Impact of smoking on orbital Hypoxia-inducible factor dependent responses and consequences for sex-specific progression of Graves’ orbitopathy

• Applicant: Dr. Gina-Eva Görtz
• Subject Area: Ophthalmology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 450288841

Graves’ orbitopathy (GO) is an inflammatory eye disease which usually occurs in the context of Graves’ disease and it is believed that an autoimmune reaction against the Thyrotropin Receptor (TSHR) is the common cause. Women are 5-10 times more often affected than men, but men more often develop a severe eye disease. Besides female gender, cigarette smoking is the strongest risk factor for developing a GO. Smoking adversely affects not only course and severity but also treatment outcome of GO. Adverse effects appeared more pronounced in women than in men. However, it is unkown if smoking plays a role for development of gender-differences in GO and which mechanism are involved. Our previous in vitro studies suggest that cigarette smoke extract and hypoxia or inflammation through activation of Hypoxia-inducible factor (HIF) dependent pathways stimulate orbital adipogenesis and angiogenesis. These mechanisms can contribute differently to orbital tissue remodeling in GO patients dependent on gender and smoking habits. In the last funding period, we established a Graves’ disease mouse model with GO. In the model autoimmune hyperthyroid animals developed individually either more orbital adipogenesis or muscle fibrosis. Frequency and severity of GO were relative comparable in animals both sexes. However, female mice developed predominantly muscle hypertrophy with infiltration of macrophages while adipogenesis and collagen deposition were characteristics of GO in male mice. Based on these results we propose to investigate the influence of smoking on frequency, severity and sex-specific phenotype of GO in the mouse model. The study is designed to reveal whether smoking affects orbital hypoxia and/or inflammation and consequences for sex-specific tissue remodeling and progression of GO. To this end we will apply small animal microPET/CT (positron emission tomography/computed tomography) imaging to specifically trace hypoxia and inflammation in orbital tissues and thyroids of living immunized mice non-invasively. Our aim is to decipher at which stages of disease - subclinical, initial, early, full blown - substantial hypoxia and/or inflammatory cells and cytokines play a major role and how smoking modifies the course of disease. The influence of smoking on TSHR autoimmunity, thyroid and eye disease will be investigated in mice of both sexes. Provided that hypoxia and/or inflammation will induce growth factors like VEGF and PDGF-BB that are crucial for orbital tissue remodeling we will test targeted inhibition of these receptors as an option to prevent progression of disease upon smoking. Finally, to prove a critical involvement of OF-specific hypoxic and/or inflammatory responses as a driving mechanism we will investigate the outcome of GO in fibroblast-specific HIF-1α knock out mice.

• DFG Programme: Research Grants