Alveolar epithelial cells (AEC) undergo mitochondrial and DNA damage following acute hyperoxic lung injury in both adult and neonatal lung, and are responsive to protective signaling mediated through MAP kinase activation and possibly other parallel pathways, suggesting that novel protective approaches might ameliorate alveolar damage in adults and alveolar hypoplasia in neonates. Our preliminary results now show that Inosine is a promising candidate low molecular weight compound, that functions through activation of specific survival enhancing phosphorylation targets to both ameliorate lung injury in adults, and potentiate recovery of neonatal alveolarization. Hypothesis: Inosine protects AEC from hyperoxic DMA damage and stimulates DNA repair, thereby preserving a key reparative/progenitor function of AEC, thus potentiating recovery of the alveolar epithelium from hyperoxic injury.
Aim 1 : To determine the protective effect of Inosine on hyperoxia induced glutathione depletion, mitochondrial function and DNA damage repair in AEC from adult rats and mice.
Aim 2 : To determine whether Inosine signaling acts through adenosine receptors to preserve mitochondrial function and DNA integrity in AEC from adult rats and mice.
Aim 3 : To determine the effect of Inosine on autocrine and paracrine protective TGF-(1 signaling through Smad2 and downstream targets in AEC from adult rats and mice.
Aim 4 : To determine whether inosine, acting in concert with fibronectin, exerts a protective effect on a reparative/progenitor cell subpopulation of AEC marked by telomerase activity in adult rats and mice.
Aim 5 : To determine the potential for the protective function of Inosine to enhance recovery of alveolarization from hyperoxic injury in neonatal rat and mouse lung. Health significance and Innovation: This work could have a major public health impact in currently intractable acute lung injury states. Inosine may function as a low molecular weight therapeutic to ameliorate lung injury, protect lung progenitor cells and hence to promote recovery of the alveolar epithelium from acute injury in both adult and neonate.
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