Pulmonary fibrosis is a component of various interstitial pneumonias. These disorders are characterized by varying degrees of inflammation, aberrant fibroblast proliferation, and extracellular matrix deposition. The signaling pathways that mediate pulmonary inflammation and fibrosis have not been completely elucidated. Understanding the contribution of mediators generated during tissue injury to the regulation of inflammation and fibrosis could provide novel therapeutic approaches for lung diseases in which fibrosis is a detrimental component. Adenosine is a cellular signaling molecule that is produced in excess during situations of cellular stress and damage. Consistent with this, adenosine levels are elevated in the lungs of patients with chronic lung disease. Once produced, adenosine can engage specific G-protein-coupled receptors on the surface of cells. Evidence suggests that excess adenosine production following lung injury can access pro-fibrotic pathways and hence contribute to the development and/or maintenance of pulmonary fibrosis. Consistent with this, mice deficient in the purine catabolic enzyme adenosine deaminase (ADA) develop progressive pulmonary fibrosis in association with lung adenosine elevations. Research in the last funding period revealed that the A2B adenosine receptor (AR) is responsible for the adenosine-mediated fibrosis seen in this and other models of pulmonary fibrosis. Analysis of pro-fibrotic processes revealed an increase in angiogenesis and the up-regulation of angiogenic chemokines. In addition, the extracellular matrix/signaling molecule, osteopontin was found to be elevated in an adenosine-dependent manner. Increases in angiogenic cytokines, angiogenesis, osteopontin production and pulmonary fibrosis were all attenuated by lowering lung adenosine levels in ADA-deficient mice using ADA enzyme therapy or by blocking or genetically removing the A2BAR. The purpose of this renewal will be to decipher the mechanisms by which A2BAR signaling mediates pulmonary fibrosis. The hypothesis to be examined is that elevated adenosine levels contribute to pulmonary fibrosis by engagement of the A2BAR on various pulmonary cells that together, access pathways that exacerbate fibrotic foci. Key processes include the differentiation and proliferation of myofibroblasts and the production of angiogenic factors such as osteopontin and CXCL1 that lead to increased angiogenesis in the lung.
Three specific aims are proposed to address this far reaching hypothesis:
Aim 1. Determine the contribution of A2BAR signaling to features of adenosine-dependent pulmonary fibrosis.
Aim 2. Determine the contribution of A2BAR mediated osteopontin production to features of adenosine-dependent pulmonary fibrosis.
Aim 3. Determine the contribution of CXCL1/CXCR2-mediated angiogenesis to adenosine-mediated pulmonary fibrosis. These experiments will help guide the development of novel therapeutic approaches to treat pulmonary disorders in which fibrosis is a component.
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