Antioxidants: Friends or foes?

In SIRS (short for Systemic Inflammatory Response Syndrome), there is a severe inflammatory response throughout the body. It can be triggered by burns, severe bleeding, or major organ damage. Patients with SIRS are at risk of multiple organ failure, the mechanisms of which are still not fully understood. For this reason, only symptomatic treatment has been available for these patients until now. Recently, scientists from the LBI Trauma at the AUVA Trauma Centre Lorenz Böhler were able to decipher an important biological mechanism. This knowledge now opens up ways to new treatment options.

At the cellular level, there are two basic mechanisms that can lead to organ failure: The first is tremendous cell death in the organs so that they can no longer fulfil their function. The second is a dysfunction of the cell, leading to the accumulation of living but non-functional cells. Remarkable cell loss has not been found even in severe cases of SIRS. This suggests that multi-organ failure caused by SIRS is due to damage to cell function.

At this point, researchers’ attention was drawn to mitochondria. Mitochondria convert biomolecules and oxygen into energy, carbon dioxide and water – which is why they are called the power plants of the cell. Since mitochondria are very similar in all cell types, multi-organ failure could be explained by a common mechanism affecting mitochondria simultaneously in different organs. In order to better understand the influence of mitochondria and their functions, a group for molecular basics of organ failure was formed at the LBI in 2007 under the leadership of Doz Andrey Kozlov.

Despite all expectations, initial studies conducted at the LBI and later at other institutions worldwide have showed that SIRS is not necessarily associated with damage to mitochondrial function. In some cases, an improvement could even be observed. However, researchers have found that SIRS can alter the use of oxygen in mitochondria. Mitochondria use oxygen primarily to provide energy for the cell. However, a small amount of oxygen is used to produce so-called ROS (Reactive Oxygen Species). ROS are chemically highly reactive molecules that can rapidly oxidise and thus destroy many types of biomolecules. For this reason, mitochondrially produced ROS were long considered undesirable “by-products”. More recently, however, it has been shown that ROS also have important physiological functions, as they maintain a balance in the cell and are also involved in the transmission of signals.

The scientists at LBI Trauma first wondered whether the release of mitochondrial ROS could be critical for organ failure in SIRS. As a result of their studies, a new signalling pathway was discovered in the cell. This pathway, which they called the ROS-NOS cycle, is a vicious cycle in which, with the involvement of ROS, inflammatory responses become progressively worse. Targeted interruption of the ROS-NOS cycle through treatment with specific antioxidants actually prevents organ damage in a moderate form of SIRS. At that moment, the scientists thought they had found a therapeutic way to save SIRS patients from multi-organ failure.

However, further studies demonstrated that mitochondrial ROS not only trigger the damaging ROS-NOS cycle, but also activate an immune cell enzyme that is important for killing bacteria. Accordingly, antioxidant therapy influences two different processes: On the one hand the pathological pathway leading to organ damage and on the other hand the defence mechanisms involved in killing dangerous bacteria. If the second is more important for fighting bacterially triggered inflammatory reactions, treatment with antioxidants has negative consequences. In contrast, the use of antioxidants may be recommended when a bacterial cause of SIRS has been ruled out.

In a nutshell, antioxidant therapy should currently be avoided in patients with acute septic inflammation, while it is recommended for the treatment of SIRS without a bacterial trigger. So it comes back to what science – especially in Austria, and thus in a worldwide pioneering role – has been preaching for a long time: To distance ourselves from treatment depending on a set pattern and promote therapy tailored to the individual case.