Oxidant production by the lung alveolar epithelium has been little investigated despite its potential roles in alveolar host defense and cell signaling. Our preliminary studies in a cultured human lung cell model show that hormone-induced type II cell differentiation is associated with increased expression of the NADPH oxidase isoform dual oxidase 1 (DUOX1) and its maturation factor DUOXA1. Similarly, DUOX protein expression was found to be upregulated in vivo during late gestation in human lung. We also found a strong correlation between expression of DUOX1 and the production of hydrogen peroxide and acid by alveolar cells. To date, DUOX1 is the only known mechanism to control the regulated release of oxidants by the alveolar epithelium. We hypothesize that DUOX1 and DUOXA1 are coordinately up-regulated during differentiation of alveolar type II cells, which increases oxidant and acid production by the alveolar epithelium and contributes to host defense and cellular signaling in the newborn lung. The proposed studies will define the regulated expression of DUOX1 and DUOXA1 in a unique primary cultured cell model of alveolar epithelial cells, and help clarify the function and role of DUOX1 in alveolar innate defense, redox regulation, and cellular signaling.
Aim 1 seeks to determine the shared promoter and the regulated expression of DUOX1 and DUOXA1 during differentiation of human fetal lung type II cells.
Aim 2 will determine the effects of expression of DUOX1 on the production of hydrogen peroxide and protons, on bacterial killing, and on alveolar epithelial function.
Aim 3 will establish a controlled over-expression cell model to study the effects of Duox1 on cellular signaling, gene expression, and alveolar function. The proposed study will be a collaborative effort between two laboratories with experience in lung development/gene expression (Ballard/Gonzales) and the biophysical properties of lung epithelial cell membranes (Fischer/Illek);it will be the first study to provide information regarding regulation and function of DUOX1 in alveolar epithelial cells. This research has physiological significance related to the sterility of the alveolar air space and clinical relevance for understanding deficiencies in host defense and epithelial function in premature infants and patients with chronic lung diseases. Project Narrative Premature infants are at high risk for lung infections, an important area of public health. This research investigates a novel area of lung anti-microbial defense and will provide new information that may lead to therapeutic application.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086323-04
Application #
7989426
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Lin, Sara
Project Start
2007-12-05
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2012-11-30
Support Year
4
Fiscal Year
2011
Total Cost
$490,715
Indirect Cost
Name
Children's Hospital & Res Ctr at Oakland
Department
Type
DUNS #
076536184
City
Oakland
State
CA
Country
United States
Zip Code
94609
Cho, Do-Yeon; Nayak, Jayakar V; Bravo, Dawn T et al. (2013) Expression of dual oxidases and secreted cytokines in chronic rhinosinusitis. Int Forum Allergy Rhinol 3:376-83
Fischer, Horst (2012) Function of Proton Channels in Lung Epithelia. Wiley Interdiscip Rev Membr Transp Signal 1:247-258
Cho, Do-Yeon; Hwang, Peter H; Illek, Beate et al. (2011) Acid and base secretion in freshly excised nasal tissue from cystic fibrosis patients with ΔF508 mutation. Int Forum Allergy Rhinol 1:123-7
Mac Sweeney, R; Fischer, H; McAuley, D F (2011) Nasal potential difference to detect Na+ channel dysfunction in acute lung injury. Am J Physiol Lung Cell Mol Physiol 300:L305-18
Heine, Vivi M; Griveau, Amelie; Chapin, Cheryl et al. (2011) A small-molecule smoothened agonist prevents glucocorticoid-induced neonatal cerebellar injury. Sci Transl Med 3:105ra104
Fischer, Horst; Illek, Beate; Sachs, Lorne et al. (2010) CFTR and calcium-activated chloride channels in primary cultures of human airway gland cells of serous or mucous phenotype. Am J Physiol Lung Cell Mol Physiol 299:L585-94
Gonzalez, Robert F; Allen, Lennell; Gonzales, Linda et al. (2010) HTII-280, a biomarker specific to the apical plasma membrane of human lung alveolar type II cells. J Histochem Cytochem 58:891-901
Illek, Beate; Lei, Dachuan; Fischer, Horst et al. (2010) Sensitivity of chloride efflux vs. transepithelial measurements in mixed CF and normal airway epithelial cell populations. Cell Physiol Biochem 26:983-90
Ballard, Philip L; Lee, Jae W; Fang, Xiaohui et al. (2010) Regulated gene expression in cultured type II cells of adult human lung. Am J Physiol Lung Cell Mol Physiol 299:L36-50
Iovannisci, David; Illek, Beate; Fischer, Horst (2010) Function of the HVCN1 proton channel in airway epithelia and a naturally occurring mutation, M91T. J Gen Physiol 136:35-46

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