Urokinase plasminogen activator receptor associated protein and acute lung injury

University Of Washington, Seattle WA

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Abstract

DESCRIPTION (provided by applicant): Acute lung injury (ALI) is a common syndrome with high mortality that affects nearly 200,000 critically ill people per year in the United States. Understanding the molecular mechanisms of ALI may lead to future potential therapies. This research proposal will focus on the role of uPARAP in ALI. uPARAP is a newly described 180 kDa transmembrane protein that has at least three primary functions. First, it is a collagen receptor that binds both intact collagen and fragments, internalizes them, and targets them for lysosomal degradation. Second, it binds uPAR (urokinase plasminogen activator receptor), and may decrease uPA (urokinase plasminogen activator) activation. Third, it suppresses matrix metalloproteinase-2 (MMP-2) activity through a membrane type 1 - MMP (MT1- MMP or MMP-14) dependent pathway. Thus, uPARAP is in a unique position to affect remodeling of the extracellular matrix through its regulation of extracellular and intracellular pathways of collagen degradation. Our data show that uPARAP is highly expressed in the lung, and is solely responsible for collagen internalization in primary lung fibroblasts. Due to uPARAP's capacity to internalize and degrade collagen, and its high expression in the lung, we hypothesized that uPARAP -/- mice will have greater fibrosis following intra-tracheal bleomycin instillation. Unexpectedly, we found that uPARAP -/- mice have a significant early survival benefit prior to the development of fibrosis. In addition, we found that uPARAP -/- mice had less alveolar hemorrhage with lung injury. The goal of this fellowship-training proposal is to determine the mechanism(s) of protection in uPARAP -/- mice from bleomycin-induced acute lung injury. Specific Aim 1 will determine the cell type responsible for protection in uPARAP -/- mice through the generation of chimeric mice. Specific Aim 2 will determine whether uPARAP -/- mice have altered basement membrane function due to loss of collagen IV internalization. Specific Aim 3 will determine whether changes in uPA activity or MMP activity result in protection from lung injury in uPARAP -/- mice. These aims will increase our understanding of the unexpected role of uPARAP in acute lung injury. PUBLIC HEALTH RELEVANCE: This proposal will define the role of a new and incompletely understood mechanism of repair of Acute Lung Injury, a disease with high mortality and expense that affects 200,000 people yearly in the United States. It will help us understand how the lung coordinates several components of the repair process.