The pathogenesis and functional consequences of airway remodeling in asthma remain to be fully established. In the present study we evaluated the effect of prolonged allergen exposure on airway function and structure in rats. Sensitized Brown Norway rats were repeatedly exposed for periods of 2, 4, or 12 wk to aerosolized ovalbumin (OA) or phosphate-buffered saline (PBS). OA exposure induced a persistent increase in OA-specific serum IgE and in the number of peribronchial eosinophils. After 2 wk of OA exposure, airway histology revealed goblet-cell hyperplasia, an increase in bromodeoxyuridine-positive cells in airway epithelium, increased fibronectin deposition, and a thickening of the airway inner wall area. This coincided with airway hyperresponsiveness (AHR) to aerosolized carbachol. After OA exposure for 12 wk, increased fibronectin (p Ͻ 0.05 versus PBS) and collagen deposition (p Ͻ 0.05 versus PBS) were observed in the submucosa. After 12 wk of exposure, neither total nor inner wall area or airway responsiveness to carbachol were any longer significantly different from those of PBS-exposed animals. In conclusion, prolonged OA exposure in rats induces structural airway changes that bear similarities to airway remodeling in asthma. The study data further indicate that depending on the extent and distribution of remodeling, changes in the extracellular matrix can enhance or protect against AHR. Palmans E, Kips JC, Pauwels RA. Prolonged allergen exposure induces structural airway changes in sensitized rats. AM J RESPIR CRIT CARE MED 2000;161:627-635.Airway morphology in asthma not only displays characteristics of an acute inflammatory process, but also structural changes. These include goblet-cell hyperplasia; changes in extracellular matrix (ECM) composition, with increased subepithelial deposition of collagens I, III, and V, fibronectin, and tenascin; and neovascularization and smooth-muscle-cell hyperplasia and/or hypertrophy (1-6). These structural changes are considered to play an important role in the pathophysiology of bronchial hyperresponsiveness (BHR), the functional hallmark of asthma (7-9). The remodeling process that produces these changes is thought to result from the combination of chronic, repetitive injury to the airway wall, and the ensuing tissue repair process. A variety of proinflammatory mediators, enzymes, cytokines, and growth factors have been implicated in the pathophysiology of airway remodeling (10-18); however, both the pathogenesis and the functional consequences of such remodeling must be further established.In vivo animal models might provide interesting information in this respect. We and others have previously shown that exposure to aerosolized allergen in Brown Norway (BN) rats results in eosinophilic airway inflammation, IgE production, and an increase in airway responsiveness (19)(20)(21)(22)(23). However, in these models, airway remodeling was either not assessed or was revealed to be quite limited (20). The aim of the present study was to evaluate whether longer exposure o...

Ethical and technical reasons limit the possibility of evaluating the effects of inhaled corticosteroids on structural changes in airways of humans with asthma. We therefore evaluated whether fluticasone propionate (FP) modifies airway remodeling, induced by repeated allergen exposure in rats. Sensitized BN rats were exposed to aerosolized ovalbumin (OA) for 2 wk. To assess the effect of FP on the development of or on established airway remodeling, animals were treated with aerosolized FP or placebo during allergen exposure or for 2 wk afterward. Compared with animals exposed to phosphate-buffered saline (PBS), OA-challenged animals developed an increase in total airway wall area, enhanced fibronectin deposition, epithelial cell proliferation, goblet cell hyperplasia, and airway hyperresponsiveness. Concomitant treatment with FP decreased all allergen-induced structural changes without being able to reverse them to normal. Initiating FP treatment after the allergen exposure had no effect on any of the OA-induced structural airway changes. The increase in total airway wall area, enhanced fibronectin deposition, and epithelial cell proliferation persisted. The goblet cell hyperplasia disappeared spontaneously. In conclusion, concomitant treatment with FP partly inhibits structural airway changes as well as hyperresponsiveness induced by OA exposure. Post hoc treatment fails to reverse established airway remodeling.

Background: The interactions between airway responsiveness, structural remodelling and inflammation in allergic asthma remain poorly understood. Prolonged challenge with inhaled allergen is necessary to replicate many of the features of airway wall remodelling in mice. In both mice and humans, genetic differences can have a profound influence on allergy, inflammation, airway responsiveness and structural changes. Methods: The aim of this study was to provide a comparative analysis of allergen-induced airway changes in sensitized BALB/c and C57BL/6 mice that were exposed to inhaled allergen for 2 (‘acute’), 6 or 9 weeks (‘chronic’). Inflammation, remodelling and responsiveness were analyzed. Results: Both strains developed a Th-2-driven airway inflammation with allergen-specific IgE, airway eosinophilia and goblet cell hyperplasia upon 2 weeks of allergen inhalation. This was accompanied by a significant increase in airway smooth muscle mass and hyperresponsiveness in BALB/c but not in C57BL/6 mice. However, airway eosinophilia was more pronounced in the C57BL/6 strain. Chronic allergen exposure (6 or 9 weeks) resulted in an increase in airway smooth muscle mass as well as subepithelial collagen and fibronectin deposition in both strains. The emergence of these structural changes paralleled the disappearance of inflammation in both C57BL/6 and BALB/c mice and loss of hyperresponsiveness in the BALB/c strain. TGF-β₁ was accordingly elevated in both strains. Conclusion: Airway inflammation, remodelling and hyperresponsiveness are closely intertwined processes. Genetic background influences several aspects of the acute allergic phenotype. Chronic allergen exposure induces a marked airway remodelling that parallels a decreased inflammation, which was largely comparable between the two strains.

Diverse modes of heparin administration have been used in animal models of chronic peritoneal dialysate exposure to maintain catheter patency and prevent fibrinous adhesions. Heparin has biological actions independent of its well-known anticoagulant activity, including the ability to modulate extracellular matrix synthesis, cellular proliferation, angiogenesis, and inflammation. These actions may interfere with peritoneal membrane homeostasis. The present study evaluated the influence of the mode of heparin administration on technique survival and infection rate in a rat model of chronic dialysate exposure. Further, the incorporation of heparin in the peritoneal membrane was examined. A 3.86% glucose dialysate was injected twice daily into Wistar rats with a heparin-coated catheter (group A1), or with a standard catheter with heparin injections during the entire exposure time (group A2) or only during 1 week (group A3). Sham manipulations were performed in a fourth group and a fifth group was left untreated. Technique survival was 80% in group A1, 60% in group A2, and 40% in group A3. The rate of infection was highest in group A1 and lowest in group A2. Intraperitoneally administered heparin accumulated in the peritoneal membrane, whereas dextran, with a molecular weight similar to that of heparin, was not incorporated in the peritoneum. In conclusion, intraperitoneal heparin reduced the incidence of infection in an animal model of chronic dialysate exposure. The best technique survival was, however, obtained using a heparin-coated catheter. Heparin is incorporated in the peritoneal membrane, where it may exert diverse biological actions and thus bias study results. The use of a heparin-coated catheter in combination with antibiotics may be the optimal approach to obtaining peritoneal access in animal models of chronic dialysate exposure.

To examine whether fluticasone propionate (FP) dose-dependently inhibits inflammatory as well as structural changes, Brown Norway rats were sensitised to ovalbumin (OA) on day 0 and 7. From day 14-28, rats were exposed to aerosolised OA (1%) or phosphate buffered saline every 2 days. Thirty minutes before each allergen exposure, animals were pre-treated with aerosolised placebo or FP (0.1, 1 or 10 mg) or prednisolone 3 mg?kg -1 i.p.At day 29, 0.1 mg FP had no measurable effect, either on inflammatory or structural changes, such as goblet cell hyperplasia and airway wall thickening. The allergeninduced increase in eosinophilic inflammation in bronchoalveolar lavage fluid and in the airway mucosa, as well as increased fibronectin deposition, were inhibited by treatment with FP from a dose of 1 mg onwards. Inhibition of goblet cell hyperplasia and thickening of the airway wall required 10 mg inhaled FP. At this dose, systemic effects were observed. However, for a comparable degree of systemic activity, prednisolone was far less effective at preventing airway changes.The dose of inhaled fluticasone propionate required to inhibit allergen-induced structural alterations was higher than to prevent eosinophil influx, and caused systemic side-effects. However, for a similar systemic activity, prednisolone was ineffective in preventing airway remodelling.