Bronchopulmonary dysplasia (BPD), also known as neonatal chronic lung disease, is one of the most serious cardiopulmonary disorders in newborns, and remains a top priority for research in neonatology today. Although dexamethasone (DEX) is effective in reducing lung inflammation associated with BPD, and weaning newborns from mechanical ventilation, it produces an unacceptably high rate of serious short and long term side effects. Despite the widespread use of DEX in BPD, there has been no previous work addressing the molecular mechanisms of this therapy. Our long-term objective is to elucidate the molecular mechanisms underlying DEX function and cytokine expression in neonatal BPD. The neutrophil plays a central role in the pathogenesis of BPD. Our recent results demonstrate that DEX inhibits activation of a transcription factor known to be critical for inflammatory cytokine production in human neutrophils, nuclear factor-kappaB (NF-kappaB), and this is accompanied by increased cellular levels of the NF-kappaB inhibitor, IkappaBalpha. This proposal focuses on the specific mechanisms through which DEX suppresses activation of NF-kappaB in newborn neutrophils.
The specific aims of this proposal are the following. 1. To test the hypothesis that the mechanism of the DEX up-regulation of IkappaBalpha in newborn neutrophils consists of (I) inhibition of degradation of 1kappaBalpha, and/or (II) increased rate of IkappaBalpha synthesis. 2. To test the hypothesis that a new inhibitory protein synthesis is required for the DEX inhibition of NF-kappaB activation. 3. To investigate whether DEX inhibits NF-kappaB activation by direct protein-protein interactions between the activated glucocorticoid receptor (GR) and the NF-kappaB subunits in newborn neutrophils as well. Effective, selective and safer therapies are urgently needed for treatment of BPD, and other neutrophil-mediated pulmonary disorders. The development of such therapies will be achieved by a better understanding of the molecular mechanisms underlying the anti-inflammatory action of glucocorticoids in neutrophils.
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