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.

中文翻译：

---

腺苷和透明质酸在合并肺纤维化和肺气肿中促进肺纤维化和肺动脉高压。

合并肺纤维化和肺气肿（CPFE）是一种主要影响男性吸烟者或前吸烟者的综合征，其死亡率为55％，中位生存期为5年。肺动脉高压（PH）是CPFE的致命致命并发症。尽管预后很差，但对于没有肺移植的CPFE患者，尚无根治性方法，也不建议治疗PH。这突出显示了需要为CPFE开发新颖的治疗方法。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）的水平升高和透明质酸的增加，透明质酸是导致慢性肺损伤的糖胺聚糖。我们假设ADORA2B和透明质酸有助于CPFE。使用分离的CPFE肺组织，我们表征了ADORA2B和HAS的表达水平。接下来，使用重复CPFE功能（即空域扩大，PH和纤维化沉积）的实验性肺损伤的独特小鼠模型，我们研究了HAS抑制剂4MU是否能够抑制CPFE功能。在CPFE和我们的CPFE实验模型中检测到ADORA2B和HAS3的蛋白水平升高。用4MU治疗能够减轻PH和纤维化，但不能扩大气腔。这伴随着HAS3阳性巨噬细胞的减少。我们已经产生了临床前数据，证明了FDA批准的药物4MU在慢性肺损伤实验模型中减弱CPFE功能的能力。本文对第一人进行了第一人称采访。我们表征了ADORA2B和HAS的表达水平。接下来，使用重复CPFE功能（即空域扩大，PH和纤维化沉积）的实验性肺损伤的独特小鼠模型，我们研究了HAS抑制剂4MU是否能够抑制CPFE功能。在CPFE和我们的CPFE实验模型中检测到ADORA2B和HAS3的蛋白水平升高。用4MU治疗能够减轻PH和纤维化，但不能扩大气腔。这伴随着HAS3阳性巨噬细胞的减少。我们已经产生了临床前数据，证明了FDA批准的药物4MU在慢性肺损伤实验模型中减弱CPFE功能的能力。本文对第一人进行了第一人称采访。我们表征了ADORA2B和HAS的表达水平。接下来，使用独特的实验性肺损伤小鼠模型复制CPFE的特征，即空域扩大，PH和纤维化沉积，我们研究了HAS抑制剂4MU是否能够抑制CPFE的特征。在CPFE和我们的CPFE实验模型中检测到ADORA2B和HAS3的蛋白水平升高。用4MU治疗能够减轻PH和纤维化，但不能扩大气腔。这伴随着HAS3阳性巨噬细胞的减少。我们已经产生了临床前数据，证明了FDA批准的药物4MU在慢性肺损伤实验模型中减弱CPFE功能的能力。本文对第一人进行了第一人称采访。