Many of the transcriptional pathways involved in lung morphogenesis are expressed in the postnatal lung and induced during acute lung injury (ALI) to mediate repair of the lung. C/EBP( plays an important role in normal lung morphogenesis. The role(s) and mechanisms by which C/EBP( influences postnatal pulmonary homeostasis are presently unknown. Patients with ALI require high oxygen for survival and hyperoxia contributes to cellular injury that may exacerbate recovery. Our novel findings in Preliminary Data demonstrated that cre-mediated deletion of C/EBP( in respiratory epithelial cells using CCSP as promoter (Cebp(?/? mice) render the mice highly susceptible to hyperoxia, associated with decreased SP-B, severe lung inflammation, enlarged alveolar space, bronchiolar epithelial cell injury, and high mortality. Cebp( ?/? mice grow normally without any pulmonary disorder, suggesting that C/EBP( does not play a critical role in postnatal pulmonary homeostasis under normal conditions. In Cebpa?/? mice exposed to hyperoxia, mature SP-B in BALF was significantly decreased without any changes in SP-B mRNA or pro-SP-B expression, indicating that C/EBP( regulates the processing or trafficking of SP-B, a protein critical for lung function during hyperoxia. Furthermore, significantly delayed recovery of Cebp( ?/? mice after destruction of bronchiolar epithelial cells by naphthalene injection was demonstrated in our Preliminary Data. Recombinant human (rh) FGF-7 treatment showed considerable efficacy in protecting lung from hyperoxia and FGF-7 increased C/EBP( in cultured type II cells and rat lung. This grant application will determine the novel role(s) and mechanisms by which C/EBP( and its associated pathways mediate protection of the lung during alveolar and bronchiolar epithelial cell injury, and will identify the cellular processes and genes critical for repair of the lung (Aim 1).
In Aim 2, we will demonstrate the critical role of regulation of C/EBP( induced by rhFGF-7 treatment during hyperoxia ALI. Understanding the precise molecular mechanisms of FGF-7 treatment for survival would help in the clinical use of rhFGF-7 for treatment of ALI.

Public Health Relevance

Acute lung injury remains a major cause of morbidity and mortality. This proposal will determine the role and mechanisms by which C/EBPa mediates protection of the lung during acute lung injury. Furthermore, the molecular mechanisms, in particular the signaling pathways regulating Cebpa, of recombinant human FGF-7 treatment for acute lung injury will be determined.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095464-04
Application #
8237027
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Lin, Sara
Project Start
2009-04-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$371,250
Indirect Cost
$123,750
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Madala, Satish K; Schmidt, Stephanie; Davidson, Cynthia et al. (2012) MEK-ERK pathway modulation ameliorates pulmonary fibrosis associated with epidermal growth factor receptor activation. Am J Respir Cell Mol Biol 46:380-8
Sato, Atsuyasu; Schehr, Angelica; Ikegami, Machiko (2011) Leptin does not influence surfactant synthesis in fetal sheep and mice lungs. Am J Physiol Lung Cell Mol Physiol 300:L498-505
Xu, Yan; Saegusa, Chika; Schehr, Angelica et al. (2009) C/EBP{alpha} is required for pulmonary cytoprotection during hyperoxia. Am J Physiol Lung Cell Mol Physiol 297:L286-98