ABSTRACT:We used a rat pup model to delineate whether mechanical ventilation of Ő
4 h duration in the absence of supplemental oxygen contributes to the development of airway hyperreactivity. Eight-day-old rat pups were assigned to unventilated normoxic controls, ventilated under normoxic conditions, ventilated under hyperoxic conditions (100% O 2 ), or unventilated hyperoxic groups (ÏŸ95% O 2 ). After each intervention, they were returned to their mothers. On d 10 of life, all animals were anesthetized, paralyzed, and ventilated to measure pulmonary function. Total lung resistance (R L ) and dynamic lung compliance (Cdyn) were measured in response to increasing intravenous doses of methacholine (0.03-1 g/g) by head-out body plethysmography. Injection of methacholine caused a dose-dependent increase in R L and decrease in Cdyn. The response of both R L and Cdyn to methacholine was significantly potentiated by prior exposure to mechanical ventilation when compared with unventilated normoxic controls. The addition of hyperoxia to mechanical ventilation did not further potentiate responses to methacholine. Mechanical ventilation did not alter lung myosin or the number of inflammatory cells in airways of room air ventilated versus unventilated control animals. We conclude that a brief period of mechanical ventilation in rat pups increases airway reactivity 48 h after such exposure in the presence as well as absence of hyperoxic exposure. This represents a potentially important model to investigate the mechanisms involved in airway hyperreactivity induced by neonatal lung injury. (Pediatr Res 60: 136-140, 2006) P remature infants with a history of mechanical ventilation and/or BPD have a high incidence of reactive airway disease in later childhood and adolescence (1,2). A combination of ventilator-induced lung injury and oxygen toxicity during a critical period of lung development has been implicated in the pathogenesis of chronic lung disease in this population (3). However, using data from clinical studies in infants, it is difficult to separate the relative contributions of mechanical ventilation versus high inspired oxygen. Furthermore, it is not clear to what extent ventilator-induced functional or structural changes in the developing airway contribute to airway hyperreactivity in former preterm infants.The changes in airway reactivity induced by prolonged exposure of rat pups to hyperoxia have been well described by ourselves and others (4 -7). Unfortunately, using an animal model of hyperoxic exposure alone without additional mechanical ventilation does not seem to be consistent with clinical practice in neonatology.There is very limited information on the potential changes in airway reactivity caused by ventilator-induced lung injury in early life. Fukunaga et al. (8) have shown that intermittent mechanical ventilation over a period of 7 d induced increased tracheal contractile responses measured under in vitro conditions in 7-wk-old rats. To our knowledge, the effect of mechanical ventilation on airway reactiv...