Early biomarkers and potential mediators of ventilation-induced lung injury in very preterm lambs

ABSTRACT: BACKGROUND: Bronchopulmonary dysplasia (BPD) is closely associated with ventilator-induced lung injury (VILI) in very preterm infants. The greatest risk of VILI may be in the immediate period after birth, when the lungs are surfactant deficient, still partially filled with liquid and not uniformly aerated. However, there have been very few studies that have examined this immediate post-birth period and identified the initial injury-related pathways that are activated. We aimed to determine if the early response genes; connective tissue growth factor (CTGF), cysteine rich-61 (CYR61) and early growth response 1 (EGR1), were rapidly induced by VILI in preterm lambs and whether ventilation with different tidal volumes caused different inflammatory cytokine and early response gene expression. METHODS: To identify early markers of VILI, preterm lambs (132d gestational age; GA, term 147d) were resuscitated with an injurious ventilation strategy (VT 20mL/kg for 15 min) then gently ventilated (5mL/kg) for 15, 30, 60 or 120 min (n=4 in each). To determine if early response genes and inflammatory cytokines were differentially regulated by different ventilation strategies, separate groups of preterm lambs (125d GA; n=5 in each) were ventilated from birth with a VT of 5 (VG5) or 10mL/kg (VG10) for 135minutes. Lung gene expression levels were compared to levels prior to ventilation in age-matched control fetuses. RESULTS: CTGF, CYR61 and EGR1 lung mRNA levels were increased 25, 50 and 120-fold respectively (p