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Bleomycin-Induced Lung Injury Receptor in Acute and Chronic Distinct Roles for the A2B Adenosine Receptor in Acute and Chronic Stages of Bleomycin-Induced Lung Injury This information is current as Yang Zhou, Daniel J. Schneider, Eva Morschl, Ling Song, of September 25, 2021. Mesias Pedroza, Harry Karmouty-Quintana, Thuy Le, Chun-Xiao Sun and Michael R. Blackburn J Immunol 2011; 186:1097-1106; Prepublished online 13 December 2010; doi: 10.4049/jimmunol.1002907 Downloaded from http://www.jimmunol.org/content/186/2/1097 References This article cites 49 articles, 14 of which you can access for free at: http://www.jimmunol.org/content/186/2/1097.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 25, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Distinct Roles for the A2B Adenosine Receptor in Acute and Chronic Stages of Bleomycin-Induced Lung Injury Yang Zhou,*,† Daniel J. Schneider,*,† Eva Morschl,* Ling Song,* Mesias Pedroza,*,† Harry Karmouty-Quintana,* Thuy Le,*,† Chun-Xiao Sun,* and Michael R. Blackburn*,† Adenosine is an extracellular signaling molecule that is generated in response to cell injury where it orchestrates tissue protection and repair. Whereas adenosine is best known for promoting anti-inflammatory activities during acute injury responses, prolonged elevations can enhance destructive tissue remodeling processes associated with chronic disease states. The generation of adenosine and the subsequent activation of the adenosine 2B receptor (A2BR) is an important processes in the regulation of both acute and chronic lung disease. The goal of this study was to examine the contribution of the A2BR in models of bleomycin-induced lung injury that exhibit varying degrees of acute and chronic injury. Intratracheal bleomycin exposure results in substantial acute lung injury followed by progressive fibrosis. In this model, genetic removal of the A2BR resulted in enhanced loss of barrier function Downloaded from and increased pulmonary inflammation, with few differences in indexes of pulmonary fibrosis. These results support an anti- inflammatory role for this receptor in this model of acute lung injury. In contrast, systemic exposure of mice to bleomycin resulted in modest acute lung injury together with progressive pulmonary fibrosis. In this model, the effects of A2BR removal on acute lung injury were negligible; however, there were substantial reductions in pulmonary fibrosis, supporting a profibrotic role for this receptor. A2BR-dependent regulation of IL-6 production was identified as a potential mechanism involved in the diminished http://www.jimmunol.org/ pulmonary fibrosis seen in A2BR knockout mice exposed to i.p. bleomycin. These studies highlight the distinct roles of A2BR signaling during acute and chronic stages of lung injury. The Journal of Immunology, 2011, 186: 1097–1106. cute lung injuries and chronic lung diseases are collec- Adenosine exerts its activities by engaging cell-surface adeno- tively the third leading cause of death in the United States sine receptors. There are four adenosine receptors (A1R, A2AR, (1). Treatment options for these pulmonary disorders are A A2BR, A3R) that are widely distributed on inflammatory and limited due in part to an incomplete understanding of the cellular stromal cells (13, 14). Recent studies have identified the adenosine and molecular pathways involved in the lung’s ability to respond 2B receptor (A2BR) as an important target in the regulation of both to various forms of injury. Adenosine is an extracellular signaling acute and chronic lung disease; however, with opposing activities by guest on September 25, 2021 molecule that is generated in response to cell injury where it in these disorders. Agonists for the A2BR are being considered for orchestrates tissue protection and repair (2). Whereas adenosine the treatment of acute lung injury based on findings demonstrating is best known for promoting anti-inflammatory activities during that activation of this receptor can enhance pulmonary barrier acute injury responses (3, 4), prolonged elevations in adenosine function and dampen inflammation in models of acute lung injury can enhance destructive tissue remodeling processes associated (7, 8). In contrast, A R antagonists are being considered for the with chronic disease states (5, 6). Consistent with this paradigm, 2B treatment of chronic lung diseases based on results demonstrating adenosine serves as an anti-inflammatory molecule in models of that blockade of this receptor can diminish airspace destruction acute lung injury (7–10), whereas elevations in adenosine con- tribute to disease progression in models of chronic lung disease and fibrosis (11). These findings emphasize that understanding the (11, 12). Thus, adenosine signaling may play an important role in contribution of the A2BR to the regulation of processes associated regulating how the lung responds to injury, and targeting this with acute and chronic lung injury will be essential for guiding the pathway may provide avenues for enhancing the resolution of use of A2BR agonists and antagonists for the treatment of these acute lung injury or halting the progression of chronic lung dis- disorders. ease. Recent studies from our laboratory suggest that A2BR signaling represents an important pathway for balancing the resolution of acute lung injury versus the progression to chronic disease *Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030; and †University of Texas Graduate School of (6). Mice deficient in the purine catabolic enzyme adenosine Biomedical Sciences at Houston, Houston, TX 77030 deaminase (ADA) develop features of chronic lung disease in Received for publication August 31, 2010. Accepted for publication November 17, association with prolonged adenosine elevations (15). The pro- 2010. minent aspects of pulmonary disease seen in this model include This work was supported in part by National Institutes of Health Grant HL70952 (to macrophage and neutrophil rich inflammation, alveolar airspace M.R.B.). destruction, and fibrosis (15, 16). Genetic removal the A2BR Address correspondence and reprint request to Michael R. Blackburn, Department of from ADA-deficient mice resulted in enhanced acute lung injury Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, 6431 Fannin, Houston, TX 77030. E-mail address: michael.r.blackburn@ characterized by the loss of vascular–alveolar barrier function uth.tmc.edu and enhanced neutrophil accumulation (17). However, treatment Abbreviations used in this article: A2BR, adenosine 2B receptor; ADA, adenosine of these mice with a selective A2BR antagonist during chronic deaminase; BAL, bronchoalveolar lavage; IPF, idiopathic pulmonary fibrosis; i.t., stages of disease resulted in diminished pulmonary inflam- intratracheal; a-sma, a smooth muscle actin. mation, airspace destruction, and fibrosis (11). These findings Copyright Ó 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 suggestthattheA2BR plays a protective role during acute stages www.jimmunol.org/cgi/doi/10.4049/jimmunol.1002907 1098 THE A2B ADENOSINE RECEPTOR IN LUNG DISEASE of lung injury, whereas detrimental effects of this signaling Intratracheal bleomycin treatment pathway are manifested at stages where tissue fibrosis is pro- Avertin (250 mg/kg, i.p.) was used to anesthetize 10-wk-old female C57BL/6 +/+ 2/2 minent. A2BR or A2BR mice, and saline alone or 2.5 U/kg bleomycin (Teva These findings support the hypothesis that the A2BR is anti- Parenteral Medicines, Irvine, CA) diluted in 50 ml sterile saline was in- inflammatory during acute lung injury and profibrotic during stilled intratracheally (19). Endpoints were examined at 7 and 21 d after chronic disease stages. The goal of the current study was to ex- exposure. amine this hypothesis further by exploring the consequences of Intraperitoneal bleomycin treatment genetic removal of this receptor in models of bleomycin-induced +/+ 2/2 Six-week-old male A2BR or A2BR mice were treated intraper- lung injury. Exposing mice to this toxicant by direct intratracheal itoneally with 0.035 U/g bleomycin (Teva Parenteral Medicines) diluted (i.t.) administration or systemic exposure resulted in pulmonary in 150 ml sterile PBS or PBS alone (20). Mice were treated twice weekly fibrosis that was preceded by varying degrees of acute lung injury. for 4 wk and were sacrificed on day 10 and 33. Mice exposed to i.t. bleomycin developed substantial acute lung Bronchoalveolar lavage and histology injury followed by fibrosis. In this model, genetic removal of the A R resulted in enhanced acute lung injury, with only modest Avertin was used to anesthetize mice, and airways were lavaged three times 2B with 0.4 ml PBS, and 1 ml bronchoalveolar lavage (BAL) fluid was re- decreases
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