title: A3 adenosine receptor signaling influences pulmonary inflammation and fibrosis.
abstract: Adenosine is a signaling molecule produced during conditions that cause cellular stress or damage. This signaling pathway is implicated in the regulation of pulmonary disorders through the selective engagement of adenosine receptors. The goal of this study was to examine the involvement of the A(3) adenosine receptor (A(3)R) in a bleomycin model of pulmonary inflammation and fibrosis. Results demonstrated that A(3)R-deficient mice exhibit enhanced pulmonary inflammation that included an increase in eosinophils. Accordingly, there was a selective up-regulation of eosinophil-related chemokines and cytokines in the lungs of A(3)R-deficient mice exposed to bleomycin. This increase in eosinophil numbers was accompanied by a decrease in the amount of extracellular eosinophil peroxidase activity in lavage fluid from A(3)R-deficient mice exposed to bleomycin, an observation suggesting that the A(3)R is necessary for eosinophil degranulation in this model. Despite an increase in inflammatory metrics associated with A(3)R-deficient mice treated with bleomycin, there was little difference in the degree of pulmonary fibrosis. Examination of fibrotic mediators demonstrated enhanced transforming growth factor (TGF)-beta1 expression, but not a concomitant increase in TGF-beta1 activity. This was associated with the loss of expression of matrix metalloprotease 9, an activator of TGF-beta1, in alveolar macrophages and airway mast cells in the lungs of A(3)R-deficient mice. Together, these results suggest that the A(3)R serves antiinflammatory functions in the bleomycin model, and is also involved in regulating the production of mediators that can impact fibrosis.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Medical School, Houston, Texas77030, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Morschl
authors.forename: Jose G
authors.initials: JG
authors.lastname: Molina
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Volmer
authors.forename: Amir
authors.initials: A
authors.lastname: Mohsenin
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Pero
authors.forename: Jeong-Soo
authors.initials: JS
authors.lastname: Hong
authors.forename: Farrah
authors.initials: F
authors.lastname: Kheradmand
authors.forename: James J
authors.initials: JJ
authors.lastname: Lee
authors.forename: Michael R
authors.initials: MR
authors.lastname: Blackburn
mesh_terms: D000818:Animals; D001761:Bleomycin; D002465:Cell Movement; D004804:Eosinophils / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D008168:Lung / Q000201:enzymology / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D011014:Pneumonia / Q000150:complications* / Q000378:metabolism*; D021381:Protein Transport; D011658:Pulmonary Fibrosis / Q000150:complications* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000378:metabolism*; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D043684:Receptor, Adenosine A3; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D020780:Matrix Metalloproteinase 9