In patients with acute lung injury (ALI) or the adult respiratory distress syndrome (ARDS), disordered repair of the injured alveolar epithelium can result in lung fibrosis. Fibrosis is associated with aberrant accumulation of a collagen-rich extracellular matrix in the lung parenchyma that results in tissue stiffness and a progressive decline in lung function. We will test the hypothesis that the tissue in fibrosis induces alveolar epithelial cells (AEC) to deposit matrix enriched in the (3 laminin subunit which functions, via the cell surface receptor dystroglycan and the signaling scaffold protein plectin, to protect AEC from the harmful impact of the fibrotic milieu. To test this hypothesis, in Aim 1, we will assay (3 laminin matrix deposition in situ in normal and fibrotic lungs and in AEC maintained in vitro on substrates of varying stiffness.
In Aim 2, we will evaluate the role of ?3 laminin, dystroglycan and plectin in mediating the survival, adhesion, migration, proliferation and differentiation of AEC maintained on substrate of varying stiffness.
In Aim 3, we will assess whether the absence of the (3 laminin enhances fibrosis and inhibits disease resolution in two different mouse models of lung disease. In this aim, we propose to use an inducible lung specific (3 laminin subunit knockout mouse line. Lung fibrosis in our knockout and control mice will be initiated by treatment of animals with bleomycin or by the intratracheal instillation of an adenovirus encoding active TGF-(1.
Our aims will provide new insights into the mechanisms that underlie the variable development of fibrosis after acute lung injury, a major determinant of outcome in patients with ALI/ARDS.
In certain pulmonary diseases, lung tissue becomes fibrotic and stiffens. We propose to assay how the stiffness of the lung regulates the function of its cellular components. Our results will provide novel insight into the mechanisms of disease progression and has implications for future therapies.
|Barreiro, Esther; Sznajder, Jacob I; Nader, Gustavo A et al. (2015) Muscle dysfunction in patients with lung diseases: a growing epidemic. Am J Respir Crit Care Med 191:616-9|
|Bharat, Ankit; Cunningham, Scott A; Scott Budinger, G R et al. (2015) Disseminated Ureaplasma infection as a cause of fatal hyperammonemia in humans. Sci Transl Med 7:284re3|
|Morales-Nebreda, Luisa I; Rogel, Micah R; Eisenberg, Jessica L et al. (2015) Lung-specific loss of ?3 laminin worsens bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 52:503-12|
|Camargo Jr, Carlos A; Budinger, G R Scott; Escobar, Gabriel J et al. (2014) Promotion of lung health: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases. Ann Am Thorac Soc 11 Suppl 3:S125-38|
|Kligys, Kristina; Wu, Yvonne; Hamill, Kevin J et al. (2013) Laminin-332 and *3*1 integrin-supported migration of bronchial epithelial cells is modulated by fibronectin. Am J Respir Cell Mol Biol 49:731-40|
|Eisenberg, Jessica L; Beaumont, Kristin G; Takawira, Desire et al. (2013) Plectin-containing, centrally localized focal adhesions exert traction forces in primary lung epithelial cells. J Cell Sci 126:3746-55|
|Budinger, G R Scott; Mutlu, Gökhan M (2013) Balancing the risks and benefits of oxygen therapy in critically III adults. Chest 143:1151-1162|
|Tschumperlin, Daniel J; Jones, Jonathan C; Senior, Robert M (2012) The fibrotic matrix in control: does the extracellular matrix drive progression of idiopathic pulmonary fibrosis? Am J Respir Crit Care Med 186:814-6|
|Soberanes, Saul; Gonzalez, Angel; Urich, Daniela et al. (2012) Particulate matter Air Pollution induces hypermethylation of the p16 promoter Via a mitochondrial ROS-JNK-DNMT1 pathway. Sci Rep 2:275|
|Mutlu, Gökhan M; Budinger, G R Scott; Wu, Minghua et al. (2012) Proteasomal inhibition after injury prevents fibrosis by modulating TGF-?(1) signalling. Thorax 67:139-46|
Showing the most recent 10 out of 23 publications