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Pulmonary Emphysema: Novel Neutrophil Elastase Isoform Discovered – Possible Significance for Disease Process and Therapy Failure
Elastases of white blood cells are involved in tissue destruction and can thus cause various diseases. Scientists from the Helmholtz Zentrum München have discovered a new isoform which could be involved both in the pathogenesis of diseases such as pulmonary emphysema as well as in the failure of some therapy approaches. The results of the study have just been published in the journal Nature Communications.
A delicate balance of elastases and elastase inhibitors provides for regular tissue formation and destruction in the body. A perturbation of this balance can lead to excess elastase activity – and as a consequence, increased tissue damage. This is also the case in pulmonary emphysema: Here elastases are no longer sufficiently inactivated, and the lung tissue is destroyed.
Cleaved neutrophil elastase "aggressive and resistant“
The research team of Dr. Therese Dau, Dr. Ali Önder Yildirim and PD Dr. Dieter Jenne of the Comprehensive Pneumology Center (CPC) at Helmholtz Zentrum München has now discovered a novel elastase isoform and has studied its properties. The elastase produced by neutrophil granulocytes (the largest group of white blood cells) may be present in a cleaved (two-chain) state. It also leads to tissue damage; at the same time it appears to react less to inhibitors.
"Our results show that the cleaved elastase is particularly aggressive and resistant," said study leader Jenne. "That is why we suspect that it contributes to the development of pulmonary emphysema – especially when an inhibitor deficiency is present as a cause of disease, such as in congenital alpha-1-antitrypsin deficiency.
Basis for improved drugs
Elastase inhibitors have long been claimed as a useful therapeutic approach to neutralize the excess elastase in pulmonary emphysema, but their results did not meet expectations. "The reduced effect of inhibitors on cleaved elastase explains why some inhibitors remain ineffective," said lead author Dau. "Based on our studies, however, new inhibitory substances may be developed in the future that are effective against different elastase isoforms and thus achieve better efficiency."
Dau, T. et al. (2015): Auto-processing of neutrophil elastase near its active site reduces the efficiency of natural and synthetic elastase inhibitors, Nature communications. doi: 10.1038/ncomms7722
Link to publication: http://www.nature.com/ncomms/2015/150410/ncomms7722/full/ncomms7722.html
This work was also supported by European Union Seventh Framework Programme (FP7/2007–2013) under Grant Agreement 261382 (INTRICATE).
As German Research Center for Environmental Health Helmholtz Zentrum München pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes mellitus and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München has about 2,300 staff members and is headquartered in Neuherberg in the north of Munich. Helmholtz Zentrum München is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members.
The Comprehensive Pneumoloy Center (CPC) is a joint research project of the Helmholtz Zentrum München, the Ludwig-Maximilians-Universität Clinic Complex and the Asklepios Fachkliniken München-Gauting. The CPC's objective is to conduct research on chronic lung diseases in order to develop new diagnosis and therapy strategies. The CPC maintains a focus on experimental pneumology with the investigation of cellular, molecular and immunological mechanisms involved in lung diseases. The CPC is a site of the Deutsches Zentrum für Lungenforschung (DZL).
The German Center for Lung Research (DZL) pools German expertise in the field of pulmonology research and clinical pulmonology. The association’s head office is in Giessen. The aim of the DZL is to find answers to open questions in research into lung diseases by adopting an innovative, integrated approach and thus to make a sizeable contribution to improving the prevention, diagnosis and individualized treatment of lung disease and to ensure optimum patient care. www.dzl.de
Contact for Media
Communication Department, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, 85764 Neuherberg - Tel.: 089-3187-2238 - Fax: 089-3187-3324 - e-mail
PD Dr. Dieter Jenne, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Comprehensive Pneumoloy Center, Ingolstädter Landstr. 1, 85764 Neuherberg - Tel.: 089-3187-4664 - e-mail