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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Harabin, Andrea L
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Northwestern University at Chicago
Anatomy/Cell Biology
Schools of Medicine
United States
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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
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Takawira, Desire; Budinger, G R Scott; Hopkinson, Susan B et al. (2011) A dystroglycan/plectin scaffold mediates mechanical pathway bifurcation in lung epithelial cells. J Biol Chem 286:6301-10
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Budinger, G R Scott (2011) Angiotensin II and pulmonary fibrosis, a new twist on an old story. Am J Physiol Lung Cell Mol Physiol 301:L267-8
Hamill, Kevin J; Paller, Amy S; Jones, Jonathan C R (2010) Adhesion and migration, the diverse functions of the laminin alpha3 subunit. Dermatol Clin 28:79-87

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