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.

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.

The progression of established allergen-induced structural airway changes in sensitized rats can be inhibited by treatment with fluticasone.

In subjects insufficiently controlled with low to moderate doses of inhaled corticosteroids, adding beta-agonists is clinically more beneficial than increasing the dose of inhaled corticosteroids. In the present study, we investigated the effect of adding salmeterol to fluticasone on allergen-induced airway inflammation and remodeling. Sensitized rats, in which characteristics of remodeling had been induced by ovalbumin exposure every 2 days from Days 14 to 28, were further exposed to ovalbumin or PBS from Days 29 to 42. During the last 2 weeks, before allergen exposure, rats were treated with aerosolized fluticasone propionate (10 mg), salmeterol (1 mg), salmeterol (1 mg) plus fluticasone propionate (10 mg), or placebo. After 4 weeks of ovalbumin exposure, the airways showed inflammatory changes, goblet cell hyperplasia, and enhanced fibronectin and collagen deposition. Salmeterol in monotherapy decreased bronchoalveolar lavage fluid eosinophil number but had no influence on structural changes. Combining salmeterol with fluticasone propionate counteracted goblet cell hyperplasia, but increased the amount of fibronectin and collagen in the airway wall. These effects of salmeterol did not influence airway responsiveness. We conclude that the combination of salmeterol and fluticasone propionate enhances aspects of allergen-induced airway remodeling. This is not accompanied by changes in airway responsiveness.

It remains to be fully established whether allergen-induced airway inflammation and remodeling are influenced by age. The aim of the present study was to compare allergen-induced airway changes in young and adult rats. Brown Norway rats were sensitized at 4 weeks of age (young) or 13 weeks of age (adult) and exposed to aerosolized ovalbumin (OA) or phosphate-buffered saline for 2 weeks. In both age groups OA exposure induced an increase in OA-specific Immunoglobulin E and in the number of peribronchial eosinophils. OA-challenged animals also developed an increase in total airway wall area, enhanced fibronectin deposition, and goblet cell hyperplasia. Both inflammatory and structural alterations were more pronounced in the airways of young compared with adult OA-exposed rats. The number of peribronchial eosinophils was increased in young animals (685.4 +/- 75.0 versus 389.9 +/- 37.8/mm2 in adult rats; p < 0.001). A higher degree of goblet cell hyperplasia was observed in young rats (65.37 +/- 4.68 versus 34.74 +/- 3.68/mm basement membrane in adult rats; p < 0.001) and area of fibronectin deposition in the airway wall was higher in young compared with adult animals (5.08 +/- 0.46 versus 3.62 +/- 0.29 microm2/microm basement membrane; p < 0.005). In conclusion, in young rats airways are more susceptible to allergen-induced inflammatory and structural airway changes.

♦ Objectives The high incidence of intraperitoneal infection remains an important problem in animal models of chronic dialysate exposure. Prophylactic antibiotic administration can be used to resolve this problem, but the isolated effects of antibiotics on peritoneal membrane function and structure are unknown. The present study examined the effects of prophylactic antibiotics on infection rate and peritoneal membrane function and structure in a rat model of chronic dialysate exposure. ♦ Design A first group of rats (A; n = 12) received 10 mL 3.86% glucose dialysate twice daily through a heparin-coated catheter. In a second group of animals (B; n = 12), oxacillin 2.5 mg/day and gentamicin 0.04 mg/day were added to the dialysate. Group C ( n= 12) was injected twice daily with an identical dose of antibiotics dissolved in 1 mL of buffer solution. Group D ( n = 12) was left untreated. Dialysate cultures were obtained regularly. After 8 weeks of exposure, peritoneal transport studies were performed and samples for histology were obtained. ♦ Results Technique survival was 92% in group A and 100% in the remaining groups. Five rats in group A but none of the animals in the other groups developed peritonitis. The transport rates of small solutes were elevated and net ultrafiltration was decreased in group A compared to the controls. Fibrosis, as evaluated by quantifying Picro Sirius Red staining with image analysis, was significantly elevated in group A (3.48% ± 1.06% vs 0.72% ± 0.51% in group D, p < 0.05) but not in group B (0.29% ± 0.07%) or in group C (0.52% ± 0.28%). Vascular density, measured by counting the number of blood vessels that stained positive for endothelial NO synthase, was increased in both groups that were exposed to dialysate: 153.0 ± 12.9/μm2 in group A and 131.6 ± 14.3/μm2 in group B, versus 76.76 ± 12.37/μm2 in group C and 73.2 ± 10.4/μm2 in group D ( p < 0.01). ♦ Conclusions Prophylactic administration of oxacillin and gentamicin adequately prevented intraperitoneal infection in an animal model of chronic dialysate exposure. In addition, fibrosis was absent, suggesting intra-peritoneal infection rather than dialysate exposure is a causative factor.