Interstitial lung disease leads to more than 30,000 hospitalizations and 5,000 deaths yearly in the United States. A subset of interstitial lung disease known as idiopathic pulmonary fibrosis (IPF) is particularly devastating. Basic research into the mechanisms that govern this disease are needed to help develop novel therapies for its treatment. The focus of this proposal is to characterize a novel model of lung fibrosis that implicates adenosine signaling in this disease. Adenosine is a signaling nucleoside that engages specific adenosine receptors on the surface of target cells to elicit a vast array of cellular responses. Elevated adenosine levels are thought to play a role in inflammatory lung diseases such as asthma and COPD; however, the involvement of this signaling pathway in IPF has not been examined. We have recently generated a line of mice that contain low levels of the enzyme adenosine deaminase (ADA), which is responsible for controlling the levels of adenosine in tissues and cells. These partially ADA-deficient mice exhibit progressive elevations in lung adenosine concentrations and in turn die from severe interstitial lung disease characterized by the histologic, immunologic and inflammatory hallmarks of IPF. This suggests that chronic elevations in adenosine may access signaling pathways that lead to the inflammation and damage seen IPF. Therefore, the hypothesis being tested is that chronic elevations in adenosine contribute to lung inflammation and fibrosis.
Four specific aims are designed to address this hypothesis:
Aim 1, Characterize the lung fibrosis seen in partially ADA-deficient mice and determine the dependence of this phenotype on elevations in adenosine.
Aim 2, Characterize the pattern of adenosine receptor expression in the lungs of partially ADA-deficient mice and determine their function using genetic and pharmacologic approaches.
Aim 3, Examine adenosine-signaling pathways in an established model of lung fibrosis.
and Aim 4, Examine the efficacy of novel therapies on lung fibrosis. Knowledge obtained from these experiments will improve our understanding of the cellular signaling pathways involved in interstitial lung diseases such IPF, which will aid the development of adenosine-based therapeutics for the treatment of this deadly disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Reynolds, Herbert Y
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Health Science Center Houston
Schools of Medicine
United States
Zip Code
Garcia-Morales, Luis J; Chen, Ning-Yuan; Weng, Tingting et al. (2016) Altered Hypoxic-Adenosine Axis and Metabolism in Group III Pulmonary Hypertension. Am J Respir Cell Mol Biol 54:574-83
Luo, Fayong; Le, Ngoc-Bao; Mills, Tingting et al. (2016) Extracellular adenosine levels are associated with the progression and exacerbation of pulmonary fibrosis. FASEB J 30:874-83
Karmouty-Quintana, Harry; Philip, Kemly; Acero, Luis F et al. (2015) Deletion of ADORA2B from myeloid cells dampens lung fibrosis and pulmonary hypertension. FASEB J 29:50-60
Evans, Christopher M; Raclawska, Dorota S; Ttofali, Fani et al. (2015) The polymeric mucin Muc5ac is required for allergic airway hyperreactivity. Nat Commun 6:6281
Le, Thanh-Thuy T; Karmouty-Quintana, Harry; Melicoff, Ernestina et al. (2014) Blockade of IL-6 Trans signaling attenuates pulmonary fibrosis. J Immunol 193:3755-68
Weng, Tingting; Poth, Jens M; Karmouty-Quintana, Harry et al. (2014) Hypoxia-induced deoxycytidine kinase contributes to epithelial proliferation in pulmonary fibrosis. Am J Respir Crit Care Med 190:1402-12
Ning, Chen; Wen, Jiaming; Zhang, Yujin et al. (2014) Excess adenosine A2B receptor signaling contributes to priapism through HIF-1? mediated reduction of PDE5 gene expression. FASEB J 28:2725-35
Karmouty-Quintana, Harry; Xia, Yang; Blackburn, Michael R (2013) Adenosine signaling during acute and chronic disease states. J Mol Med (Berl) 91:173-81
Li, Hongyan; Zhang, Zhijing; Blackburn, Michael R et al. (2013) Adenosine and dopamine receptors coregulate photoreceptor coupling via gap junction phosphorylation in mouse retina. J Neurosci 33:3135-50
Eckle, Tobias; Hughes, Kelly; Ehrentraut, Heidi et al. (2013) Crosstalk between the equilibrative nucleoside transporter ENT2 and alveolar Adora2b adenosine receptors dampens acute lung injury. FASEB J 27:3078-89

Showing the most recent 10 out of 35 publications