β-Arrestin Deficiency Protects Against Pulmonary Fibrosis in Mice and Prevents Fibroblast Invasion of Extracellular Matrix

The signaling molecule β-arrestin is required for the fibroblast invasion of extracellular matrix and thus for the development of pulmonary fibrosis. Keeping Fibroblasts in Their Place Weeds are plants that grow unchecked in spaces where they are unwelcome, often crowding out the garden’s invited guests. Similarly, when excess connective tissue invades an unsuitable space in the body, it can have lethal consequences. This process—called fibrosis—has its place in normal physiology during wound healing. But when fibrosis occurs in the lung, for example, the displaced connective tissue built from encroaching fibroblast cells interferes with oxygen exchange, making breathing difficult to impossible. One fibrotic disease of the lung, idiopathic pulmonary fibrosis (IPF), has no known cause, as the name suggests, and no effective treatment. The authors of Lovgren et al. may now have identified the disease’s Achilles heel in a mouse model of IPF in which the lungs are chemically damaged and respond with pathological fibrosis. The new study shows that fibroblasts require the signaling protein β-arrestin to invade and degrade the extracellular matrix, and without this ability, the animals are protected from deadly lung fibrosis. Because IPF appears later in life without warning, an animal model that directly mimics the disease has not been developed. Instead, genetically tractable mice are treated with the antibiotic bleomycin and develop resulting lung fibrosis that resembles IPF. When the authors individually deleted the genes that encode each of two isoforms of β-arrestin from these bleomycin-treated mice, the animals were protected from the bleomycin-induced fibrosis, showing almost normal architecture and pliability of the lungs. These results are a major improvement, as stiffening of the normally elastic lungs is a hallmark of IPF. β-Arrestin did not contribute to lung fibrosis by participating in the inflammatory response, the authors showed, because the number or type of inflammatory cells in the lung was similar whether β-arrestin was present or not. Similarly, downstream transforming growth factor–β signaling pathways were intact. Instead, the β-arrestin was required for the behavior of the fibroblasts themselves. Although lung fibroblasts that lacked β-arrestins migrated normally toward injured lung secretions, the cells could not effectively invade the basement membrane matrix. Furthermore, these genetically modified fibroblasts displayed changes in connective tissue gene expression, likely a result of deficiencies in signaling pathways downstream of β-arrestins. The authors determined that this inability to invade also plagued fibroblasts isolated from IPF patients when β-arrestin expression was suppressed in the cells. In addition to its role in tissue invasion and deposition demonstrated here, β-arrestin participates in other signaling mechanisms that may contribute to pathogenic fibrosis. Thus, a therapeutic agent that targets this versatile signaling molecule may be useful for fighting IPF as well other fibrotic diseases. The hope is to limit fibrosis to regions where it will do more good than harm. Idiopathic pulmonary fibrosis is a progressive disease that causes unremitting extracellular matrix deposition with resulting distortion of pulmonary architecture and impaired gas exchange. β-Arrestins regulate G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptors through receptor desensitization while also acting as signaling scaffolds to facilitate numerous effector pathways. Here, we examine the role of β-arrestin1 and β-arrestin2 in the pathobiology of pulmonary fibrosis. In the bleomycin-induced mouse lung fibrosis model, loss of either β-arrestin1 or β-arrestin2 resulted in protection from mortality, inhibition of matrix deposition, and protected lung function. Fibrosis was prevented despite preserved recruitment of inflammatory cells and fibroblast chemotaxis. However, isolated lung fibroblasts from bleomycin-treated β-arrestin–null mice failed to invade extracellular matrix and displayed altered expression of genes involved in matrix production and degradation. Furthermore, knockdown of β-arrestin2 in fibroblasts from patients with idiopathic pulmonary fibrosis attenuated the invasive phenotype. These data implicate β-arrestins as mediators of fibroblast invasion and the development of pulmonary fibrosis, and as a potential target for therapeutic intervention in patients with idiopathic pulmonary fibrosis.