Hyperoxia-induced airway hyperresponsiveness and remodeling in immature rats

We exposed 21-day-old rats to either normoxia or hyperoxia (>95% O₂) for 8 days and assessed in vivo airway responsiveness to aerosolized and intravenous methacholine (MCh) and airway architecture. Airway responsiveness was determined using a plethysmographic method. Hyperoxia increased airway cholinergic responsiveness, as reflected in a decreased mean ED₂₀₀ (concentration of MCh required to increase respiratory system resistance by 100%) for both aerosolized MCh [air exposed, 5.94 ± 2.50 vs. O₂ exposed, 0.29 ± 3.34 (SD) mg/ml, P = 0.0013, unpaired t test] and intravenous MCh (air, 1.40 x 10^-8 vs. O₂, 2.45 x 10^-10 mol/kg, P = 0.0002). Airway morphometry was studied in a separate cohort of animals. After fixation by distension with Formalin at 25 cmH₂O pressure, each airway cross section was photographed, and airway circumference, epithelial area, and smooth muscle layer area were determined by means of contour tracing using a digitizing pad and microcomputer. For the small airways (circumference < 1,000 μm), hyperoxia increased both mean epithelial thickness (air, 4.88 ± 0.53; O₂, 8.64 ± 0.90 μm) and mean smooth muscle layer thickness (air, 2.69 ± 0.11; O₂, 4.79 ± 0.56 μm; P < 0.0001 for each). O₂ had similar effects on the larger (1,000-3,000 μm) central airways (P < 0.0001 for both layers). We conclude that chronic hyperoxic exposure induces both airway hyperresponsiveness and airway wall thickening in immature rats.