The complex architecture of the mammalian alveolus, has made it difficult to elucidate the balance of fluid secretion vs. absorption that characterizes the air-filled alveolar surface. Recent data from human alveolar Type 2 cells, utilizing novel """"""""thin film"""""""" confocal microscopy, coupled with Ca(2+)(i), nucleotide release, and patch clamp studies, suggest that the physiology of fluid transport under air-filled conditions is substantially different from """"""""flooded"""""""" conditions (in vivo flooded lung, Ussing chambers). Project III tests the hypothesis that the mammalian alveolus both absorbs and secretes fluid, and that the direction of fluid transport reflects signals contained in alveolar surface liquid, e.g., extracellular nucleotides. Project III will test this overarching hypothesis in four Specific Aims.
Specific Aim 1 tests the hypothesis that purinergic signaling regulates the direction of AT2 fluid transport via coordinate inhibition of ENaC and activation of CFTR that reside in separate apical membrane compartments.
Specific Aim 2 tests the hypothesis that regulation of secretory vs. absorptive functions can be characterized in novel single cell ATI assays.
Specific Aim 3 tests the hypothesis that CFTR is not the """"""""only"""""""" secretory pathway in the alveolus, e.g., 'alternative Cl(-) channels'and passive forces are important.
Specific Aim 4 tests the hypotheses that: a) the intact alveolus in vivo balances active ion/water secretion and absorption;and b) that a fraction of the secreted liquid transits onto distal airway surfaces. The Project strategy is to build a knowledge base from studies of isolated AT2 cells and ATI cells with thin film confocal technologies, supplemented with novel single cell volume flow and conventional Ca(2+)(i), nucleotide release, and patch clamp technologies;then study the integrated alveolar physiology in vivo with complementary confocal and novel transgenic techniques to test whether data from isolated AT2/AT1 cells predict in vivo physiology. The overarching goal is to understand the regulation of the balance of liquids on alveolar surfaces in health, with an emphasis on purinoceptors, and utilize this information to design the necessary novel therapies to treat effectively pulmonary diseases with alveolar flooding as their main pathogenic feature.

Public Health Relevance

Major human diseases are characterized by excess alveolar surface liquid, i.e., pulmonary edema. These diseases include congestive left ventricular heart failure and acute respiratory distress syndromes (ARDS). Recent therapeutic trials of novel agents, e.g., inhaled 3 agonists, have been less successful than hoped. It is a goal of this PPG to provide information that will provide the framework and design of the novel therapeutic agents required to treat these life-threatening human diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Chapel Hill
United States
Zip Code
Donoghue, Lauren J; Livraghi-Butrico, Alessandra; McFadden, Kathryn M et al. (2017) Identification of trans Protein QTL for Secreted Airway Mucins in Mice and a Causal Role for Bpifb1. Genetics 207:801-812
Sandefur, Conner I; Boucher, Richard C; Elston, Timothy C (2017) Mathematical model reveals role of nucleotide signaling in airway surface liquid homeostasis and its dysregulation in cystic fibrosis. Proc Natl Acad Sci U S A 114:E7272-E7281
Wang, Ling; Ariyarathna, Yamuna; Ming, Xin et al. (2017) A Novel Family of Small Molecules that Enhance the Intracellular Delivery and Pharmacological Effectiveness of Antisense and Splice Switching Oligonucleotides. ACS Chem Biol 12:1999-2007
Livraghi-Butrico, Alessandra; Grubb, Barbara R; Wilkinson, Kristen J et al. (2017) Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease. Mucosal Immunol 10:395-407
Sesma, Juliana I; Weitzer, Clarissa D; Livraghi-Butrico, Alessandra et al. (2016) UDP-glucose promotes neutrophil recruitment in the lung. Purinergic Signal 12:627-635
Esther Jr, Charles R; Turkovic, Lidija; Rosenow, Tim et al. (2016) Metabolomic biomarkers predictive of early structural lung disease in cystic fibrosis. Eur Respir J 48:1612-1621
Dickey, Audrey S; Pineda, Victor V; Tsunemi, Taiji et al. (2016) PPAR-? is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically. Nat Med 22:37-45
Yu, Dongfang; Davis, Richard M; Aita, Megumi et al. (2016) Characterization of Rat Meibomian Gland Ion and Fluid Transport. Invest Ophthalmol Vis Sci 57:2328-43
Shobair, Mahmoud; Dagliyan, Onur; Kota, Pradeep et al. (2016) Gain-of-Function Mutation W493R in the Epithelial Sodium Channel Allosterically Reconfigures Intersubunit Coupling. J Biol Chem 291:3682-92
Kirby, Brett S; Schwarzbaum, Pablo J; Lazarowski, Eduardo R et al. (2015) Liberation of ATP secondary to hemolysis is not mutually exclusive of regulated export. Blood 125:1844-5

Showing the most recent 10 out of 41 publications