Researchers from the Max Planck Institute for Heart and Lung Research of Germany are working at IBioBA to understand the role of certain proteins in pulmonary hypertension and lung infection.

In 2007 the group directed by Eduardo Arzt, researcher of CONICET and Director of the Biomedicine Research Institute of Buenos Aires (IBioBA, CONICET – Partner Institute of the Max Planck Society) discovered and characterized the RSUME protein. Over time, this protein proved to be an important component in hypoxia-signaling and inflammation in several publications.

Now, Werner Seeger, leading the Max Planck Department for Lung Development and Remodeling in Bad Nauheim/Giessen, Germany, has established a collaborative guest lab at IBioBA. Here, Mareike Gierhardt and Balachandar Selvakumar are working to investigate the role RSUME plays in Pulmonary Hypertension (PH) and Acute lung injury/acute Respiratory Distress Syndrome (ARDS), respectively.

If no underlying disease can be identified and treated, PH can’t be cured and leads to right-heart failure and death. ARDS significantly damages the lung’s tissues and lacks a satisfactory therapy, 26 – 58 % of patients with diagnosed ARDS die.

For five years Gierhardt will study at the Max Planck Guest Laboratory of IBioBA how reduced oxygen levels (hypoxia), which are occurring for example due to exposition to high altitude, lead to PH, while Selvakumar will analyze and investigate how infection (by virus) damages the lung tissue and how to treat the damaged lungs.

For this, special equipment and facilities have been installed at the laboratory, such as a high end cell sorter and a complete state-of-the-art physiology and molecular biology laboratory including echocardiography and heart catheterization.

What is Pulmonary Hypertension (PH)?

The body has two circulations. The systemic one carries oxygenated blood from the left ventricle of the heart to the body, where the oxygen is consumed by the organs. The pulmonary circulation carries deoxygenated blood from the right ventricle through the lungs where it gets re-oxygenated for again distributing oxygen to the body via the systemic circulation. “Many people suffer for systemic hypertension, which is a common and treatable disease, but pulmonary arterial hypertension is rare, non-curable and deadly”, says Gierhardt.

Different etiologies are discovered to induce pulmonary hypertension. Exposure to high altitude with reduced atmospheric oxygen (hypoxia) is one of many. Research has shown that various triggers like hypoxia and inflammation contribute to the vessel changes, which include increased wall thickness, narrowed vessel lumen and higher rigidity.

“Imagine that the heart has to pump the same volume of blood through these remodeled, stiffer vessels. This will generate a higher pressure in the pulmonary circulation, medically termed pulmonary hypertension, and the heart has to pump against it. The right ventricle will gain more and more muscular mass, until finally the compensatory mechanisms are depleted. In most cases the patients die because the right heart is not able to pump against this pressure anymore and fails”, she explains.

Due to intensive research in this field now available drug treatments are able to prolong the lifespan and to improve life-quality of the patients. But even after a heart and lung transplantation (as ultima ratio), the 5-years survival rate is only 45 – 50 %.

In the search for a treatment for this multi-faced disease, Gierhardt decided to study at IBioBA on the potential role of RSUME. “There is evidence that this protein is interfering in PH pathophysiology. RSUME is involved in the regulation of two key-proteins of PH, Hypoxia-inducible factor 1 (HIF1) and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells)”, explains Gierhardt. For both, HIF1 and NF-κB, it has already been shown that they contribute to changes in cellular signaling under hypoxia.

What is Acute Respiratory Distress Syndrome (ARDS)?

It is a rapidly progressive disease where liquid leaks inside the lung’s alveoli. The gas exchange between blood and air is impaired or even impossible, medically termed as Respiratory Failure. ARDS is a consequence of severe acute lung injury lesions. Currently there is no treatment, except supporting patients with artificial ventilation while the patient’s lungs heal, or as ultima ratio Extracorporeal Membrane Oxygenation (ECMO), an artificial supply of oxygen to the blood. According to the American Lung Association, even with the best medical care 30 up to 50 % mortality has been observed in the patients with diagnosed ARDS.

“I’m working on acute lung injury as a model for ARDS, which can be caused by different reasons, the most important is infection-induced by either bacteria or virus”, says Selvakumar.
And he adds: “In this disease the injuries are caused by inflammation, involving various numbers of cells derived from the bone marrow, like macrophages, and molecules that are secreted and released by those cells. Therefore, I am interested in RSUME, which is modulating inflammation -and this is exactly what we are trying to understand in detail”.

And he adds: “We already have identified promising molecules in the model of acute lung injury, and we hope from this we can develop a suitable treatment for patients with ARDS”.
Alongside the teams working with RSUME at IBioBA, they established models to study these pathologies and analyze how these mediators of inflammation act during lung injuries.

You can find this story published in the website of the National Scientific and Technical Research Council (CONICET) (in Spanish)