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

慢性阻塞性肺疾病（COPD）是一种发病率不断上升的主要疾病。据预测，到2030年，它将成为全球最常见的死亡原因的第三位。这种迄今无法治愈的疾病的主要诱因是吸入性吸烟和空气污染。尽管高达70%的COPD患者患有肺动脉高压（PH），但其对COPD发病机制的影响尚未解决。最近的一个假说假设血管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，所应用的小鼠模型很好地反映了人类疾病的时间进程。我们的研究确定了诱导型一氧化氮合酶（iNOS）作为烟雾诱导的PH和肺气肿的发展的关键酶：敲除小鼠的iNOS基因导致对疾病的完全保护。此外，药理学iNOS抑制（使用L-NIL）不仅可以预防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）。以前的研究表明，成纤维细胞生长因子10（FGF 10），在早期胚胎肺发育过程中结合FGFR 2b和FGFR 1b受体的关键配体，在发展烟草烟雾诱导的PH和肺气肿的时间过程中下调，甚至在建立的肺气肿/PH中，特别是在肺泡隔中。此外，我们观察到Fgf 10的表达被治愈性L-NIL治疗逆转。由于肺再生和PH逆转发生在这些小鼠中，与Fgf 10的上调相关，我们假设肺气肿后的肺再生与Fgf 10有因果关系。提出了两个主要目的：目的1：确定Fgf 10或其受体Fgfr 2b或Fgfr 1b的部分失活是否导致自发性肺气肿或对香烟烟雾的敏感性增加，从而加速肺气肿和PH的发展。目的2：以确定在肺气肿/PH建立后Fgf 10的诱导性过表达是否可以改善肺功能并触发肺再生。关于可能的患者前瞻性治疗，我们计划使用烟雾和弹性蛋白酶诱导的肺气肿/PH模型来覆盖COPD患者人群。通过对COPD患者的人肺样本进行平行研究，我们研究的总体目标是确定不仅用于预防而且用于肺气肿肺再生的新策略。

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.