Abnormalities of lung mechanics and gas exchange with acute lung injuries result directly from alterations in the surfactant system. There is almost no information concerning normal surfactant homeostasis or surfactant homeostasis with lung injury other than the knowledge that the system is metabolically active and responsive to physiological stimuli. The projects will utilize transgenic mice with abnormalities in surfactant components and regulation and newly constructed knockout and bitransgenic mice to ask which factors influence which cell types to maintain surfactant homeostasis. The projects will focus on 1) the normal alveolar forms and catabolic pathways of surfactant components and the effects of altered surfactant protein content on surfactant function, 2) the structural requirements for the intracellular trafficking, secretion and function of SP-3 and 3) the importance of SP-A in non-immune and biologic measurements of surfactant component processing and trafficking in vitro, recycling and catabolism in vivo and studies of mechanisms of host defense response of the lung. The three projects will be closely integrated by common themes and by the use of similar transgenic mouse models. The goal is to develop a better assessment of surfactant function in health and the contributions of surfactant abnormalities to disease. An understanding of how surfactant is regulated will lead to new strategies for improving surfactant function in diseases such as ARDS, viral pneumonias and alveolar proteinosis.

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)
Program Officer
Gail, Dorothy
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cincinnati Children's Hospital Medical Center
United States
Zip Code
Whitsett, Jeffrey A; Weaver, Timothy E (2015) Alveolar development and disease. Am J Respir Cell Mol Biol 53:1-7
Conkright, Juliana J; Apsley, Karen S; Martin, Emily P et al. (2010) Nedd4-2-mediated ubiquitination facilitates processing of surfactant protein-C. Am J Respir Cell Mol Biol 42:181-9
Xu, Yan; Zhang, Minlu; Wang, Yanhua et al. (2010) A systems approach to mapping transcriptional networks controlling surfactant homeostasis. BMC Genomics 11:451
Suzuki, Takuji; Sakagami, Takuro; Young, Lisa R et al. (2010) Hereditary pulmonary alveolar proteinosis: pathogenesis, presentation, diagnosis, and therapy. Am J Respir Crit Care Med 182:1292-304
Hardie, William D; Hagood, James S; Dave, Vrushank et al. (2010) Signaling pathways in the epithelial origins of pulmonary fibrosis. Cell Cycle 9:2769-76
Whitsett, Jeffrey A; Wert, Susan E; Weaver, Timothy E (2010) Alveolar surfactant homeostasis and the pathogenesis of pulmonary disease. Annu Rev Med 61:105-19
Kramer, Elizabeth L; Mushaben, Elizabeth M; Pastura, Patricia A et al. (2009) Early growth response-1 suppresses epidermal growth factor receptor-mediated airway hyperresponsiveness and lung remodeling in mice. Am J Respir Cell Mol Biol 41:415-25
Wang, Mei; Bridges, James P; Na, Cheng-Lun et al. (2009) Meckel-Gruber syndrome protein MKS3 is required for endoplasmic reticulum-associated degradation of surfactant protein C. J Biol Chem 284:33377-83
Hardie, William D; Glasser, Stephan W; Hagood, James S (2009) Emerging concepts in the pathogenesis of lung fibrosis. Am J Pathol 175:3-16
Korfhagen, Thomas R; Le Cras, Timothy D; Davidson, Cynthia R et al. (2009) Rapamycin prevents transforming growth factor-alpha-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 41:562-72

Showing the most recent 10 out of 91 publications