosinophil infiltration and mucus production in nasal epithelium of OVA-challenged allergic rats; however, LPS-induced mucus production was significantly inhibited with indomethacin (Figure 6).
Effect of Treatment with CysLTs Antagonist, ONO1078
Treatment with ONO1078 had no significant effect on eosinophil infiltration in nasal mucosa of OVA-challenged allergic rats (Figure 7A). Mucus production in nasal epithelium of allergic rats was significantly inhibited by the administration of ONO1078 at 1 h before OVA challenge; however, LPS-induced mucus production was not affected with this drug (Figure 7B).
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Effect of Treatment with Antirat Neutrophil Antiserum
The numbers of circulating total white blood cells in neutrophil-depleted rats are described in Figure 8. Polymorphonuclear cells were completely depleted by the intraperitoneal injection of antirat neutrophil antiserum. The number of other white blood cells decreased significantly in these rats.
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Eosinophil infiltration into nasal mucosa of OVA-challenged allergic rats was completely abolished in these neutrophil-depleted rats (Figure 9A). Despite the total suppression of eosinophil infiltration, intraepithelial mucus production was not affected; however, LPS-induced mucus production was significantly inhibited in neutrophil-depleted rats (Figure 9B).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In the present study, intranasal instillation of OVA induced hypertrophic and metaplastic changes of goblet cells in nasal epithelium of OVA-sensitized rats. Intraepithelial mucosubstance increased significantly at 24 h after 3 or 7 d of OVA instillation, accompanied by mucosal infiltration of eosinophils. Several recent reports have described animal models of allergic asthma; intratracheal instillation or inhalation of OVA (antigen) induced goblet cell hyperplasia and mucous hypersecretion in OVA-sensitized guinea pigs and mice (8, 16). Many kinds of allergic mediators and inflammatory cells are capable of stimulating mucous hypersecretion; however, the mechanism by which antigen induces mucous hypersecretion is not well understood. This is the first report showing the goblet cell metaplasia and mucus production in nasal epithelium of allergic animals. The instillation procedure is easy and atraumatic, and the results are reproducible. The precise mechanism of epithelial mucus production in allergic inflammation was examined using specific inhibitors of allergic mediators and inflammatory cells in nasal epithelium of this animal model.
Histamine is an important mediator in the initiation and the development of antigen-induced airway responses. In allergic rhinitis, rhinorrhea can be induced by the increased vascular permeability and glandular secretion (17, 18). H1-receptors are present in endothelial cells, and sensory nerves in nasal mucosa, where they increase vascular permeability and glandular secretion through the parasynthetic reflex and the axon reflex as acute-phase responses (19, 20). The role of histamine in the synthesis and secretion of mucous glycoprotein remains controversial. Takeyama and coworkers (21) evaluated the mucous secretion by the decrease in intraepithelial mucosubstance, in vivo, in guinea pig trachea. They showed that inhaled histamine stimulated goblet secretion through the H2-receptor, and that intravenous histamine increased parasynthetic nerve-mediated secretion through the H1-receptor. On the contrary, Liu and coworkers (22) showed that histamine did not enhance SO4-labeled mucous secretion, in vitro, in guinea pig trachea, and that antigen-induced mucous secretion was not affected by H1-antagonist and H2-antagonist. In the present study, antigen-induced intraepithelial mucus production was not affected by H1-antagonist or H2-antagonist in rat nasal epithelium. In addition, intranasal instillation of histamine (0.1 to 1,000 µg in 100 µl saline for 3 consecutive days) did not induce goblet cell metaplasia or mucus production in rat nasal epithelium (data not shown). These results indicate that histamine may not be involved in antigen-induced mucus production, which occurs at 24 h after antigen challenge.
Histamine may facilitate the recruitment of airway eosinophils by stimulating eosinophil chemotaxis (23). In the present study, H1-antagonist inhibited the antigen-induced eosinophil infiltration into nasal mucosa. Antirat neutrophil antiserum totally suppressed circulating polymorphonuclear cells and eosinophil infiltration in nasal mucosa. The mechanism by which antineutrophil antiserum inhibited eosinophil accumulation is unclear. It may directly suppressed circulating eosinophils, or circulating polymorphonuclear cells may be important for the accumulation of eosinophils in nasal mucosa. Despite the partial or total suppression of eosinophil infiltration, there was no suppression of intraepithelial mucus production. These results were consistent with the previous report of Blyth and coworkers (8, 16) in which goblet cell hyperplasia began to appear before eosinophil infiltration into airway mucosa after a single intratracheal OVA instillation in OVA-sensitized mice. Haile and coworkers (12) have shown that vinblastin-induced suppression of eosinophil recruitment did not affect antigen-induced goblet cell metaplasia of mice bronchial epithelium. These findings supported the hypothesis that the migration of eosinophils is not essential for the induction of intraepithelial mucus production.
CysLTs (LTC4, D4, and E4) are potent allergic mediators released from mast cells and other various inflammatory cells. They may increase microvascular permeability, vasodilatation, and mucous hypersecretion in allergic rhinitis (17, 18). Increased cysLTs have been demonstrated in nasal lavage fluid in patients with allergic rhinitis after antigen provocation (24), and nasal provocation of LTD4 induced rhinorrhea and nasal congestion, as indicated by increase in nasal secretion and nasal airway resistance (25). CysLTs antagonist has been clinically effective in relieving rhinorrhea and nasal congestion in patients with allergic rhinitis (26). In the present study, cysLTs antagonist, ONO1078 (Planlukast), significantly inhibited antigen-induced mucus production at 24 h after antigen challenge; indicating that cysLTs are important and direct mediators for mucus production of epithelial goblet cells in allergic inflammation. These effects of ONO1078 are consistent with previous in vitro studies, where antigen-induced mucous secretion was significantly inhibited in sensitized guinea pig trachea (22). Because only partial suppression of epithelial mucus production occurred after oral administration of high-dose ONO1078 (200 mg/kg), it is conceivable that other allergic mediators such as proteases from macrophage, platelet-activating factor, tumor necrosis factor, and hydroxyeicosatetraenoic acid, may also contribute to antigen-induced mucus production in this rat model.
Neutrophil plays an important role in LPS-induced mucus production; LPS-induced change was significantly inhibited in neutrophil-depleted rat, produced by intraperitoneal injection of antirat neutrophil antiserum. In our previous study (27), intranasal instillation of IL-8, which is a strong chemoatractant for neutrophils, markedly induced intraepithelial mucus production in neutrophil-infiltrating rat nasal epithelium; suggesting that neutrophils themselves stimulate epithelial mucus production. Neutrophil elastase and other neutrophil proteases have strong secretagogue effects on airway mucous glycoprotein; intratracheal or intranasal instillation of neutrophil products induced goblet cell metaplasia and epithelial mucus production in hamster (3, 4) and rat (5). We have shown that LPS-induced intraepithelial mucus production was partially inhibited by the neutrophil elastase inhibitor ONO5046, and that elastase-induced mucus production was not inhibited by neutrophil-depletion (27). These results indicate that neutrophil elastase and other neutrophil proteases may be direct mediators for epithelial mucus production induced by LPS. On the other hand, antigen-induced mucus production was not affected by neutrophil-depletion, indicating that neutrophils are not essential for intraepithelial mucus production in allergic inflammation. Other inflammatory mediators are also involved in LPS-induced change. Intraperitoneal injection of indomethacin partially inhibits LPS-induced mucus production, but the cysLTs antagonist ONO1078 did not affect this change; suggesting that cyclooxygenase products but not cysLTs mediate LPS-induced intraepithelial mucus production.
In conclusion, we have demonstrated that intranasal instillation of OVA induced hypertrophic and metaplastic changes of goblet cells in nasal epithelium of OVA-sensitized rats. Mucous hypersecretion was important pathologic findings of allergic inflammation, but no direct study on its mechanism is available. Animal models such as ours can contribute to the understanding of these changes of goblet cells and underlying mechanism of epithelial mucus production. The present study suggests that cysLTs may be important mediators for antigen-induced mucus production, and that histamine, eosinophil, and neutrophil are not essential for this change. These results were different from LPS-induced changes, in which neutrophil and cyclooxygenase products may play important roles in mucus production; indicating that there are different mechanisms of mucus production between allergic inflammation and LPS stimulation. It is hoped that such studies will improve the understanding and the treatment of mucous hypersecretion in airway diseases.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. Takeshi Shimizu, Department of Otorhinolaryngology, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514, Japan. E-mail: tshimizu{at}clin.medic.mie-u.ac.jp
(Received in original form August 23, 1999 and in revised form November 1, 1999).
Acknowledgments: The writers would like to thank Ms. Chieko Shinohara for her help in the preparation of figures.
Supported in part by Grant-in-Aid for General Scientific Research No. 10470355 from the Ministry of Education of Japan and by a Grant-in-Aid (1999) from the Mie Medical Research Foundation.
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References |
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INTRODUCTION
METHODS
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DISCUSSION
REFERENCES
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T. SHIMIZU, H. HIRANO, S. SHIMIZU, C. KISHIOKA, Y. SAKAKURA, and Y. MAJIMA Differential Properties of Mucous Glycoproteins in Rat Nasal Epithelium . A Comparison between Allergic Inflammation and Lipopolysaccharide Stimulation Am. J. Respir. Crit. Care Med., September 15, 2001; 164(6): 1077 - 1082. [Abstract] [Full Text] [PDF]
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