Department of Pediatrics, University of Miami School of Medicine, Miami, Florida, USA
Oxygen exposure to treat respiratory failure results in lung inflammation and long-term damages to lung structure and function that affect patients from neonates to adults. The research of our laboratory has been focused on identify novel therapeutic targets in the prevention and treatment of bronchopulmonary dysplasia (BPD), the most common and serious chronic lung disease of premature infants. BPD is characterized by lung-term alterations of lung structure including impaired alveolarization, poor vascular growth and interstitial fibrosis, and chronic respiratory failure. Most importantly, the severe form of this disease is often complicated with pulmonary hypertension that significantly increases the mortality up to 50% by 2-years of age. Similar to adult lung fibrosis with pulmonary hypertension, the etiology and pathogenesis of this disease is poorly understood, and there is no effective therapy.
Our research focus is on the differential signaling mechanisms by which CCN family proteins including CCN1 (CYR61) and CCN2 (connective tissue growth factor, CTGF) regulate alveolar and vascular formation, interstitial fibrosis and pulmonary hypertension. The CCN family contains six members of early gene products (Cyr61/Cef10, CTGF, Nov, WISP-1, WISP-2 and WISP). Each family member has four distinct protein modules: an insulin-like growth factor-binding protein module; a von Willebrand factor type C repeat; a thrombospondin type 1 repeat; and a C-terminal module. Genetic association studies and experimental models have shown that altered CCN gene structure or expression is associated with injurious stimuli, such as mechanical stress, oxygen exposure, ischemia and inflammation. Consequently, increased organ-specific susceptibility to structural damages ensues.
We have discovered that CCN2 is a causal factor while CCN1 is a protector for hyperoxia-induced rodent models of BPD with pulmonary hypertension. Critical data to support this conclusion include that hyperoxia up-regulates CCN2 expression but down-regulates CCN1 expression in rat lungs. Genetic gain of function of CCN2 by targeted overexpression of CTGF in alveolar type II epithelial cells induces the pathological hallmarks of BPD including inflammation, structural damage and pulmonary hypertension. More importantly, we have identified that the GSK-3β and β-catenin signaling pathways play an important role in mediating CCN2-induced these pathologies. In contrast, Treatment with recombinant CCN1 prevents lung inflammation, fibrosis and pulmonary hypertension in hyperoxia-exposed rats. These novel findings have not been previously described in neonatal models of lung injury.
Our data highlight the importance of CCNs in neonatal lung injury and repair.