RT Journal Article
SR Electronic
T1 β-Arrestin Deficiency Protects Against Pulmonary Fibrosis in Mice and Prevents Fibroblast Invasion of Extracellular Matrix
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP 74ra23
OP 74ra23
DO 10.1126/scitranslmed.3001564
VO 3
IS 74
A1 Lovgren, Alysia Kern
A1 Kovacs, Jeffrey J.
A1 Xie, Ting
A1 Potts, Erin N.
A1 Li, Yuejuan
A1 Foster, W. Michael
A1 Liang, Jiurong
A1 Meltzer, Eric B.
A1 Jiang, Dianhua
A1 Lefkowitz, Robert J.
A1 Noble, Paul W.
YR 2011
UL http://stm.sciencemag.org/content/3/74/74ra23.abstract
AB 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.