title: β-arrestin deficiency protects against pulmonary fibrosis in mice and prevents fibroblast invasion of extracellular matrix.
abstract: 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.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Alysia Kern
authors.initials: AK
authors.lastname: Lovgren
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Kovacs
authors.forename: Ting
authors.initials: T
authors.lastname: Xie
authors.forename: Erin N
authors.initials: EN
authors.lastname: Potts
authors.forename: Yuejuan
authors.initials: Y
authors.lastname: Li
authors.forename: W Michael
authors.initials: WM
authors.lastname: Foster
authors.forename: Jiurong
authors.initials: J
authors.lastname: Liang
authors.forename: Eric B
authors.initials: EB
authors.lastname: Meltzer
authors.forename: Dianhua
authors.initials: D
authors.lastname: Jiang
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lefkowitz
authors.forename: Paul W
authors.initials: PW
authors.lastname: Noble
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects; D019390:Arrestins / Q000172:deficiency* / Q000235:genetics; D001761:Bleomycin / Q000009:adverse effects; D001992:Bronchoalveolar Lavage Fluid; D002448:Cell Adhesion; D002465:Cell Movement; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000071557:beta-Arrestins
chemical_list: D000903:Antibiotics, Antineoplastic; D019390:Arrestins; D016212:Transforming Growth Factor beta; D000071557:beta-Arrestins; D001761:Bleomycin