Genetic and Pharmacological Inhibition of PAPP-A Reduces Bleomycin-Induced Pulmonary Fibrosis in Aged Mice via Reduced IGF Signaling

Idiopathic pulmonary fibrosis (IPF) is an age-associated lung disease of unknown etiology that is characterized by exaggerated deposition of extracellular matrix (ECM), leading to distorted lung architecture, respiratory failure, and death. There are no truly effective treatment options for IPF, thus highlighting the importance of exploring new pathogenic mechanisms that underlie the development of fibrosis and of identifying new therapeutic targets. Insulin-like growth factors (IGFs) are known to be pro-fibrotic. However, the ubiquity and essentiality of IGF receptor signaling in normal physiology limit its potential as a direct therapeutic target. In a recent study, we found a highly significant correlation between expression of pregnancy-associated plasma protein (PAPP)-A in human IPF lung tissue and disease severity. PAPP-A is a unique metalloprotease that enhances local IGF action. In vitro studies support a role for proteolytically active PAPP-A in promoting a fibrotic phenotype in adult human lung fibroblasts. Here, we show that PAPP-A is preferentially expressed in mouse lung fibroblasts and that inhibition of PAPP-A in vivo through PAPP-A gene deletion or a specific neutralizing monoclonal antibody against PAPP-A markedly reduced the progression of bleomycin-induced lung fibrosis, as measured by significantly decreased ECM expression and improved lung histology. Surrogate markers of local IGF receptor activity in the lung were also significantly reduced, indicating indirect modulation of IGF signaling through PAPP-A. These results establish a role for PAPP-A in pulmonary fibrosis and point to PAPP-A as a selective and pharmacologically tractable target for IPF and possibly other fibrotic disorders.