Abstract
Mechanical ventilation from birth with normal tidal volumes (V(T)) causes lung injury and systemic responses in preterm sheep. The addition of budesonide to surfactant therapy decreases these injury markers. Budesonide and surfactant will decrease the injury from injurious V(T) ventilation in preterm sheep. Lambs at 126 ± 1 day gestational age were ventilated from birth with either: 1) Normal V(T) [surfactant 200 mg/kg before ventilation, positive end expiratory pressure (PEEP) 5 cmH(2)O, V(T) 8 mL/kg] or 2) Injury V(T) (high pressure, 100% oxygen, no PEEP) for 15 min, then further randomized to surfactant + saline or surfactant + 0.25 mg/kg budesonide with Normal V(T) for 6 h. Lung function and lung, liver, and brain tissues were evaluated for indicators of injury. Injury V(T) + saline caused significant injury and systemic responses, and Injury V(T) + budesonide improved lung physiology. Budesonide decreased lung inflammation and decreased pro-inflammatory cytokine mRNA in the lung, liver, and brain to levels similar to Normal V(T) + saline. Budesonide was present in plasma within 15 min of treatment in both ventilation groups, and less than 5% of the budesonide remained in the lung at 6 h. mRNA sequencing of liver and periventricular white matter demonstrated multiple pathways altered by both Injury V(T) and budesonide and the combination exposure. In lambs receiving Injury V(T), the addition of budesonide to surfactant improved lung physiology and decreased pro-inflammatory cytokine responses in the lung, liver, and brain to levels similar to lambs receiving Normal V(T).