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About BMB

About BMB

Meet the BMB Faculty Members

Dr. Michael Blackburn, Professor and Vice-Chairman

Dr. Michael BlackburnDepartment of Biochemistry and Molecular Biology
Program in Biochemistry and Molecular Biology

University of Texas-Houston Medical School
P.O. Box 20708 - Houston, Texas 77225
(713) 500-6087: fax (713) 500-0652
email: Michael.R.Blackburn@uth.tmc.edu

Ph.D., Thomas Jefferson University
NIH Postdoctoral Fellow, Baylor College of Medicine

Junior Investigator Award, Sandler Program for Asthma Research

Career Investigator Award, American Lung Association

Molecular Models of Adenosine Signaling

and Chronic Lung Disease

Inflammatory and remodeling responses are prominent features of chronic lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis. In contrast to most injury and repair responses, the inflammation and remodeling seen in these diseases may last throughout the life of the afflicted individual. Although signaling pathways associated with the genesis of inflammation and the control of tissue remodeling have been described, little is known about signaling pathways that serve to regulate the chronic nature of these diseases. The major goal of my laboratory is to identify pathways that regulate the chronicity of asthma, COPD and pulmonary fibrosis with the intent of developing novel therapeutic strategies.

A central hypothesis of my laboratory is that the signaling nucleoside adenosine is an amplifier of lung inflammation and damage. Adenosine is generated in response to cell stress or damage and is therefore a byproduct of the inflammation and damage set up by any number of initiators of lung inflammation. It is our belief that as adenosine levels increase in the lung they access pathways that serve to promote airway inflammation and remodeling. Adenosine signals by engaging specific adenosine receptors on target cells such as mast cells, lymphocytes, eosinophils, macrophages, airway epithelial cells and smooth muscle cells. Most of the projects in my laboratory focus on understanding the mechanisms by which adenosine receptor signaling influences the activities of these cells in the context of lung inflammation and remodeling.

We make extensive use of genetically modified mice to examine the role of adenosine signaling in chronic lung disease. This includes knockout mice deficient in enzymes of adenosine metabolism and knockout mice deficient in the various adenosine receptors. In addition, we utilize transgenic mice that over express components of adenosine signaling specifically in the lung. With these genetic tools we can assess the contribution of specific aspects of adenosine signaling in chronic lung diseases in the context of the whole animal.

Figure 1

Model of adenosine-mediated amplification of chronic lung disease

Multiple factors contribute to the generation of chronic lung diseases such as asthma and COPD. The ensuing inflammation and damage that occurs in these conditions leads to the catabolism of ATP to adenosine. Adenosine then interacts with various adenosine receptors on the surface of target cells to increase the production of mediators that drive chronic airway inflammation and remodeling.

 
Selected References

Zaynagetdinov R, Ryzhov S, Goldstein A.E., Yin H, Novitskiy S.V., Goleniewska K, Polosukhin V.V., Newcomb D.C., Mitchell D, Morschl E, Zhou Y, Blackburn M.R., Peebles Jr R.S., Biaggioni I, Feoktistov I. Attenuation of Chronic Pulmonary Inflammation in A2B Adenosine Receptor Knockout Mice. Am J Respir Cell Mol Biol. 2009 Jun 25. [Epub ahead of print]

Zhou Y, Mohsenin A, Morschl E, Young H.W., Molina J.G., Ma W, Sun C.X., Martinez-Valdez H, Blackburn M.R. Enhanced airway inflammation and remodeling in adenosine deaminase-deficient mice lacking the A2B adenosine receptor. J Immunol. 182:8037-46. 2009.

Zhou Y, Schneider D.J., Blackburn M.R. Adenosine signaling and the regulation of chronic lung disease. Pharmacol Ther. 123:105-116, 2009

Peng Z, Borea P.A., Varani K, Wilder T, Yee H, Chiriboga L, Blackburn M.R., Azzena G, Resta G, Cronstein B.N. Adenosine signaling contributes to ethanol-induced fatty liver in mice. J Clin Invest. 119:582-94, 2009. Erratum in: J Clin Invest. 119:1052, 2009.

Zhai Y, Zhong Z, Chen C.Y., Xia Z, Song L, Blackburn M.R., Shyu A.B. Coordinated changes in mRNA turnover, translation, and RNA processing bodies in bronchial epithelial cells following inflammatory stimulation. Mol Cell Biol. 28:7414-7426, 2008

Joachims M.L., Marble P, Knott-Craig C, Pastuszko P, Blackburn M.R, Thompson L.F. Inhibition of deoxynucleoside kinases in human thymocytes prevents dATP accumulation and induction of apoptosis. Nucleosides Nucleotides Nucleic Acids. 27:816-820, 2008.

Morschl E, Molina J.G., Volmer J.B., Mohsenin A, Pero R.S., Hong J.S., Kheradmand F, Lee J.J., Blackburn M.R. A3 adenosine receptor signaling influences pulmonary inflammation and fibrosis. Am J Respir Cell Mol Biol. 39:697-705 2008.

Novitskiy S.V., Ryzhov S, Zaynagetdinov R, Goldstein A.E., Huang Y, Tikhomirov O.Y., Blackburn M.R., Biaggioni I, Carbone D.P., Feoktistov I, Dikov M.M. Adenosine receptors in regulation of dendritic cell differentiation and function. Blood. 112:1822-1831, 2008.

Ryzhov S, Zaynagetdinov R, Goldstein A.E., Novitskiy S.V., Dikov M.M., Blackburn M.R., Biaggioni I, Feoktistov I. Effect of A2B adenosine receptor gene ablation on proinflammatory adenosine signaling in mast cells. J Immunol. 180:7212-7220, 2008.

Fernández P, Trzaska S, Wilder T, Chiriboga L, Blackburn M.R., Cronstein B.N., Chan E.S. Pharmacological blockade of A2A receptors prevents dermal fibrosis in a model of elevated tissue adenosine. Am J Pathol. 172:1675-1682, 2008.

Carbonaro D.A., Jin X, Cotoi D, Mi T, Yu X.J., Skelton D.C., Dorey F, Kellems RE., Blackburn M.R., Kohn D.B. Neonatal bone marrow transplantation of ADA-deficient SCID mice results in immunologic reconstitution despite low levels of engraftment and an absence of selective donor T lymphoid expansion. Blood. 111:5745-5754, 2008.

Mi T, Abbasi S, Zhang H, Uray K, Chunn JL, Xia L.W., Molina J.G., Weisbrodt N.W., Kellems R.E., Blackburn M.R., Xia Y. Excess adenosine in murine penile erectile tissues contributes to priapism via A2B adenosine receptor signaling. J Clin Invest. 118:1491-1501, 2008.

Lewis C.C., Yang J.Y., Huang X, Banerjee S.K., Blackburn M.R., Baluk P, McDonald D.M., Blackwell TS, Nagabhushanam V, Peters W, Voehringer D, Erle D.J. Disease-specific gene expression profiling in multiple models of lung disease. Am J Respir Crit Care Med. 177:376-387, 2008.

Ryzhov S, Zaynagetdinov R, Goldstein .A.E, Novitskiy S.V., Blackburn M.R., Biaggioni I, Feoktistov I. Effect of A2B adenosine receptor gene ablation on adenosine-dependent regulation of proinflammatory cytokines. J Pharmacol Exp Ther. 324:694-700, 2008.

Mohsenin A, Mi T, Xia Y, Kellems R.E., Chen J.F., Blackburn M.R. Genetic removal of the A2A adenosine receptor enhances pulmonary inflammation, mucin production, and angiogenesis in adenosine deaminase-deficient mice. Am J Physiol Lung Cell Mol Physiol. 293:L753-761, 2007.

Ochkur S.I., Jacobsen E.A., Protheroe C.A., Biechele T.L., Pero R.S., McGarry M.P., Wang H, O'Neill K.R., Colbert D.C., Colby TV, Shen H, Blackburn M.R., Irvin C.C., Lee J.J., Lee N.A. Coexpression of IL-5 and eotaxin-2 in mice creates an eosinophil-dependent model of respiratory inflammation with characteristics of severe asthma. J Immunol. 178:7879-7889, 2007.

Csóka B, Németh Z.H., Virág L, Gergely P, Leibovich S.J., Pacher P, Sun C.X., Blackburn M.R., Vizi E.S., Deitch E.A., Haskó G. A2A adenosine receptors and C/EBPbeta are crucially required for IL-10 production by macrophages exposed to Escherichia coli. Blood. 110:2685-2695, 2007.

Blackburn M.R. A role for neural pathways in adenosine-induced bronchoconstriction. Am J Physiol Lung Cell Mol Physiol. 293:L22-24, 2007.

Young H.W., Williams O.W., Chandra D, Bellinghausen L.K., Pérez G, Suárez A, Tuvim M.J., Roy M.G., Alexander S.N., Moghaddam S.J., Adachi R, Blackburn M.R., Dickey B.F., Evans C.M. Central role of Muc5ac expression in mucous metaplasia and its regulation by conserved 5' elements. Am J Respir Cell Mol Biol. 37:273-290, 2007.

Mohsenin, A., Burdick, M. D., Molina, J. G., Keane, M. P. and Blackburn, M. R. Adenosine mediated CXCL1 production and angiogenesis in the lungs of adenosine deaminase deficient mice.  FASEB J. 21, 1026-1036, 2007.

Reichelt M.E., Willems L, Peart J.N., Ashton K.J., Matherne G.P., Blackburn M.R., Headrick J.P. Modulation of ischaemic contracture in mouse hearts: a 'supraphysiological' response to adenosine. Exp Physiol. 92:175-185, 2007.

Chunn, J. L., Mohsenin, A., Young, H. W. J., Lee, C. G., Elias, J. A., Kellems, R. E. and Blackburn, M. R. Partially adenosine deaminase-deficient mice develop pulmonary fibrosis in association with adenosine elevations. Am. J. Phys. Lung Cell Mol. Physiol. 290, 579-587, 2006

Volmer, J. B., Thompson, L. F. and Blackburn, M. R. A protective role for ecto-5’-nucleotidase (CD73) in bleomycin-induced pulmonary fibrosis.  J. Immunol. 176, 4449-4458, 2006

Young, H. W. J., Sun, C.-X., Evans, C. M., Jacobson, M. A., Dickey, B. and Blackburn, M. R. A3 adenosine receptor signaling contributes to airway mucin secretion following allergen challenge. Am. J. Respir. Cell Mol. Biol. 35, 549-558, 2006

Sun, C. X., Zhong, H., Mohsenin, A., Morschl, E., Chunn, J. L., Molina, J. G., Belardinelli, L., Zeng, D. and Blackburn, M. R. Role of A2B adenosine receptor signaling in adenosine-dependent pulmonary inflammation and injury in adenosine deaminase deficient mice. J. Clin. Invest. 116, 2173-2182, 2006.

Search PubMed for a complete list of Dr. Blackburn's publications.