Little is known about the mechanisms that drive the progressive tissue remodeling and destruction that is seen in chronic lung diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Extracellular adenosine is a signaling molecule that is produced following cellular injury that is elevated in the lungs of patients with chronic lung disease. Work from our lab using mouse models of COPD and pulmonary fibrosis have shown that adenosine contributes to disease progression in these models. Moreover, adenosine-based therapies are useful in treating features of alveolar airway destruction and pulmonary fibrosis in these models. The predictability of success of adenosine-based therapies in these models is associated with specific alterations in enzymes of adenosine metabolism and the adenosine receptors;a feature we call """"""""purinergic remodeling"""""""". The focus of this proposal is to utilize tissues from the Lung Tissue Research Consortium (LTRC) to determine if """"""""purinergic remodeling"""""""" exists in patients with COPD and/or pulmonary fibrosis. Our specific hypothesis is that that purinergic signaling components will be altered in a manner that promotes adenosine production in tissue samples from patients with COPD and pulmonary fibrosis.
Two Specific Aims are designed to address this hypothesis:
Aim 1. Profile purinergic remodeling components at the transcript and protein level using tissue specimens from COPD and IPF patients;
Aim 2. Indentify the cellular localization of key components of purinergic metabolism and signaling in paraffin embedded lung tissue from COPD and IPF patients. Successful completion of these experiments will provide novel and important proof of concept information into patient populations that may be suitable for adenosine- based therapies. (End of Abstract)

Public Health Relevance

PROJECT NARRATIVE Lung diseases such as chronic obstructive pulmonary disease (COPD) and interstitial lung disease affect millions of individuals in this country and result in billions of dollars in heath care expenditures. Treatment options for these diseases are lacking. The research proposed here will determine if the alterations in adenosine metabolism and signaling seen in mouse models of chronic lung disease, also exists in humans with chronic lung disease. This will provide important proof of concept information that will be useful in developing novel therapies for the treatment of these diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Small Research Grants (R03)
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Special Emphasis Panel (ZHL1-CSR-D (S1))
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Croxton, Thomas
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University of Texas Health Science Center Houston
Schools of Medicine
United States
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Schneider, Daniel J; Lindsay, Janci C; Zhou, Yang et al. (2010) Adenosine and osteopontin contribute to the development of chronic obstructive pulmonary disease. FASEB J 24:70-80
Zhou, Yang; Schneider, Daniel J; Blackburn, Michael R (2009) Adenosine signaling and the regulation of chronic lung disease. Pharmacol Ther 123:105-16