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

慢性阻塞性肺疾病(COPD)是一种发病率呈上升趋势的重大疾病。据预测，到2030年，它将在全球最常见的死因中排名第三。这种迄今无法治愈的疾病的主要诱因是吸入性吸烟和空气污染。虽然高达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得到解决。最近的一项假说认为，血管改变会引发肺气肿的发展。在这方面，我们最近在一个小鼠模型中表明，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。我们的研究证实，诱导型一氧化氮合酶(INOS)是烟雾诱导的肺高压和肺气肿发生的关键酶：在小鼠中敲除iNOS基因可以完全保护小鼠免受疾病的侵袭。此外，药物诱导型一氧化氮合酶抑制剂(使用L-NIL)不仅可以防止肺高压和肺气肿的发展，甚至可以逆转已建立的肺气肿和肺高压，从而导致肺再生(1)。以往的研究表明，成纤维细胞生长因子10(FGF10)是胚胎肺发育早期与FGFR2b和FGFR1b受体结合的关键配体，在烟草烟雾诱导的PH和肺气肿的发生过程中，甚至在已建立的肺气肿/PH中，FGF10的表达下调，尤其是在肺泡间隔。此外，我们还观察到，根治性L-Nil治疗可逆转FGF10的表达。由于肺气肿小鼠的肺再生和PH逆转与Fgf10表达上调有关，我们推测肺气肿后的肺再生与FGF10有因果关系。我们提出两个主要目的：目的1：确定部分失活Fgf10或其受体FGFR2b或Fgfr1b是否会导致自发性肺气肿，或增加对香烟烟雾的敏感性，从而加速肺气肿和肺高压的发生。目的2：确定建立肺气肿/肺高压模型后，诱导的Fgf10过表达是否可以改善肺功能并触发肺再生。关于患者可能的前瞻性治疗，我们计划使用烟雾和弹力酶诱导的肺气肿/PH模型来覆盖COPD患者的人群。通过对COPD患者的人类肺样本进行平行研究，我们研究的总体目标不仅是确定新的预防策略，还包括肺气肿肺的再生。

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.