High Tidal Volume Ventilation Activates Smad2 and Upregulates Expression of Connective Tissue Growth Factor in Newborn Rat Lung

摘要

High tidal volume (VT) ventilation plays a key role in ventilator induced lung injury and bronchopulmonary dysplasia. However, little is known about the effect of high VT 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 VT on CTGF expression in newborn rat lungs. Newborn rats were ventilated with normal VT (10 mL/kg) or high VT (25 mL/kg) for 6 h. Nonventilated animals served as controls. We found that high VT upregulated CTGF expression. To identify the potential signaling pathways mediating high VT induction of CTGF, newborn rats were ventilated with high VT for 1 or 3 h. Temporal expression of TGF-βs, p-Smad2, Smad7, and CTGF was analyzed. High VT ventilation did not change gene expression of TGF-βs 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 Vt ventilation activates the Smad2 pathway, which may be responsible for downstream induction of CTGF expression in newborn rat lungs.Abbreviations: BPD, bronchopulmonary dysplasia; CTGF, connective tissue growth factor; ECM, extracellular matrix; ETCO2, end-tidal CO2; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HE, hematoxylin and eosin; PEEP, positive end-expiratory pressure; PIP, peak inspiratory pressure; p-Smad2, phosphorylated Smad2; VILI, ventilator induced lung injury; VT, tidal volume