Role of PAPP-A in Pulmonary Fibrosis

Project: Research project

Project Details

Description

PROJECT SUMMARY Idiopathic pulmonary fibrosis (IPF) is an age-associated fatal lung disease of unknown etiology, and patients with IPF have few therapeutic options. Therefore, it is important to explore new pathogenic mechanisms underlying development of the fibrosis, and to identify potential therapeutic targets for this deadly disease. Transforming growth factor (TGF)-? is a major fibrogenic factor. However, TGF-? appears to work synergistically with other factors to direct and promote excessive fibrosis. One of these is insulin-like growth factor (IGF)-I. Nevertheless, there are large gaps in our knowledge about the role of IGF receptor activation in the initiation and/or progression of pulmonary fibrosis. Furthermore, there are concerns about its usefulness as a direct therapeutic target. We suggest an alternative approach. We discovered a novel zinc metalloproteinase, PAPP-A, that enhances local IGF action through specific cleavage of inhibitory IGF binding protein-4 in many cell types, including fibroblasts. We have shown that pro-inflammatory cytokines associated with the wounding response are potent stimulators of PAPP-A expression. Our preliminary data indicate that TGF-? can also stimulate PAPP-A expression in lung fibroblasts. Inhibition of PAPP-A expression or its proteolytic activity represents an innovative approach to decreasing IGF availability with moderate restraint of IGF receptor signaling. We have shown that inhibition of PAPP-A through gene deletion in mice has many beneficial effects on aging-related diseases. We can also inhibit the ability of PAPP-A to cleave IGFBP-4 in vitro and in vivo with a novel neutralizing monoclonal antibody generated against a unique exosite in PAPP-A. Specific Aim 1 will focus on the regulation and function of PAPP-A in human lung fibroblasts in vitro, but will include assessment of other components of the IGF system that could be novel contributors to fibrosis. Experiments in this aim will also determine the effect of PAPP-A-regulated IGF-I bioavailability on proliferation, migration, extracellular matrix production, and apoptosis. Specific Aim 2 will test the hypothesis that inhibition of PAPP-A gene expression or its proteolytic activity reduces the development of fibrosis in a mouse lung injury model. Preliminary data indicate increased PAPP-A expression in lungs of mice following a bleomycin-induced injury, and intense PAPP-A immunostaining at fibroblastic foci in lungs from patients with IPF. Thus, we propose exploratory in vitro and in vivo studies to test novel hypotheses with anticipated results that could ultimately lead to a novel therapy for patients with IPF.
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