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Keeping chemokines apart

New approach helps to alleviate acute lung injury

Munich, 01/18/2012

Acute lung injury results from bacterial infections, sepsis – commonly known as blood poisoning – or to the aspiration of gastric juice. Other noxious agents may also induce or contribute to acute lung injury, and in about 40% of cases the condition is fatal, despite modern advances in intensive care medicine. In a newly published study, a team of researchers led by LMU clinician Privatdozent Dr. Dr. Oliver Soehnlein identifies an innovative and promising strategy, which may provide an effective means of treating this life-threatening syndrome. In various animal models, the team was able to specifically block the action of signal molecules that attract a class of immune cells called neutrophilic granulocytes to sites of acute lung injury. Recruitment leads to infiltration of granulocytes into the lung in large numbers, a process of crucial importance in the acute lung failure.“If the recruitment process is abrogated, the resulting injury to the lung is much less severe,” says Soehnlein. “We now hope to test whether or not this molecular mechanism also plays a role in prominent inflammatory reactions such as those that contribute to atherosclerosis and chronic obstructive pulmonary disease.” (American Journal of Respiratory and Critical Care Medicine online, 12.January 2012)

Results obtained in earlier studies had suggested that blood platelets are important for the recruitment of granulocytes. It was also known that interference with platelet activation also reduces the extent of infiltration of granulocytes into the lungs. “We wanted to determine exactly how platelets act to recruit granulocytes and whether the mechanisms responsible might be accessible to therapeutic interventions,” says Soehnlein.

The experiments reported in the new work showed that recruitment is controlled by signal molecules known as chemokines that are released by activated platelets. The secreted chemokines CCL5 and CXCL4 interact to form complexes consisting of one of each type of molecule. Indeed, the researchers were able to detect the presence of such CCL5-CXCL4 “heterodimers” in the inflamed lungs of mice, as well as in specimens from patients with acute lung injury. They then asked if inhibiting the assembly of such heterodimers had any therapeutic effect on the progression of the condition, and used a specific antagonist to prevent the chemokines from forming the characteristic couples.

“With the help of these inhibitory agents, we were able to reduce the level of recruitment of granulocytes in our model system, and observed that this also markedly alleviated the subsequent damage to the lung,” says Soehnlein. “This provides a promising therapeutic strategy, based on a known molecular mechanism. In future studies, we intend to test whether a similar mechanism plays a role in the recruitment of granulocytes in the inflammatory responses in atherosclerosis or chronic obstructive pulmonary disease.”(suwe)

Disruption of Platelet-derived Chemokine Heteromers Prevents Neutrophil Extravasation in Acute Lung Injury
Jochen Grommes, Jean-Eric Alard, Maik Drechsler, Sarawuth Wantha, Matthias Mörgelin, Wolfgang M Kuebler, Michael Jacobs, Philipp von Hundelshausen, Philipp Markart, Malgorzata Wygrecka, Klaus T Preissner, Tilman M Hackeng, Rory R Koenen, Christian Weber, and Oliver Soehnlein
American Journal of Respiratory and Critical Care Medicine online, 12.January 2012

Privatdozent Dr. Dr. Oliver Soehnlein
Institute for Prophylaxis and Epidemiology of Cardiovascular Diseases (IPEK)
LMU Munich University Hospital
Phone: 089 / 5160-4673


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