Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Dis Model Mech. 2019 May 15;12(5):dmm038711. doi: 10.1242/dmm.038711.
Combined pulmonary fibrosis and emphysema (CPFE) is a syndrome that predominantly affects male smokers or ex-smokers and it has a mortality rate of 55% and a median survival of 5 years. Pulmonary hypertension (PH) is a frequently fatal complication of CPFE. Despite this dismal prognosis, no curative therapies exist for patients with CPFE outside of lung transplantation and no therapies are recommended to treat PH. This highlights the need to develop novel treatment approaches for CPFE. Studies from our group have demonstrated that both adenosine and its receptor ADORA2B are elevated in chronic lung diseases. Activation of ADORA2B leads to elevated levels of hyaluronan synthases (HAS) and increased hyaluronan, a glycosaminoglycan that contributes to chronic lung injury. We hypothesize that ADORA2B and hyaluronan contribute to CPFE. Using isolated CPFE lung tissue, we characterized expression levels of ADORA2B and HAS. Next, using a unique mouse model of experimental lung injury that replicates features of CPFE, namely airspace enlargement, PH and fibrotic deposition, we investigated whether 4MU, a HAS inhibitor, was able to inhibit features of CPFE. Increased protein levels of ADORA2B and HAS3 were detected in CPFE and in our experimental model of CPFE. Treatment with 4MU was able to attenuate PH and fibrosis but not airspace enlargement. This was accompanied by a reduction of HAS3-positive macrophages. We have generated pre-clinical data demonstrating the capacity of 4MU, an FDA-approved drug, to attenuate features of CPFE in an experimental model of chronic lung injury.This article has an associated First Person interview with the first author of the paper.
合并性肺纤维化和肺气肿（CPFE）是一种主要影响男性吸烟者或戒烟者的综合征，其死亡率为 55%，中位生存期为 5 年。肺动脉高压（PH）是 CPFE 的一种常见致命并发症。尽管预后不佳，但除肺移植外，CPFE 患者尚无治愈疗法，也不推荐任何疗法来治疗 PH。这凸显了为 CPFE 患者开发新治疗方法的必要性。我们小组的研究表明，腺苷及其受体 ADORA2B 在慢性肺部疾病中均升高。ADORA2B 的激活导致透明质酸合酶（HAS）水平升高和透明质酸增加，透明质酸是一种糖胺聚糖，可导致慢性肺损伤。我们假设 ADORA2B 和透明质酸有助于 CPFE。我们使用分离的 CPFE 肺组织，对 ADORA2B 和 HAS 的表达水平进行了特征描述。接下来，使用一种独特的实验性肺损伤小鼠模型，该模型复制了 CPFE 的特征，即气腔扩大、PH 和纤维沉积，我们研究了 HAS 抑制剂 4MU 是否能够抑制 CPFE 的特征。CPFE 和我们的 CPFE 实验模型中均检测到 ADORA2B 和 HAS3 蛋白水平升高。4MU 治疗能够减轻 PH 和纤维化，但不能减轻气腔扩大。这伴随着 HAS3 阳性巨噬细胞的减少。我们已经生成了临床前数据，证明了 4MU（一种 FDA 批准的药物）在慢性肺损伤的实验模型中能够减轻 CPFE 的特征。本文附有该论文第一作者的第一人称采访。
