Dr. Dominik Hartl, who was recently appointed professor at the University Children’s Hospital in Tübingen, particularly focuses on the cellular processes associated with airway inflammation in cystic fibrosis. His research results will be featured as the cover story in Nature Medicine in September 2010.
Inflammation plays a primary role in the pathogenesis of cystic fibrosis: neutrophils accumulate in the diseased lung tissue and, when activated, release DNA fibres decorated with antimicrobial proteins, forming neutrophil extracellular traps. In their study involving cystic fibrosis animal models, to be published as the cover story in Nature Medicine in September 2010, the scientists showed that blocking a specific receptor results in reduced trap formation and improved lung function. Although neutrophils are bactericidal and normally contribute to innate host defence, the new study has now linked neutrophils to the pathogenesis of cystic fibrosis. However, the mechanisms that regulate the action of neutrophils, in particular during inflammation, are still poorly understood. The DFG-funded Emmy Noether research group led by Prof. Hartl at the University Hospital in Tübingen has now for the first time ever been able to show that the neutrophils found in the airway fluids of cystic fibrosis patients form neutrophil extracellular traps (NETs), which affect the airways and reduce their respiratory function. The research group led by Prof. Hartl discovered that the mechanism regulating NET formation is mediated by the G-protein coupled receptor CXCR2. Since G-protein coupled receptors are ideal pharmacological target structures, the researchers carried out therapeutic studies with a cystic fibrosis mouse model. These studies showed that the intra-airway delivery of small-molecule antagonists blocked the CXCR2 receptor and led to the inhibition of NET formation as well as improved lung function in vivo. Hartl and his colleagues envisage that the results will help them to develop new treatment strategies to prolong the median survival rate of cystic fibrosis patients, which is currently between 37 and 40 years of age.The research relating to the blockage of the CXCR2 receptor to improve lung function in vivo was carried out in close interdisciplinary cooperation with paediatricians, pulmonologists, microbiologists and immunologists. In addition to Prof. Hartl’s group, the study also involved Prof. Marcus Mall from the University Hospital Heidelberg, Prof. Gerd Döring from the Department of Microbiology at the University of Tübingen and researchers from the Helmholtz Zentrum München, the University of Amsterdam and the University of Salzburg.
Title of original publicationCXCR2 mediates NADPH oxidase-independent neutrophil extracellular trap formation in cystic fibrosis airway inflammation. Marcos V, Zhou Z, Yildirim A, Bohla A, Hector A,Vitkov L, Wiedenbauer EM, Krautgartner W, Stoiber W, Belohradsky BH, Rieber N, Kormann M, Koller B, Roscher A, Roos D, Griese M, Eickelberg O, Döring G, Mall MA and Hartl D. Nature Medicine, published online 5 September 2010 (doi:10.1038/nm.2209)
Further information:University Hospital TübingenProf. Dr. med. Dominik HartlDFG-funded Emmy Noether GroupProfessor of Paediatric Infectiology and ImmunologyChildren's Hospital, Department I and Interdisciplinary Centre for Infection Medicine Tübingen (IZIT)Hoppe-Seyler-Str. 1, 72076 TübingenE-mail: dominik.hartl[at]med.uni-tuebingen.deTel.: +49 (0)7071/29-8 71 99