Bronchopulmonary dysplasia (BPD) is a chronic lung disease that develops in newborn infants treated with oxygen and positive pressure ventilation for respiratory distress at birth. BPD is characterized by decreased alveolar and capillary development and increased fibrosis and remains a major cause of morbidity and mortality throughout childhood and young adulthood. Prolonged exposure of neonatal mice to hyperoxia results in lung fibrosis that is similar to BPD. No effective therapy was established to improve BPD. Therefore, it is important to explore new strategies for the BPD treatment. The renin-angiotensin system (RAS) is a key regulator of blood pressure and fluid homeostasis. Angiotensin (Ang) II is main effector molecule of the RAS and is produced from the substrate angiotensinogen through sequential enzymatic cleavages by renin and angiotensin converting enzyme (ACE). It has been suggested that compartmentalized RAS may work within individual organ system with some degree of autonomy to influence regional response. Ang II produced from proteolytic processing of angiotensinogen and generated locally in the lung tissue may have autocrine and paracrine actions at the cellular level. Connective tissue growth factor (CTGF) is implicated in fibroblast proliferation, cellular adhesion, angiogenesis, and extracellular matrix synthesis and has been reported to be a mediator of Ang II-induced fibrosis. The regulation of the fibrosis-promoting CTGF gene is probably under various vasoactive substances, growth factors, and locally acting cytokines. The relationship of RAS and CTGF in the pathogenesis of hyperoxia-induced lung fibrosis has not yet been established. The role of Ang II in the pathophysiology of hyperoxia-induced pulmonary fibrosis and the therapeutic potential for targeting Ang II in pulmonary fibrosis is unclear. Our preliminary studies found that hyperoxia increased collagen content in MRC-5 cells in a time-dependent manner and angiotensinogen and CTGF mRNA expressions are upregulated at time points preceding the increased collagen production. We hypothesize that RAS is involved in hyperoxia-induced CTGF up-regulation and mediates hyperoxia-induced lung fibrosis and blockage of this pathway may prevent the development of lung fibrosis in the hyperoxia-exposed rats. The aims of this study are (1) to establish an in vitro and in vivo model of lung fibrosis induced by hyperoxia and confirm that collagen upregulation and lung fibrosis is mediated via up-regulation of RAS, (2) to explore the role of RAS and its signaling pathways in hyperoxia-induced lung fibrosis, and (3) to evaluate various treatment strategies including ACE inhibitor, Ang II receptor blocker, and CTGF siRNA in the hyperoxia-induced lung fibrosis.
|Effective start/end date||8/1/10 → 7/31/11|
- angiotensin converting enzyme
- bronchopulmonary dysplasia
- connective tissue growth factor