Cerebral white matter injury is common in preterm infants, and can result from a multitude of insults during pregnancy and after birth. Ventilation onset after preterm birth in lambs can instigate an injurious cascade resulting in ventilation-induced brain injury, particularly if high tidal volumes are used. This is especially relevant given that up to 80% of preterm infants inadvertently receive high VT ventilation in the delivery room due to the limitations of the devices used. The major mechanisms leading to ventilation-induced brain injury include: 1) altered pulmonary blood flow, leading to adverse cardiac output and consequent abnormal changes to cerebral blood flow and 2) the initiation of a profound pulmonary inflammatory response that initiates a systemic inflammatory cascade resulting in a localized inflammatory response within the cerebral WM. These mechanisms are consistent with previously identified pathways of brain injury in preterm infants. Importantly, these pathways highlight the critical interaction between the lungs, heart and brain in the progression of preterm brain injury during the immediate transition at birth. Importantly, improving the initial ventilation strategy at birth mitigates ventilation-induced brain injury in otherwise healthy preterm lambs. This relationship has not been investigated in prenatally compromised models, such as preterm lambs exposed to intrauterine inflammation. Intrauterine inflammation, diagnosed clinically as chorioamnionitis, affects almost 10% of pregnancies with the incidence inversely proportional to gestational age ; up to two-thirds of extremely preterm infants are exposed to chorioamnionitis. Chorioamnionitis impairs development and LY2109761 causes gross injury to organs such as the lungs and brain, and is associated with an increased risk and severity of intraventricular haemorrhage and diffuse WM injury in preterm infants. Furthermore, preterm infants exposed to chorioamnionitis are at an increased risk of developing cerebral palsy and schizophrenia later in life. Studies have demonstrated that intrauterine inflammation induces a profound pulmonary, systemic and cerebral inflammatory response. Further, as intrauterine inflammation in of itself can alter fetal cerebral haemodynamics and increase the prevalence of impaired cerebral autoregulation, the mechanisms of inflammationinduced brain injury are consistent with that of perinatal brain injury. However, few studies have investigated the consequences of mechanical ventilation on lung and brain inflammation and injury after chorioamnionitis. We investigated whether the initiation of ventilation exacerbates inflammation and injury of the lungs and brain after intrauterine inflammation induced by intra-amniotic lipopolysaccharide injection two days prior to delivery. We hypothesized that high VT ventilation after acute intrauterine inflammation would exacerbate lung and cerebral white matter inflammation and injury, and a protective ventilation strategy would reduce this injury.