PT Unknown AU Abdelsadik, AMK TI Hypoxia induces processes related to inflammation and remodelling in the airways of the fruit fly Drosophila melanogaster PY 2012 PU Christian-Albrechts-Universität zu Kiel WP https://macau.uni-kiel.de/receive/diss_mods_00008330 LA en DE Hypoxie; Entzündungen; Atemwege; Fruchtfliege; Drosophila melanogaster AB The tracheal system of insects is a purely epithelial tissue that is primarily devoted to gas ex-change. All airway epithelial cells of the fruit fly Drosophila melanogaster are immune-competent, meaning that they are able to mount an immune response if confronted with patho-gens such as bacteria or fungi. Strong and prolonged activation of this epithelial immune response is able to elicit different responses including inflammation-like states and structural changes that are reminiscent to those observed in chronic inflammatory diseases of the human lung such as asthma or COPD (Chronic Obstructive Pulmonary Disease). The simplicity of the fly’s airway system makes it to a credible candidate to examine the mechanisms underlying these inflammatory diseases. Patient suffering from Asthma bronchiale or COPD often experience hypoxia and/or hypercap-nia. The current study demonstrates that hypoxia can mount an immune response in the airway epithelium of the fruit fly, as shown by the induced expression of antimicrobial peptide genes. This response is triggered without any contact to pathogens or pathogen associated molecular patterns (PAMPs). Instead, this hypoxia-induced immune response depends on the transcription factor dFoxO. Translocation of dFoxO into the nuclei of airway epithelial cells precedes the expression of antimicrobial peptides under control of this transcription factor. Apparently, dFoxO mediates a danger-like response of the airway epithelium to this stressor. In addition, I could show using microarray analyses, that dFoxO is not only necessary for the hypoxia induced immune activation, but also for a great variety of other hypoxia-induced tran-scriptomic responses. Comparing the transcriptomes between wild-type airway epithelia and those of animals lacking functional dFoxO revealed only a marginal overlap in the cohorts of genes regulated following hypoxia. Taken together, I have shown that dFoxO plays a much larger role for hypoxia-induced gene regulation than it has previously been thought. In addition, I identified another dFoxO dependent process that is related to hypoxia-induced responses. Following hypoxia, the airways show structural changes including building of new terminal branches. To enable this, the matrix metalloproteinase MMP-1 is required to degrade the extra-cellular matrix around these structures. Expression of mmp1 is induced following infection, but also following other stressors such as hypoxia. On the other hand, overexpression of mmp1 in airway epithelia induces an immune response. Thus, MMP-1 apparently is part of a positive feedback loop leading to a prolonged and more severe immune response in the airway epithe-lium following an infection. Both, ectopic activation of the innate immune pathway IMD or of dFoxO are sufficient to induce mmp1 expression. Epistatic analyses revealed that both res-ponses critically depend on the presence of dFoxO, which in turn appears to be activated via the JNK-pathway. The current study reveals that hypoxia induces a great number of unexpected responses in the airway epithelium that are mainly transduced via activation of dFoxO. These results are medi-cally relevant because hypoxia is frequently experienced in different inflammatory diseases of the airways (e.g. Asthma and COPD). Apparently, dFoxO is, in addition to HIFs, a novel key molecule in the oxygen homeostasis, thus opening a new area for research in this field. PI Kiel ER