Abstract
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide. The development of pulmonary hypertension (PH) in patients with COPD is strongly associated with increased mortality. Chronic inflammation and changes to the lung extracellular matrix (ECM) have been implicated in the pathogenesis of COPD, yet the mechanisms that lead to PH secondary to COPD remain unknown. Our experiments using human lung tissue show increased expression levels of the adenosine A2B receptor (ADORA2B) and a heightened deposition of hyaluronan (HA; a component of the ECM) in remodeled vessels of patients with PH associated with COPD. We also demonstrate that the expression of HA synthase 2 correlates with mean pulmonary arterial pressures in patients with COPD, with and without a secondary diagnosis of PH. Using an animal model of airspace enlargement and PH, we show that the blockade of ADORA2B is able to attenuate the development of a PH phenotype that correlates with reduced levels of HA deposition in the vessels and the down-regulation of genes involved in the synthesis of HA.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine A2 Receptor Antagonists / pharmacology
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Adenosine Deaminase / deficiency
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Adenosine Deaminase / genetics
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Aged
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Animals
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Collagen Type I / genetics
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Collagen Type I, alpha 1 Chain
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Disease Models, Animal
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Female
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Humans
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Hyaluronic Acid / metabolism*
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Hypertension, Pulmonary / etiology*
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Hypertension, Pulmonary / pathology
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Hypertension, Pulmonary / physiopathology*
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Lung / blood supply
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Lung / pathology
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Male
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Mice
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Mice, Knockout
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Middle Aged
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Pulmonary Disease, Chronic Obstructive / complications*
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Pulmonary Disease, Chronic Obstructive / pathology
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Pulmonary Disease, Chronic Obstructive / physiopathology*
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Purines / pharmacology
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Pyrazoles / pharmacology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptor, Adenosine A2B / genetics
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Receptor, Adenosine A2B / metabolism*
Substances
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Adenosine A2 Receptor Antagonists
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Collagen Type I
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Collagen Type I, alpha 1 Chain
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Purines
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Pyrazoles
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RNA, Messenger
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Receptor, Adenosine A2B
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3-ethyl-1-propyl-8-(1-(3-trifluoromethylbenzyl)-1H-pyrazol-4-yl)-3,7-dihydropurine-2,6-dione
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Hyaluronic Acid
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Ada protein, mouse
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Adenosine Deaminase