Identification of the superoxide source of tobacco-smoke-induced emphysema and pulmonary hypertension, pathogenesis and regeneration.

• Applicant: Professor Dr. Norbert Weißmann, since 8/2016
• Subject Area: Pneumology, Thoracic Surgery
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 275165338

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 the COPD pathogenesis is not uncovered yet. A recent hypothesis even 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 lung emphysema and PH: A knockout of the iNOS gene in mice resulted in complete protection from the disease. Moreover, a pharmacological iNOS inhibition could not only prevent PH and emphysema development, but even reversed established emphysema and PH and thus led to lung regeneration (Seimetz et al., Cell, 2011). The pathophysiological concept based on our results claimed peroxynitrite, formed by the reaction of NO (generated by a vascular iNOS) with superoxide, as a key mediator of emphysema and PH development. While the NO source was identified, the superoxide-generating system is still unknown. With this proposal we thus will focus on the superoxide source and its signaling. In a preceding screening, we could already identify an NADPH oxidase (NOX) isoform as a potential superoxide source. The cytosolic subunit NOX organizer 1 (NOXO1) was the only NOX subunit upregulated in the alveolar and vascular compartment in tobacco smoke-exposed mice during the entire time course of the disease development. An analogous regulation was found in our investigations in human COPD lungs. Against this background we have already generated floxed NOXO1 mice. Thus, with the current proposal we aim i) to identify the detailed role of the NOXO1-dependent superoxide formation for the pathogenesis of lung emphysema and PH and ii) the suitability of NOXO1 and its signaling as a target for regenerative emphysema and PH therapy. Furthermore, the aim of the planned experiments is the identification of the cell types being responsible for emphysema and PH development. In this regard our concept postulates an essential role of superoxide-producing cells in the vascular compartment. With parallel investigation 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
• Cooperation Partner: Professor Dr. Sawa Kostin
• Ehemaliger Antragsteller: Dr. Michael Seimetz, until 8/2016