Modifikation der Genexpression respiratorischen Epithels mittels Oligonukleotiden zur Entwicklung innovativer Behandlungsstrategien von entzündlichen Erkrankungen der Atemwege

The airway epithelium as part of the innate immune system is capable of recognising microbial agents and of inducing an inflammatory reaction. It was the aim of the present study to investigate the interaction of nucleic acids and airway epithelium. The study revealed that the application of antisense oligonucleotides and small interfering RNA (siRNA) directed against the p65 subunit of NF-kappa B modulated gene expression in airway epithelium and that inflammatory reactions can be modified that way. The uptake of nucleic acids depends on the transfection reagent and the differentiation status of the cells. A comparison between both approaches revealed that the inflammation in airway epithelium is inhibited more effectively by the application of siRNA than by antisense oligonucleotides. On the other hand nucleic acids are capable of inducing inflammatory reactions in airway epithelium. Investigation of the underlying mechanisms revealed that the system of the Toll-like receptors (TLR), especially TLR3 and TLR9 are responsible for these reactions. Consequently the airway epithelium is not only a passive barrier against microbial components, but actively participates in the induction of an inflammatory response. Recently gained new insights in the pathophysiology of inflammatory rections provided the basis for the development of new therapeutic approaches. The present study shows that the application of small nucleic acids represents a new therapeutic modality for inflammatory lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. The results also point out the limitations of this approach. The poor susceptibility of the airway epithelium respresents the major problem. The fact that small nucleic acids induce inflammatory reactions in airway epithelium makes clear that a careful selection of the sequence is critical for the therapeutic success.