Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, Texas, United States of America.
PLoS One. 2010 Feb 16;5(2):e9224. doi: 10.1371/journal.pone.0009224.
BACKGROUND: Adenosine is generated in response to cellular stress and damage and is elevated in the lungs of patients with chronic lung disease. Adenosine signaling through its cell surface receptors serves as an amplifier of chronic lung disorders, suggesting adenosine-based therapeutics may be beneficial in the treatment of lung diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Previous studies in mouse models of chronic lung disease demonstrate that the key components of adenosine metabolism and signaling are altered. Changes include an up-regulation of CD73, the major enzyme of adenosine production and down-regulation of adenosine deaminase (ADA), the major enzyme for adenosine metabolism. In addition, adenosine receptors are elevated. METHODOLOGY/PRINCIPAL FINDINGS: The focus of this study was to utilize tissues from patients with COPD or IPF to examine whether changes in purinergic metabolism and signaling occur in human disease. Results demonstrate that the levels of CD73 and A(2B)R are elevated in surgical lung biopsies from severe COPD and IPF patients. Immunolocalization assays revealed abundant expression of CD73 and the A(2B)R in alternatively activated macrophages in both COPD and IPF samples. In addition, mediators that are regulated by the A(2B)R, such as IL-6, IL-8 and osteopontin were elevated in these samples and activation of the A(2B)R on cells isolated from the airways of COPD and IPF patients was shown to directly induce the production of these mediators. CONCLUSIONS/SIGNIFICANCE: These findings suggest that components of adenosine metabolism and signaling are altered in a manner that promotes adenosine production and signaling in the lungs of patients with COPD and IPF, and provide proof of concept information that these disorders may benefit from adenosine-based therapeutics. Furthermore, this study provides the first evidence that A(2B)R signaling can promote the production of inflammatory and fibrotic mediators in patients with these disorders.
背景：腺苷是在细胞应激和损伤时产生的，在慢性肺病患者的肺部中升高。通过其细胞表面受体的腺苷信号传递作为慢性肺疾病的放大器，这表明基于腺苷的治疗方法可能有益于治疗慢性阻塞性肺疾病（COPD）和特发性肺纤维化（IPF）等肺部疾病。先前在慢性肺病的小鼠模型中的研究表明，腺苷代谢和信号的关键组成部分发生改变。变化包括 CD73 的上调，这是产生腺苷的主要酶，以及腺苷脱氨酶（ADA）的下调，ADA 是腺苷代谢的主要酶。此外，腺苷受体也升高。 方法/主要发现：本研究的重点是利用 COPD 或 IPF 患者的组织，研究嘌呤能代谢和信号的变化是否发生在人类疾病中。结果表明，严重 COPD 和 IPF 患者的手术肺活检中 CD73 和 A(2B)R 的水平升高。免疫定位检测显示 COPD 和 IPF 样本中交替激活的巨噬细胞中 CD73 和 A(2B)R 表达丰富。此外，在这些样本中，A(2B)R 调节的介质，如 IL-6、IL-8 和骨桥蛋白，也升高，并且 A(2B)R 在 COPD 和 IPF 患者气道分离细胞上的激活被证明可以直接诱导这些介质的产生。 结论/意义：这些发现表明，在 COPD 和 IPF 患者的肺部中，腺苷代谢和信号的组成部分以促进腺苷产生和信号传递的方式发生改变，并提供了这些疾病可能受益于基于腺苷的治疗方法的概念验证信息。此外，本研究首次提供了证据，表明 A(2B)R 信号可以促进这些疾病患者中炎症和纤维化介质的产生。
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