PROLONGED HIGH INTERMITTENT POSITIVE-PRESSURE VENTILATION INDUCES AIRWAY REMODELING AND REACTIVITY IN YOUNG-RATS

We postulated that prolonged exposure to intermittent positive-pressur e ventilation (IPPV) with high pressure (HIPPV) alone without hyperoxi a promotes the development of airway hyperresponsiveness and remodelin g. To test this hypothesis, young rats were ventilated under halothane anesthesia with HIPPV (maximum inspiratory pressure at 32-35 cmH(2)O in 70% nitrous oxide and 30% O-2) for 3.5-4 h daily for 6 days. Contro l rats were ventilated with low IPPV (maximum inspiratory pressure < 1 3 cmH(2)O) during the same time period with the same gas mixture. With the use of tracheal rings isolated from these rats and a setup in tis sue baths, contractile responses to carbachol(10(-6) to 10(-2) mM), 5- hydroxytryptamine (5-HT; 10(-9) to 10(-5) mM) and KCl (1-100 mM) were examined isometrically. In tracheal rings from HIPPV rats compared wit h low-pressure IPPV rats, the concentration tension curves showed a si gnificantly enhanced response to all agonists (P < 0.005). Sensitivity to carbachol, 5-HT, and KCl was also significantly increased (P < 0.0 5) compared with control rats as evidenced by decreases in EC50. Maxim um tension (reactivity) to 5-HT and KCl in the HIPPV group increased s ignificantly (P < 0.05), and there was a trend (P = 0.07) toward incre ased reactivity to carbachol in this group as well. Histological exami nations of tracheal rings demonstrated epithelial squamous metaplasia in the HIPPV group. Morphometric studies demonstrated tracheal smooth muscle thickening (P < 0.05) without changes in the thickness of the m ucosa or the lamina propria. When contractile responses were normalize d for the smooth muscle cross-sectional area (i.e., stress), reactivit y to all contractile agents was reduced, whereas reactivity to 5-HT st ill demonstrated significant increase (P < 0.005). Sensitivity of trac heal segments to all three agents was not affected by this normalizati on. These findings suggest that prolonged exposure to HIPPV without hy peroxia and the resultant overdistension of lung tissues (volutrauma) induced airway remodeling and airway hyperreactivity.