FGF10/FGFR2b signaling in lung emphysema as a target for lung regeneration

肺气肿中的 FGF10/FGFR2b 信号作为肺再生的靶点

• 批准号: 269289029
• 负责人: Professor Dr. Saverio Bellusci
• 金额: --
• 依托单位: Excellence Cluster Cardio-Pulmonary System (ECCPS)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/269289029?language=en
• 关键词: FGF10; FGFR2b; signaling; lung; emphysema

Chronic obstructive pulmonary disease (COPD) is a major disease with ever increasing incidence. It is predicted to be ranked third place of the most frequent causes of death worldwide in 2030. Major triggers of this hitherto incurable disease are inhalative tobacco-smoking and air pollution. Although up to 70% of COPD patients suffer from pulmonary hypertension (PH) its impact on COPD pathogenesis is not resolved yet. A recent hypothesis postulated that vascular alterations can trigger emphysema development. In this regard we recently showed in a mouse model that PH precedes emphysema development, with the applied mouse model quite well reflecting the time course of the human disease. Our investigations identified the inducible NO synthase (iNOS) as key enzyme for the development of smoke-induced PH and lung emphysema: A knockout of the iNOS gene in mice resulted in complete protection from the disease. Moreover, a pharmacological iNOS inhibition (using L-NIL) could not only prevent PH and emphysema development, but even reversed established emphysema and PH and thus led to lung regeneration (1). Previous own investigations showed that Fibroblast Growth Factor 10 (FGF10), a key ligand during early embryonic lung development binding to FGFR2b and FGFR1b receptors , was downregulated during the time course of developing tobacco smoke-induced PH and emphysema and even in established emphysema/PH, especially in alveolar septi. Moreover, we observed that the expression of Fgf10 was reversed by curative L-NIL treatment. Since lung regeneration and reversal of PH occurred in those mice, associated with an upregulation of Fgf10, we hypothesize that lung regeneration after emphysema is causally linked to FGF10.Two main aims are proposed:Aim 1: to determine whether partial inactivation of Fgf10 or its receptors Fgfr2b or Fgfr1b lead to spontaneous emphysema or increase sensibility to cigarette smoke resulting in accelerated emphysema and PH development.Aim 2: to determine whether inducible overexpression of Fgf10 after establishment of emphysema/PH can improve lung function and triggers lung regeneration. Regarding possible prospective treatment of patients, we plan to use smoke- and elastase-induced emphysema/PH models to cover the populace of COPD patients. With parallel investigations in human lung samples from patients with COPD the overall aim of our study is to identify new strategies not only for prevention but also for regeneration of emphysematous lungs.

慢性阻塞性肺疾病（COPD）是一种发病率不断上升的主要疾病。预计到2030年，它将在全球最常见的死亡原因中排名第三。这种迄今无法治愈的疾病的主要诱因是吸入烟草和空气污染。尽管高达70%的COPD患者患有肺动脉高压（pulmonary hypertension， PH），但其对COPD发病机制的影响尚不清楚。最近的一项假说认为，血管的改变可以引发肺气肿的发展。在这方面，我们最近在小鼠模型中表明PH先于肺气肿的发展，应用的小鼠模型很好地反映了人类疾病的时间进程。我们的研究发现，诱导型NO合成酶（iNOS）是烟雾诱导的PH和肺气肿发展的关键酶：敲除小鼠的iNOS基因可以完全保护疾病。此外，药理抑制iNOS（使用L-NIL）不仅可以阻止PH和肺气肿的发展，甚至可以逆转已建立的肺气肿和PH，从而导致肺再生(1)。先前的研究表明，成纤维细胞生长因子10 （FGF10）是早期胚胎肺发育的关键配体，与FGFR2b和FGFR1b受体结合，在烟草烟雾诱导的PH和肺气肿形成的时间过程中，甚至在肺气肿/PH形成的时间过程中下调，特别是在肺泡中间隔。此外，我们观察到Fgf10的表达被治愈性的L-NIL治疗逆转。由于这些小鼠的肺再生和PH逆转与Fgf10的上调有关，我们假设肺气肿后的肺再生与Fgf10有因果关系。目的1：确定Fgf10或其受体Fgfr2b或Fgfr1b的部分失活是否会导致自发性肺气肿或增加对香烟烟雾的敏感性，从而加速肺气肿和PH的发展。目的2：探讨肺气肿/PH建立后诱导过表达Fgf10是否能改善肺功能，触发肺再生。关于可能的前瞻性治疗患者，我们计划使用烟雾和弹性酶诱导的肺气肿/PH模型来覆盖广大COPD患者。通过对COPD患者肺样本的平行研究，我们研究的总体目标是确定预防和再生肺气肿肺的新策略。