Antibiotic administration in an animal model of chronic peritoneal dialysate exposure.

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/microm2 in group A and 131.6 +/- 14.3/microm2 in group B, versus 76.76 +/- 12.37/microm2 in group C and 73.2 +/- 10.4/microm2 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 intraperitoneal infection rather than dialysate exposure is a causative factor.

The effects of heparin administration in an animal model of chronic peritoneal dialysate exposure.

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.

Effect of combining salmeterol and fluticasone on the progression of airway remodeling.

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.

Effect of age on allergen-induced structural airway changes in brown Norway rats.

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.