Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL044060-15A2
Application #
7142468
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Berberich, Mary Anne
Project Start
1991-01-01
Project End
2011-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
15
Fiscal Year
2006
Total Cost
$393,750
Indirect Cost

  Institution

Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
052277936
City
Los Angeles
State
CA
Country
United States
Zip Code
90027

  Publications

Bower, Danielle V; Lansdale, Nick; Navarro, Sonia et al. (2017) SERCA directs cell migration and branching across species and germ layers. Biol Open 6:1458-1471
Buckley, Susan; Shi, Wei; Xu, Wei et al. (2015) Increased alveolar soluble annexin V promotes lung inflammation and fibrosis. Eur Respir J 46:1417-29
Garcia, Orquidea; Carraro, Gianni; Turcatel, Gianluca et al. (2013) Amniotic fluid stem cells inhibit the progression of bleomycin-induced pulmonary fibrosis via CCL2 modulation in bronchoalveolar lavage. PLoS One 8:e71679
El-Hashash, Ahmed H K; Turcatel, Gianluca; Varma, Saaket et al. (2012) Eya1 protein phosphatase regulates tight junction formation in lung distal epithelium. J Cell Sci 125:4036-48
Driscoll, Barbara; Kikuchi, Alex; Lau, Allison N et al. (2012) Isolation and characterization of distal lung progenitor cells. Methods Mol Biol 879:109-22
Turcatel, Gianluca; Rubin, Nicole; El-Hashash, Ahmed et al. (2012) MIR-99a and MIR-99b modulate TGF-* induced epithelial to mesenchymal plasticity in normal murine mammary gland cells. PLoS One 7:e31032
El-Hashash, Ahmed H K; Warburton, David (2012) Numb expression and asymmetric versus symmetric cell division in distal embryonic lung epithelium. J Histochem Cytochem 60:675-82
Sala, Frederic G; Del Moral, Pierre-Marie; Tiozzo, Caterina et al. (2011) FGF10 controls the patterning of the tracheal cartilage rings via Shh. Development 138:273-82
Jackson, Sha-Ron; Lee, Jooeun; Reddy, Raghava et al. (2011) Partial pneumonectomy of telomerase null mice carrying shortened telomeres initiates cell growth arrest resulting in a limited compensatory growth response. Am J Physiol Lung Cell Mol Physiol 300:L898-909
El-Hashash, Ahmed H K; Al Alam, Denise; Turcatel, Gianluca et al. (2011) Six1 transcription factor is critical for coordination of epithelial, mesenchymal and vascular morphogenesis in the mammalian lung. Dev Biol 353:242-58

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