Pulmonary Effects of Chorioamnionitis and Postnatal Hyperoxia in Rat Offspring

Project: A - Government Institutionb - Ministry of Science and Technology

Description

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 remains a major cause of morbidity and mortality throughout childhood and young adulthood. No effective therapy was established to improve BPD. Pulmonary inflammation also has a central role in the multifactorial and complex pathogenesis of BPD. Chorioamnionitis is associated with an increased risk of bronchopulmonary dysplasia. Epidemiological data suggest a strong association between chorioamnionitis and the development of BPD, which indicates a systemic inflammatory response during chorioamnionitis, are independent risk factors of BPD. Intra-amniotic lipopolysaccharide injection and postnatal hyperoxia exposure result in lung fibrosis that is similar to BPD. However, the mechanisms by which chorioamnionitis and hyperoxia mediates these effects were not clear. 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. A number of cytokines, particularly interleukin (IL)-1, IL-6, and IL-8 have been implicated in the pathogenesis of chorioamnionitis-induced fetal inflammation. The relationship of cytokines and RAS in the pathogenesis of chorioamnionitis and hyperoxia-induced lung injury has not yet been established. The role of RAS in the pathophysiology of chorioamnionitis and hyperoxia-induced pulmonary fibrosis and the therapeutic potential for targeting Ang II in pulmonary fibrosis is unclear. Our preliminary studies found that chorioamnionitis and hyperoxia increased lung collagen deposition in rat offspring. We hypothesize that cytokine and RAS are involved in chorioamnionitis and hyperoxia-induced lung injury and blockage of these pathways may prevent the development of lung injury in the rat offspring. The aims of this study are (1) to establish an in vivo and in vitro model of lung injury induced by chorioamnionitis and hyperoxia and confirm that collagen upregulation and is mediated via up-regulation of RAS, (2) to explore the role of cytokine and RAS and its signaling pathways in chorioamnionitis and hyperoxia-induced lung injury, and (3) to evaluate various treatment strategies including IL-1 receptor antagonist, ACE inhibitor, and Ang II receptor blocker in the chorioamnionitis and hyperoxia-induced lung injury.
StatusFinished
Effective start/end date8/1/117/31/12

Keywords

  • hyperoxia
  • pulmonary fibrosis
  • Rho-kinase