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Enhanced CXCL1 production and angiogenesis in adenosine-mediated lung disease

Amir Mohsenin^*,, Marie D. Burdick, Jose G. Molina^*, Michael P. Keane and Michael R. Blackburn^*,,1

^* Department of Biochemistry and Molecular Biology and

The Graduate School of Biomedical Sciences, University of Texas Houston Medical School, Houston, Texas, USA; and

Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, Los Angeles, California, USA

¹Correspondence: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston Medical School, 6431 Fannin St, Houston, TX 77030, USA. E-mail: michael.r.blackburn{at}uth.tmc.edu

Angiogenesis is a feature of chronic lung diseases such as asthma and pulmonary fibrosis; however, the pathways controlling pathological angiogenesis during lung disease are not completely understood. Adenosine is a signaling molecule that has been implicated in the exacerbation of chronic lung disease and in the regulation of angiogenesis; however, the relationship between these factors has not been investigated. The current study utilized adenosine deaminase (ADA)-deficient mice to determine whether chronic elevations in adenosine in vivo result in pulmonary angiogenesis. Results demonstrate substantial angiogenesis in the tracheas of ADA-deficient mice in association with adenosine elevations. ADA replacement enzyme therapy resulted in a lowering of adenosine levels and reversal of tracheal angiogenesis, indicating that the increases in vessel number are dependent on adenosine elevations. Levels of the angiogenic chemokine CXCL1 (mouse functional homologue of human IL-8) were found to be elevated in an adenosine-dependent manner in the lungs of ADA-deficient mice. Neutralization of CXCL1 and its receptor, CXCR2, resulted in the inhibition of angiogenic activity, which suggests that CXCL1 signaling through the CXCR2 receptor mediated the observed increases in angiogenesis. Our findings suggest that adenosine plays an important role, via CXCL1, in the induction of pulmonary angiogenesis.—Mohsenin, A., Burdick, M. D., Molina, J. G., Keane, M. P., Blackburn, M. R. Enhanced CXCL1 production and angiogenesis in adenosine mediated lung disease.

Key Words: chemokine • asthma • macrophage • adenosine deaminase

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