1 Department of Biochemistry and Molecular Biology, and.
Am J Respir Cell Mol Biol. 2013 Dec;49(6):1038-47. doi: 10.1165/rcmb.2013-0089OC.
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.
慢性阻塞性肺疾病（COPD）是全球第四大致死原因。COPD 患者肺动脉高压（PH）的发展与死亡率的增加密切相关。慢性炎症和肺细胞外基质（ECM）的改变与 COPD 的发病机制有关，但导致 COPD 继发 PH 的机制尚不清楚。我们使用人类肺组织的实验表明，与 COPD 相关的 PH 患者中，腺苷 A2B 受体（ADORA2B）的表达水平升高，透明质酸（HA；ECM 的组成部分）在重塑的血管中的沉积增加。我们还证明，在伴有和不伴有 PH 继发诊断的 COPD 患者中，HA 合酶 2 的表达与平均肺动脉压相关。使用气腔扩大和 PH 的动物模型，我们表明 ADORA2B 的阻断能够减轻 PH 表型的发展，该表型与血管中 HA 沉积减少以及参与 HA 合成的基因下调相关。
