The Spanish flu outbreak of 1918 killed between 30 and 50 million people. In the infected patients, the ultimate cause of death was acute respiratory distress syndrome (ARDS). This fatal condition is a massive reaction of the body during which the lung becomes severely damaged. ARDS can be induced by various bacterial and viral infections, but also by chemical agents. These could be toxic gases that are inhaled or gastric acid when aspirated. Once ARDS has developed, survival rates drop dramatically. Among patients infected with H5N1 bird flu, about 50 percent die of ARDS.
An international team of scientists has been addressing the underlying disease mechanisms for the past five years. The team involved researchers from leading institutions in Vienna, Stockholm, Cologne, Beijing, Hongkong, and Toronto as well as the US-army at Fort Detrick. The international effort was coordinated by Josef Penninger and Yumiko Imai of the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences.
A first breakthrough came in 2005 when IMBA-scientists identified ACE2 as the essential receptor for SARS virus infections and showed that ACE2 can protect from acute lung failure in disease models (Imai et al. Nature 2005; Kuba et al. Nature Medicine 2005). Based on these data, ACE2 is now under therapeutic development.
In a paper published by Cell this week, the authors describe an essential key injury pathway that is operational in multiple lung injuries and directly links oxidative stress to innate immunity. They also report for the first time a common molecular disease pathway explaining how diverse non-infectious and infectious agents such as anthrax, lung plague, SARS, and H5N1 avian influenza may cause severe and often lethal lung failure with similar pathologies.
To identify these pathways, the researchers studied numerous tissue samples from deceased humans and animals. Victims of bird flu and SARS were examined in Hongkong, and the US-army provided samples from animals infected with Anthrax and lung plague. Common to all ARDS samples was the massive amount of oxidation products found within the cells. Based on these findings, the scientists showed that oxidative stress is the common trigger that ultimately leads to lung failure.
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 body’s 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 body’s 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 Penninger’s 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.“
Dr. Heidemarie Hurtl | EurekAlert!
Turning carbon dioxide into liquid fuel
06.08.2020 | DOE/Argonne National Laboratory
Tellurium makes the difference
06.08.2020 | Friedrich-Schiller-Universität Jena
Scientists at the Fraunhofer Institute for Laser Technology ILT have come up with a striking new addition to contact stamping technologies in the ERDF research project ScanCut. In collaboration with industry partners from North Rhine-Westphalia, the Aachen-based team of researchers developed a hybrid manufacturing process for the laser cutting of thin-walled metal strips. This new process makes it possible to fabricate even the tiniest details of contact parts in an eco-friendly, high-precision and efficient manner.
Plug connectors are tiny and, at first glance, unremarkable – yet modern vehicles would be unable to function without them. Several thousand plug connectors...
An international research team has found a new approach that may be able to reduce bone loss in osteoporosis and maintain bone health.
Osteoporosis is the most common age-related bone disease which affects hundreds of millions of individuals worldwide. It is estimated that one in three women...
Traditional single-cell sequencing methods help to reveal insights about cellular differences and functions - but they do this with static snapshots only...
“Core-shell” clusters pave the way for new efficient nanomaterials that make catalysts, magnetic and laser sensors or measuring devices for detecting electromagnetic radiation more efficient.
Whether in innovative high-tech materials, more powerful computer chips, pharmaceuticals or in the field of renewable energies, nanoparticles – smallest...
An international research team with Prof. Cornelia Denz from the Institute of Applied Physics at the University of Münster develop for the first time light fields using caustics that do not change during propagation. With the new method, the physicists cleverly exploit light structures that can be seen in rainbows or when light is transmitted through drinking glasses.
Modern applications as high resolution microsopy or micro- or nanoscale material processing require customized laser beams that do not change during...
23.07.2020 | Event News
21.07.2020 | Event News
07.07.2020 | Event News
06.08.2020 | Earth Sciences
06.08.2020 | Power and Electrical Engineering
06.08.2020 | Life Sciences