Enhanced Airway Inflammation and Remodeling in Adenosine Deaminase-deficient Mice Lacking the A2B Adenosine Receptor

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2009 Jun 5

PMID 19494329

Citations 37

Authors

Yang Zhou

Amir Mohsenin

Eva Morschl

Hays W J Young

Jose G Molina

Wenbin Ma

Chun-Xiao Sun

Hector Martinez-Valdez

Michael R Blackburn

Affiliations

Soon will be listed here.

Abstract

Adenosine is a signaling nucleoside that is generated in response to cellular injury and orchestrates the balance between tissue protection and the progression to pathological tissue remodeling. Adenosine deaminase (ADA)-deficient mice develop progressive airway inflammation and remodeling in association with adenosine elevations, suggesting that adenosine can promote features of chronic lung disease. Furthermore, pharmacological studies in ADA-deficient mice demonstrate that A(2B)R antagonism can attenuate features of chronic lung disease, implicating this receptor in the progression of chronic lung disease. This study examines the contribution of A(2B)R signaling in this model by generating ADA/A(2B)R double-knockout mice. Our hypothesis was that genetic removal of the A(2B)R from ADA-deficient mice would lead to diminished pulmonary inflammation and damage. Unexpectedly, ADA/A(2B)R double-knockout mice exhibited enhanced pulmonary inflammation and airway destruction. Marked loss of pulmonary barrier function and excessive airway neutrophilia are thought to contribute to the enhanced tissue damage observed. These findings support an important protective role for A(2B)R signaling during acute stages of lung disease.

Citing Articles

Lung regeneration: diverse cell types and the therapeutic potential.

Chen Y, Li Z, Ji G, Wang S, Mo C, Ding B MedComm (2020). 2024; 5(2):e494.

PMID: 38405059 PMC: 10885188. DOI: 10.1002/mco2.494.

Possible role of purinergic signaling in COVID-19.

Franciosi M, Lima M, Schetinger M, Cardoso A Mol Cell Biochem. 2021; 476(8):2891-2898.

PMID: 33740184 PMC: 7973800. DOI: 10.1007/s11010-021-04130-4.

Purinergic Regulation of Endothelial Barrier Function.

Aslam M, Gunduz D, Troidl C, Heger J, Hamm C, Schulz R Int J Mol Sci. 2021; 22(3).

PMID: 33530557 PMC: 7865261. DOI: 10.3390/ijms22031207.

Sustained adenosine exposure causes endothelial mitochondrial dysfunction via equilibrative nucleoside transporters.

Ko J, Rounds S, Lu Q Pulm Circ. 2020; 10(2):2045894020924994.

PMID: 32523687 PMC: 7235668. DOI: 10.1177/2045894020924994.

The Purinergic System as a Pharmacological Target for the Treatment of Immune-Mediated Inflammatory Diseases.

Antonioli L, Blandizzi C, Pacher P, Hasko G Pharmacol Rev. 2019; 71(3):345-382.

PMID: 31235653 PMC: 6592405. DOI: 10.1124/pr.117.014878.

References

Blackburn M, Volmer J, Thrasher J, Zhong H, Crosby J, Lee J . Metabolic consequences of adenosine deaminase deficiency in mice are associated with defects in alveogenesis, pulmonary inflammation, and airway obstruction. J Exp Med. 2000; 192(2):159-70. PMC: 2193256. DOI: 10.1084/jem.192.2.159. View

Atkinson J, Senior R . Matrix metalloproteinase-9 in lung remodeling. Am J Respir Cell Mol Biol. 2002; 28(1):12-24. DOI: 10.1165/rcmb.2002-0166TR. View

Sime P, OReilly K . Fibrosis of the lung and other tissues: new concepts in pathogenesis and treatment. Clin Immunol. 2001; 99(3):308-19. DOI: 10.1006/clim.2001.5008. View

Kolachala V, Vijay-Kumar M, Dalmasso G, Yang D, Linden J, Wang L . A2B adenosine receptor gene deletion attenuates murine colitis. Gastroenterology. 2008; 135(3):861-70. PMC: 2632861. DOI: 10.1053/j.gastro.2008.05.049. View

Ryzhov S, Zaynagetdinov R, Goldstein A, Novitskiy S, Blackburn M, Biaggioni I . Effect of A2B adenosine receptor gene ablation on adenosine-dependent regulation of proinflammatory cytokines. J Pharmacol Exp Ther. 2007; 324(2):694-700. DOI: 10.1124/jpet.107.131540. View

Ma B, Blackburn M, Lee C, Homer R, Liu W, Flavell R . Adenosine metabolism and murine strain-specific IL-4-induced inflammation, emphysema, and fibrosis. J Clin Invest. 2006; 116(5):1274-83. PMC: 1451205. DOI: 10.1172/JCI26372. View

Eckle T, Faigle M, Grenz A, Laucher S, Thompson L, Eltzschig H . A2B adenosine receptor dampens hypoxia-induced vascular leak. Blood. 2007; 111(4):2024-35. PMC: 2739365. DOI: 10.1182/blood-2007-10-117044. View

Shao M, Nadel J . Neutrophil elastase induces MUC5AC mucin production in human airway epithelial cells via a cascade involving protein kinase C, reactive oxygen species, and TNF-alpha-converting enzyme. J Immunol. 2005; 175(6):4009-16. DOI: 10.4049/jimmunol.175.6.4009. View

Fredholm B, IJzerman A, Jacobson K, Klotz K, Linden J . International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev. 2001; 53(4):527-52. PMC: 9389454. View

10.

Foronjy R, Nkyimbeng T, Wallace A, Thankachen J, Okada Y, Lemaitre V . Transgenic expression of matrix metalloproteinase-9 causes adult-onset emphysema in mice associated with the loss of alveolar elastin. Am J Physiol Lung Cell Mol Physiol. 2008; 294(6):L1149-57. DOI: 10.1152/ajplung.00481.2007. View

11.

Mohsenin A, Blackburn M . Adenosine signaling in asthma and chronic obstructive pulmonary disease. Curr Opin Pulm Med. 2005; 12(1):54-9. DOI: 10.1097/01.mcp.0000199002.46038.cb. View

12.

Snider G, Ciccolella D, Morris S, Stone P, LUCEY E . Putative role of neutrophil elastase in the pathogenesis of emphysema. Ann N Y Acad Sci. 1991; 624:45-59. DOI: 10.1111/j.1749-6632.1991.tb17005.x. View

13.

Blackburn M, Lee C, Young H, Zhu Z, Chunn J, Kang M . Adenosine mediates IL-13-induced inflammation and remodeling in the lung and interacts in an IL-13-adenosine amplification pathway. J Clin Invest. 2003; 112(3):332-44. PMC: 166289. DOI: 10.1172/JCI16815. View

14.

Rosenberger P, Schwab J, Mirakaj V, Masekowsky E, Mager A, Morote-Garcia J . Hypoxia-inducible factor-dependent induction of netrin-1 dampens inflammation caused by hypoxia. Nat Immunol. 2009; 10(2):195-202. DOI: 10.1038/ni.1683. View

15.

Driver A, Kukoly C, Ali S, Mustafa S . Adenosine in bronchoalveolar lavage fluid in asthma. Am Rev Respir Dis. 1993; 148(1):91-7. DOI: 10.1164/ajrccm/148.1.91. View

16.

Valls M, Cronstein B, Carmen Montesinos M . Adenosine receptor agonists for promotion of dermal wound healing. Biochem Pharmacol. 2008; 77(7):1117-24. PMC: 2671632. DOI: 10.1016/j.bcp.2008.11.002. View

17.

Blackburn M, Datta S, Kellems R . Adenosine deaminase-deficient mice generated using a two-stage genetic engineering strategy exhibit a combined immunodeficiency. J Biol Chem. 1998; 273(9):5093-100. DOI: 10.1074/jbc.273.9.5093. View

18.

Thannickal V, Toews G, White E, Lynch 3rd J, Martinez F . Mechanisms of pulmonary fibrosis. Annu Rev Med. 2004; 55:395-417. DOI: 10.1146/annurev.med.55.091902.103810. View

19.

Mohsenin A, Burdick M, Molina J, Keane M, Blackburn M . Enhanced CXCL1 production and angiogenesis in adenosine-mediated lung disease. FASEB J. 2007; 21(4):1026-36. DOI: 10.1096/fj.06-7301com. View

20.

Young H, Molina J, Dimina D, Zhong H, Jacobson M, Chan L . A3 adenosine receptor signaling contributes to airway inflammation and mucus production in adenosine deaminase-deficient mice. J Immunol. 2004; 173(2):1380-9. DOI: 10.4049/jimmunol.173.2.1380. View