Connective Tissue Growth Factor Antibody Therapy Attenuates Hyperoxia-Induced Lung Injury in Neonatal Rats

Abstract

Despite recent advances in neonatal intensive care and surfactant therapy, bronchopulmonary dysplasia (BPD) continues to be one of the most common long-term pulmonary complications associated with preterm birth. Clinical efforts to prevent and treat BPD have been largely unsuccessful due to its multifactorial nature and poorly understood disease process. Connective tissue growth factor (CTGF) is a matricellular protein that plays an important role in tissue development and remodeling. Previous studies have demonstrated that hyperoxia exposure up-regulates CTGF expression in neonatal rat lungs. Whether CTGF overexpression plays a role in the pathogenesis of BPD, and whether CTGF antagonism has a therapeutic potential for BPD, are unknown. In the present study, we examined CTGF expression in lung autopsy specimens from patients with BPD and control subjects with no BPD. We assessed the effect of a CTGF-neutralizing monoclonal antibody (CTGF Ab) on preventing hyperoxia-induced lung injury in neonatal rats. Our study demonstrates that CTGF expression is increased in BPD lungs. In newborn rats, exposure to 90% oxygen for 14 days resulted in activation of β-catenin signaling, decreased alveolarization and vascular development, and physiological and histological evidence of pulmonary hypertension (PH). However, treatment with CTGF Ab prevented β-catenin signaling activation, improved alveolarization and vascular development, and attenuated PH during hyperoxia. These data indicate that CTGF-β-catenin signaling plays a critical role in the pathogenesis of experimental BPD. CTGF antagonism may offer a novel therapeutic strategy to alleviate BPD and PH in neonates.