This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Despite remarkable advances in perinatal and neonatal intensive care, chronic lung disease remains a common occurrence after premature birth or critical illness in the neonatal period or early infancy. Chronic lung disease of infancy (CLDI), as it is now frequently referred to, encompasses a heterogeneous group of conditions stemming from severe illness in the neonatal period or early in life, which often includes disorders other than those primarily affecting the lung. The treatment of an acute non-pulmonary illness, such as sepsis or congenital heart disease, may result in CLDI2. The overall thrust of this proposal is to study key components of the pathogenesis of BPD and CLDI. To do this, we will focus on two specific factors that contribute importantly to the development of chronic lung disease, oxygen toxicity (hyperoxia) and barotrauma. We will focus on outcomes that are highly relevant to the development of BPD and CLDI. These will include assessment of mediators of inflammation, innate antibacterial factors in the airway, the airway remodeling process and histological evidence of both necrotic and apoptotic cell injury. Intracellular regulatory mechanisms will also be evaluated focusing on the central role of the NF-kb pathway in inflammation. Finally, through the selective use of important clinical and pre-clinical treatments, we will assess the potential usefulness of these drugs and strategies and explore their mechanisms of action at the cellular level.
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