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

• Applicants: Professor Dr. Saverio Bellusci; Professor Dr. Norbert Weißmann, since 8/2016
• Subject Area: Pneumology, Thoracic Surgery
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 269289029

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.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Dr. Michael Seimetz, until 8/2016