Role of A2B adenosine receptor signaling in adenosine-dependent pulmonary inflammation and injury.

Adenosine has been implicated in the pathogenesis of chronic lung diseases such as asthma and chronic obstructive pulmonary disease. In vitro studies suggest that activation of the A2B adenosine receptor (A2BAR) results in proinflammatory and profibrotic effects relevant to the progression of lung diseases; however, in vivo data supporting these observations are lacking. Adenosine deaminase-deficient (ADA-deficient) mice develop pulmonary inflammation and injury that are dependent on increased lung adenosine levels. To investigate the role of the A2BAR in vivo, ADA-deficient mice were treated with the selective A2BAR antagonist CVT-6883, and pulmonary inflammation, fibrosis, and airspace integrity were assessed. Untreated and vehicle-treated ADA-deficient mice developed pulmonary inflammation, fibrosis, and enlargement of alveolar airspaces; conversely, CVT-6883-treated ADA-deficient mice showed less pulmonary inflammation, fibrosis, and alveolar airspace enlargement. A2BAR antagonism significantly reduced elevations in proinflammatory cytokines and chemokines as well as mediators of fibrosis and airway destruction. In addition, treatment with CVT-6883 attenuated pulmonary inflammation and fibrosis in wild-type mice subjected to bleomycin-induced lung injury. These findings suggest that A2BAR signaling influences pathways critical for pulmonary inflammation and injury in vivo. Thus in chronic lung diseases associated with increased adenosine, antagonism of A2BAR-mediated responses may prove to be a beneficial therapy.

[1]  J. Elias,et al.  Partially adenosine deaminase-deficient mice develop pulmonary fibrosis in association with adenosine elevations. , 2006, American journal of physiology. Lung cellular and molecular physiology.

[2]  B. Fredholm,et al.  The G(s)-coupled adenosine A(2B) receptor recruits divergent pathways to regulate ERK1/2 and p38. , 2003, Experimental cell research.

[3]  F. Villarreal,et al.  Functional effects of enhancing or silencing adenosine A2b receptors in cardiac fibroblasts. , 2004, American journal of physiology. Heart and circulatory physiology.

[4]  M. Blackburn,et al.  Adenosine-Dependent Airway Inflammation and Hyperresponsiveness in Partially Adenosine Deaminase-Deficient Mice1 , 2001, The Journal of Immunology.

[5]  S. E. Brodie.  New York, New York, USA , 1996 .

[6]  M. Blackburn.  Too much of a good thing: adenosine overload in adenosine-deaminase-deficient mice. , 2003, Trends in pharmacological sciences.

[7]  L. Zacharia,et al.  A2B Receptors Mediate the Antimitogenic Effects of Adenosine in Cardiac Fibroblasts , 2001, Hypertension.

[8]  J. Linden,et al.  Characterization of human A(2B) adenosine receptors: radioligand binding, western blotting, and coupling to G(q) in human embryonic kidney 293 cells and HMC-1 mast cells. , 1999, Molecular pharmacology.

[9]  I. Horváth,et al.  Adenosine in exhaled breath condensate in healthy volunteers and in patients with asthma , 2002, European Respiratory Journal.

[10]  M. Blackburn,et al.  The Use of Enzyme Therapy to Regulate the Metabolic and Phenotypic Consequences of Adenosine Deaminase Deficiency in Mice , 2000, The Journal of Biological Chemistry.

[11]  Taosheng Chen,et al.  A2B Adenosine and P2Y2 Receptors Stimulate Mitogen-activated Protein Kinase in Human Embryonic Kidney-293 Cells , 1999, The Journal of Biological Chemistry.

[12]  A. G. Driver,et al.  Adenosine in bronchoalveolar lavage fluid in asthma. , 1993, The American review of respiratory disease.

[13]  S. Goya,et al.  A p38 MAPK inhibitor, FR-167653, ameliorates murine bleomycin-induced pulmonary fibrosis. , 2002, American journal of physiology. Lung cellular and molecular physiology.

[14]  Darrell R. Abernethy,et al.  International Union of Pharmacology: Approaches to the Nomenclature of Voltage-Gated Ion Channels , 2003, Pharmacological Reviews.

[15]  I. Biaggioni,et al.  A2B Adenosine Receptors Increase Cytokine Release by Bronchial Smooth Muscle Cells , 2004 .

[16]  J. Linden.  Molecular approach to adenosine receptors: receptor-mediated mechanisms of tissue protection. , 2001, Annual review of pharmacology and toxicology.

[17]  L. Belardinelli,et al.  Synergy between A2B adenosine receptors and hypoxia in activating human lung fibroblasts. , 2005, American journal of respiratory cell and molecular biology.

[18]  B. Fredholm,et al.  International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. , 2001, Pharmacological reviews.

[19]  M. Mirabet,et al.  IFN-gamma up-regulates the A2B adenosine receptor expression in macrophages: a mechanism of macrophage deactivation. , 1999, Journal of immunology.

[20]  L. Thompson,et al.  Ecto-5′-Nucleotidase (CD73)-Mediated Adenosine Production Is Tissue Protective in a Model of Bleomycin-Induced Lung Injury1 , 2006, The Journal of Immunology.

[21]  F. Martinez,et al.  Mechanisms of pulmonary fibrosis. , 2004, Annual review of medicine.

[22]  J. Elias,et al.  Adenosine mediates IL-13-induced inflammation and remodeling in the lung and interacts in an IL-13-adenosine amplification pathway. , 2003, The Journal of clinical investigation.

[23]  S. Shapiro,et al.  Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. , 1997, Science.

[24]  B. Ma,et al.  Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and -12 in IL-13-induced inflammation and remodeling. , 2002, The Journal of clinical investigation.

[25]  S. Mutsaers,et al.  The role of gp130/IL-6 cytokines in the development of pulmonary fibrosis: critical determinants of disease susceptibility and progression? , 2003, Pharmacology & therapeutics.

[26]  Tiejuan Mi,et al.  Adenosine-Dependent Pulmonary Fibrosis in Adenosine Deaminase-Deficient Mice1 , 2005, The Journal of Immunology.

[27]  B. Ma,et al.  New insights into the pathogenesis of asthma. , 2003, The Journal of clinical investigation.

[28]  B. Fredholm,et al.  Signalling from adenosine receptors to mitogen-activated protein kinases. , 2003, Cellular signalling.

[29]  D. Erle,et al.  Abnormal alveolar development associated with elevated adenine nucleosides. , 2004, American journal of respiratory cell and molecular biology.

[30]  K. Klotz,et al.  [(3)H]MRE 3008F20: a novel antagonist radioligand for the pharmacological and biochemical characterization of human A(3) adenosine receptors. , 2000, Molecular pharmacology.

[31]  James J. Lee,et al.  Metabolic Consequences of Adenosine Deaminase Deficiency in Mice Are Associated with Defects in Alveogenesis, Pulmonary Inflammation, and Airway Obstruction , 2000, The Journal of experimental medicine.

[32]  I Biaggioni,et al.  Adenosine A2B receptors. , 1997, Pharmacological reviews.

[33]  I. Biaggioni,et al.  Role of p38 mitogen-activated protein kinase and extracellular signal-regulated protein kinase kinase in adenosine A2B receptor-mediated interleukin-8 production in human mast cells. , 1999, Molecular pharmacology.

[34]  B. Sperlágh,et al.  Ischemic-like condition releases norepinephrine and purines from different sources in superfused rat spleen strips , 2000, Journal of Neuroimmunology.

[35]  A. Fishman.  Pulmonary Diseases and Disorders , 1980 .

[36]  James J. Lee,et al.  A3 Adenosine Receptor Signaling Contributes to Airway Inflammation and Mucus Production in Adenosine Deaminase-Deficient Mice1 , 2004, The Journal of Immunology.

[37]  I. Biaggioni,et al.  Adenosine A2b receptors evoke interleukin-8 secretion in human mast cells. An enprofylline-sensitive mechanism with implications for asthma. , 1995, The Journal of clinical investigation.

[38]  R. Guieu,et al.  High adenosine plasma concentration as a prognostic index for outcome in patients with septic shock , 2000, Critical care medicine.

[39]  John C. Lee,et al.  SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung. , 2000, American journal of physiology. Lung cellular and molecular physiology.

[40]  Liping Huang,et al.  Protection from ischemic liver injury by activation of A2A adenosine receptors during reperfusion: inhibition of chemokine induction. , 2004, American journal of physiology. Gastrointestinal and liver physiology.

[41]  M. Jacobson,et al.  References Subscriptions Permissions Email Alerts A Class I MHC-Restricted Recall Response to a Viral Peptide Is Highly Polyclonal Despite Stringent CDR3 Selection: Implications for Establishing Memory T Cell Repertoires in ''Real-World' ' Conditions , 2013 .

[42]  J. Schnermann,et al.  A protective role for the A1 adenosine receptor in adenosine-dependent pulmonary injury. , 2005, The Journal of clinical investigation.

[43]  A. IJzerman,et al.  Why are A(2B) receptors low-affinity adenosine receptors? Mutation of Asn273 to Tyr increases affinity of human A(2B) receptor for 2-(1-Hexynyl)adenosine. , 2000, Molecular pharmacology.

[44]  W. Thurlbeck,et al.  Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality. , 2001, American journal of respiratory and critical care medicine.

[45]  S. Shapiro,et al.  The macrophage in chronic obstructive pulmonary disease. , 1999, American journal of respiratory and critical care medicine.

[46]  A. Ohta,et al.  Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage , 2001, Nature.

[47]  M. Blackburn,et al.  Adenosine Deaminase-deficient Mice Generated Using a Two-stage Genetic Engineering Strategy Exhibit a Combined Immunodeficiency* , 1998, The Journal of Biological Chemistry.

[48]  G. Hunninghake,et al.  Both Erk and p38 kinases are necessary for cytokine gene transcription. , 1999, American journal of respiratory cell and molecular biology.

[49]  I. Biaggioni,et al.  Adenosine-Activated Mast Cells Induce IgE Synthesis by B Lymphocytes: An A2B-Mediated Process Involving Th2 Cytokines IL-4 and IL-13 with Implications for Asthma12 , 2004, The Journal of Immunology.