title: Deletion of ADORA2B from myeloid cells dampens lung fibrosis and pulmonary hypertension.
abstract: Idiopathic pulmonary fibrosis (IPF) is a lethal, fibroproliferative disease. Pulmonary hypertension (PH) can develop secondary to IPF and increase mortality. Alternatively, activated macrophages (AAMs) contribute to the pathogenesis of both IPF and PH. Here we hypothesized that adenosine signaling through the ADORA2B on AAMs impacts the progression of these disorders and that conditional deletion of ADORA2B on myeloid cells would have a beneficial effect in a model of these diseases. Conditional knockout mice lacking ADORA2B on myeloid cells (Adora2B(f/f)-LysM(Cre)) were exposed to the fibrotic agent bleomycin (BLM; 0.035 U/g body weight, i.p.). At 14, 17, 21, 25, or 33 d after exposure, SpO2, bronchoalveolar lavage fluid (BALF), and histologic analyses were performed. On day 33, lung function and cardiovascular analyses were determined. Markers for AAM and mediators of fibrosis and PH were assessed. Adora2B(f/f)-LysM(Cre) mice presented with attenuated fibrosis, improved lung function, and no evidence of PH compared with control mice exposed to BLM. These findings were accompanied by reduced expression of CD206 and arginase-1, markers for AAMs. A 10-fold reduction in IL-6 and a 5-fold decrease in hyaluronan, both linked to lung fibrosis and PH, were also observed. These data suggest that activation of the ADORA2B on macrophages plays an active role in the pathogenesis of lung fibrosis and PH.
authors.affiliation: Department of Biochemistry and Molecular Biology and.
authors.forename: Harry
authors.initials: H
authors.lastname: Karmouty-Quintana
authors.affiliation: Department of Biochemistry and Molecular Biology and.
authors.forename: Kemly
authors.initials: K
authors.lastname: Philip
authors.affiliation: Department of Biochemistry and Molecular Biology and.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Acero
authors.affiliation: Department of Biochemistry and Molecular Biology and.
authors.forename: Ning-Yuan
authors.initials: NY
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology and.
authors.forename: Tingting
authors.initials: T
authors.lastname: Weng
authors.affiliation: Department of Biochemistry and Molecular Biology and.
authors.forename: Jose G
authors.initials: JG
authors.lastname: Molina
authors.affiliation: Department of Biochemistry and Molecular Biology and.
authors.forename: Fayong
authors.initials: F
authors.lastname: Luo
authors.affiliation: Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA; and.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Davies
authors.affiliation: Department of Biochemistry and Molecular Biology and.
authors.forename: Ngoc-Bao
authors.initials: NB
authors.lastname: Le
authors.affiliation: Department of Biochemistry and Molecular Biology and.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bunge
authors.affiliation: Department of Biochemistry and Molecular Biology and.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Volcik
authors.affiliation: Department of Biochemistry and Molecular Biology and.
authors.forename: Thanh-Thuy T
authors.initials: TT
authors.lastname: Le
authors.affiliation: Department of Pediatrics, University of Texas Medical School at Houston, Houston, Texas, USA;
authors.forename: Richard A
authors.initials: RA
authors.lastname: Johnston
authors.affiliation: Department of Biochemistry and Molecular Biology and.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
authors.affiliation: Department of Biochemistry and Molecular Biology and michael.r.blackburn@uth.tmc.edu.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Blackburn
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D004195:Disease Models, Animal; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D054990:Idiopathic Pulmonary Fibrosis / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D008262:Macrophage Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000502:physiology; D043704:Receptor, Adenosine A2B / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
chemical_list: D043704:Receptor, Adenosine A2B; D001761:Bleomycin
keywords: adenosine receptors; alternatively activated macrophages; hyaluronan; vascular remodeling