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Adenosine Receptor A1 Regulates Polymorphonuclear Cell Trafficking and Microvascular Permeability in Lipopolysaccharide-Induced Lung Injury This information is current as of October 1, 2021. Kristian-Christos Ngamsri, Rosalyn Wagner, Irene Vollmer, Stefanie Stark and Jörg Reutershan J Immunol 2010; 185:4374-4384; Prepublished online 20 August 2010; doi: 10.4049/jimmunol.1000433 Downloaded from http://www.jimmunol.org/content/185/7/4374 References This article cites 53 articles, 15 of which you can access for free at: http://www.jimmunol.org/content/185/7/4374.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 October 1, 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 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Adenosine Receptor A1 Regulates Polymorphonuclear Cell Trafficking and Microvascular Permeability in Lipopolysaccharide-Induced Lung Injury Kristian-Christos Ngamsri, Rosalyn Wagner, Irene Vollmer, Stefanie Stark, and Jo¨rg Reutershan Extracellular adenosine and adenosine receptors are critically involved in various inflammatory pathways. Adenosine receptor A1 (A1AR) has been implicated in mediating transmigration of leukocytes to sites of inflammation. This study was designed to char- acterize the role of A1AR in a murine model of LPS-induced lung injury. LPS-induced transmigration of polymorphonuclear cells (PMNs) and microvascular permeability was elevated in A1AR2/2 mice. Pretreatment of wild-type mice with the specific A1AR agonist 29Me–2-chloro-N6-cyclopentyladenosine attenuated PMN accumulation in the interstitium and alveolar space as well as microvascular permeability. Lower PMN counts in the lungs of pretreated wild-type mice were associated with reduced amounts Downloaded from of the chemotactic cytokines TNF-a, IL-6, and CXCL2/3 in the bronchoalveolar lavage. Pretreatment was only effective when A1AR was expressed on hematopoietic cells as demonstrated in chimeric mice. These findings were confirmed by in vitro trans- migration assays demonstrating that chemokine-induced transmigration of PMNs was reduced when PMNs but not when pul- monary endothelial or alveolar epithelial cells were pretreated. 29Me–2-chloro-N6-cyclopentyladenosine prevented pulmonary endothelial but not epithelial cells from LPS-induced cellular remodeling and cell retraction. Our data reveal what we believe to be a previously unrecognized distinct role of A1AR for PMN trafficking and endothelial integrity in a model of acute lung http://www.jimmunol.org/ injury. The Journal of Immunology, 2010, 185: 4374–4384. cute lung injury (ALI) and acute respiratory distress inflammation and proved beneficial in patients with ALI/ARDS syndrome (ARDS) in their most severe forms are still (4–6). A major challenges in modern intensive care medicine that Excessive recruitment of PMNs into the lung is a key event in significantly contribute to morbidity and mortality of critically ill the early development of ALI and ARDS. A variety of experimental patients (1). ALI and ARDS develop as a result of direct lung studies implicate that modulation of PMN trafficking improves by guest on October 1, 2021 damage (e.g., pneumonia, aspiration, or lung trauma) or indirectly course and outcome of ALI (7–9). The significance of PMNs in in the course of remote or systemic inflammation (e.g., sepsis). ALI is highlighted by clinical studies showing that ARDS can Inflammatory response of the lungs is characterized by excessive deteriorate when patients recover from neutropenia (10). Lung infiltration of polymorphonuclear cells (PMNs), disruption of the function in ARDS patients negatively correlates with neutrophil alveolo-capillary barrier, and release of chemotactic cytokines (2, counts in the blood. Persisting pulmonary neutrophilia in ARDS is 3). Destruction of the pulmonary architecture results in interstitial correlated with poor outcome (11). PMN recruitment into the lung and alveolar edema and ultimately threatens pulmonary gas ex- occurs in a cascade-like sequence of activation, sequestration in change. Despite numerous experimental and clinical studies, mol- pulmonary vessels, transendothelial [from blood to the intersti- ecular mechanisms that regulate the inflammatory response of the tium (IS)], and transepithelial (from the IS to the alveolar air- lung have not been fully elucidated. Accordingly, specific thera- space) migration (8). Each migration step is regulated by distinct peutic options in ALI are not available. So far, only mechanical molecules, and the importance of investigating discrete steps of ventilation with low tidal volumes has been demonstrated to limit PMN migration in the lung has been emphasized (8, 12). Besides adhesion molecules (13), chemokines (14), and intra- cellular molecules (15), extracellular adenosine is an essential Department of Anesthesiology and Intensive Care Medicine, University Hospital of mediator of leukocyte trafficking to inflammatory sites. Adenosine Tu¨bingen, Tu¨bingen, Germany signals through four subtypes of G protein-coupled adenosine Received for publication February 9, 2010. Accepted for publication July 20, 2010. receptors (ARs; A1, A2a, A2b, and A3) that are ubiquitary ex- This work was supported by German Research Foundation Grant RE 1683/3-1 (to pressed on various hematopoietic and nonhematopoietic cells. J.R.). Activation of ARs induces a variety of cell responses through Address correspondence and reprint requests to Dr. Jo¨rg Reutershan, Department of Anesthesiology and Intensive Care Medicine, University of Tu¨bingen, Hoppe- changes in intracellular levels of cAMP, diacylglycerol, and ino- Seyler-Strasse 3, 72076 Tu¨bingen, Germany. E-mail address: joerg.reutershan@ sitoltriphosphate. Recent studies identified CD39 and CD73, both uni-tuebingen.de rate-limiting enzymes for the generation of extracellular adeno- 2 2 Abbreviations used in this paper: A1AR, adenosine receptor A1; A1AR / , A1AR sine, as critical mediators in pulmonary inflammation (16, 17). In knockout; ADA, adenosine deaminase; ALI, acute lung injury; AR, adenosine receptor; ARDS, acute respiratory distress syndrome; BAL, bronchoalveolar lavage; BM, bone addition, activation of ARs A2a and A2b has been demonstrated to marrow; BW, body weight; HMVEC-L, human lung microvascular endothelial cell; IS, attenuate organ damage in LPS- and ventilator-induced lung in- interstitium; IV, intravascular; 29Me-CCPA, 29Me-2-chloro-N6-cyclopentyladenosine; jury (18, 19). PFA, paraformaldehyde; PMN, polymorphonuclear cell. The role of AR A1 (A1AR) in mediating inflammatory pathways Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 has not been studied systematically. A1AR signals through Gi and www.jimmunol.org/cgi/doi/10.4049/jimmunol.1000433 The Journal of Immunology 4375 + Go and inhibits adenylyl cyclase, activates K channels, and in- LPS served as negative control. Total RNA samples were analyzed with hibits Ca2+ channels in various cells (20). Physiologic functions sense/antisense primers for wild-type mice (59-GTACATCTCGGCCTT- of A1AR signaling include bradycardia, reduced glomerular fil- CCAGG-39 and 59-GAG AATACCTGGCTGACTAG-39) and for A1 gene- deficient mice (59-ACAACAGACAATCGGCTGCTCTGATG-39 and 59- tration, antinociception, neuronal hyperpolarization, and ischemic TGCGCGCCTTGAGCCTGG CGAAC-39) using the iCycler iQ Real- preconditioning (21). A1AR is constitutively expressed in various Time Detection System (Bio-Rad, Hercules, CA). Values were determined tissues including the lung and brain (22). In the lung, A1AR is using iCycler iQ Real-Time Detection System Software version 3.1 (Bio- expressed on endothelial, airway, and alveolar epithelial cells and, Rad) and normalized to murine b-actin (59-ACATTGGCATGGCTTTGTTT- 39 and 59-GTTTGCTCCAACCAACTGCT-39). at high concentrations, on alveolar macrophages (23). The role of A1AR in pulmonary inflammation has been discussed controver- Western blotting sially. In an early study, pharmacologic blocking of A1AR at- LPS-induced expression of A1AR protein in whole lung tissue was eval- tenuated LPS-induced lung injury in cats (24). In more recent uated by Western blotting as previously described (15). Briefly, lungs were studies, protective effects of A1AR have been demonstrated in snap frozen and lysed in RIPA buffer [1% Nonidet P-40, 1% deoxycholate, models of ischemia reperfusion- and endotoxin-induced lung in- 0.1% SDS, 50 mM Tris (pH 7.4), 150 mM NaCl, protease, and phosphatase jury (25, 26). In adenosine deaminase (ADA)-deficient mice, which I and II inhibitors]. Lysates were cleared by centrifugation at 14,000 3 g exhibit elevated adenosine levels, genetic removal of the A1AR for 20 min, and protein concentration was determined using the DC protein assay (Bio-Rad). A total of 30 mg protein from each
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