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-betas, p-Smad2, Smad7, and CTGF was analyzed. High V(T) ventilation did not change gene expression of TGF-betas 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.
Wu
Shu
S
Department of Pediatrics, Division of Neonatology, University of Miami School of Medicine, Miami, Florida 33101, USA. swu2@med.miami.edu
Capasso
Letizia
L
Lessa
Andrea
A
Peng
Jinghong
J
Kasisomayajula
Kalyani
K
Rodriguez
Maria
M
Suguihara
Cleide
C
Bancalari
Eduardo
E
D000818:Animals; D000831:Animals, Newborn; D055513:Connective Tissue Growth Factor; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008171:Lung Diseases / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010766:Phosphorylation; D011175:Positive-Pressure Respiration / Q000009:adverse effects*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism*; D051906:Smad7 Protein / Q000378:metabolism; D013990:Tidal Volume; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha; D015854:Up-Regulation
C526316:CCN2 protein, rat; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D012333:RNA, Messenger; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051906:Smad7 Protein; C497808:Smad7 protein, rat; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D055513:Connective Tissue Growth Factor