High tidal volume ventilation activates Smad2 and upregulates expression of connective tissue growth factor in newborn rat lung

High tidal volume (V-T) ventilation plays a key role in ventilator induced lung injury and bronchopulmonary dysplasia. However, little is known about the effect of high V-T on expression of growth factors that are critical to lung development. In a previous study, we demonstrated that connective tissue growth factor (CTGF) inhibits branching morphogenesis. In this study, we investigated the effect of high V-T on CTGF expression in newborn rat lungs. Newborn rats were ventilated with normal V-T (10 mL/kg) or high V-T (25 mL/kg) for 6 h. Nonventilated animals served as controls. We found that high V-T upregulated CTGF expression. To identify the potential signaling pathways mediating high V-T induction of CTGF, newborn rats were ventilated with high V-T for 1 or 3 h. Temporal expression of TGF-beta s, p-Smad2, Smad7, and CTGF was analyzed. High V-T ventilation did not change gene expression of TGF-beta s and Smad7 but induced rapid and sustained expression of p-Smad2 that precedes increased CTGF expression. CTGF and p-Smad2 were localized in bronchiolar epithelial cells, alveolar walls and septa. These data suggest that high V-T ventilation activates the Smad2 pathway, which may be responsible for downstream induction of CTGF expression in newborn rat lungs.