Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY A key feature of interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF), is the excessive deposition of extracellular matrix (ECM) and scar tissue. Fibroblasts persist in fibrotic lungs and lay down matrix, contributing to a progressive and persistent phenotype in patients. Matrix metalloproteinases (MMPs) are enzymes that cleave and break down ECM during wound repair and the degradation and removal of scar tissue is essential for fibrosis resolution. The expression of MMP-9 is increased in the lungs of IPF patients. However, MMP-9 is not present in the active form rendering it unable to cleave collagens. Our preliminary data in MMP-9 deficient mice support that active MMP-9 is necessary for fibrosis resolution. We therefore asked if MMP-9 activation is inhibited in IPF lungs limiting its ability to successfully initiate repair through matrix degradation. MMP-9 is activated from its latent-form through a series of activating enzymes beginning with urokinase plasminogen activating enzyme (uPA). uPA cleaves plasminogen into plasmin which in turn is a major activator of MMP-9. However, in IPF, plasminogen activator inhibitor-1 (PAI-1) inhibits uPA thus inhibiting the activation cascade needed for downstream MMP-9-activation and matrix degradation. Due to the poor quality and significantly reduced life expectancy associated with ILDs, it is becoming increasingly important to identify molecular pathways that are targetable for therapeutic intervention. This proposal seeks to address this unmet need by investigating the central hypothesis that MMP-9 activation by plasmin is necessary for fibrosis resolution and that this pathway can be induced through beneficial TNF-a signaling. Based on our robust preliminary studies, we propose three specific aims to test this central hypothesis. Specific Aim 1 will test the hypothesis that beneficial TNF-a signaling increases urokinase and expression of MMP-9 in fibroblasts. This will be tested using genetic approaches to determine if conditional deletion of MMP-9 in fibroblasts is sufficient to prevent fibrosis resolution in a spontaneously resolving fibrosis model and if exogenous TNF-a is sufficient to activate the uPA/plasminogen/MMP-9 pathway, inducing resolution in a non-resolving fibrosis model. Specific Aim 2 will test the hypothesis that MMP-9 activation by plasmin contributes to the resolution of bleomycin-induced fibrosis. This will be tested through the generation of a non-cleavable MMP-9 mutant and through pharmacological inhibition of MMP-9 in vivo. Specific Aim 3 will test the hypothesis that a clinical formulation of recombinant urokinase (KinlyticTM) promotes the resolution of established pulmonary fibrosis by activating pro-MMP-9 through the plasminogen/plasmin cascade. This will be tested by treating mice with persistent fibrosis with recombinant urokinase to induce plasmin and MMP-9 activation as a mechanism of fibrosis resolution. The proposed studies will provide a novel understanding about how activating an anti-fibrotic pathway (uPA/plasminogen/MMP-9) may contribute to the resolution of fibrosis. Furthermore, the outcomes of these pre-clinical, therapeutic studies will significantly impact our understanding of the mechanisms that control fibrosis resolution.
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