To elucidate the entire pathway, Yumiko Imai of IMBA developed several mouse models. She was now able to show that a molecule called TLR4 (Toll-like receptor 4) is responsible for initiating the critical signalling pathway. TLR4 is displayed at the surface of certain lung cells called macrophages, important players of the bodys immune system. Once activated, TLR4 initiates an entire chain reaction which ends with the fatal failure of the lungs. Surprisingly, mice challenged with inactivated H5N1 avian influenza virus also dveloped the full reaction. On the other hand, mutant mice in which the function of TLR4 was genetically impaired were protected from lung failure in repsonse to the inactivated virus.
Based on these findings, the researchers can now outline a common molecular disease pathway: Microbial or chemical lung pathogens trigger the oxidative stress machinery. Oxidation products are intrepreted as danger-signals by the receptor TLR4. Subsequently, the bodys innate immune system is activated. This defense machinery in turn leads to a chain of reactions with severe and often fatal lung damage as a consequence.
For Yumiko Imai, a Postdoc in Josef Penningers team and pediatrician by training, these results are highly satisfying. Her motivation to study ARDS is based on personal experience in over 10 years at a pediatric intensive care unit. I have seen so many children die from acute lung failure and felt utterly helpless, Imai says. Since we found a common injury pathway, our hopes are high that we may be able to develop a new and innovative strategy for tackling severe lung infections.
|Contact: Dr. Heidemarie Hurtl|
Research Institute of Molecular Pathology