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Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Adage, T; Konya, V; Weber, C; Strutzmann, E; Fuchs, T; Zankl, C; Gerlza, T; Jeremic, D; Heinemann, A; Kungl, AJ.
Targeting glycosaminoglycans in the lung by an engineered CXCL8 as a novel therapeutic approach to lung inflammation.
Eur J Pharmacol. 2015; 748(10):83-92
Doi: 10.1016/j.ejphar.2014.12.019
Web of Science
PubMed
FullText
FullText_MUG
- Co-authors Med Uni Graz
- Fuchs Tamara
- Heinemann Akos
- Konya Viktoria
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- Abstract:
- It is broadly recognized that chemokine-activated neutrophils play a crucial role in the inflammation and disruption of lung tissue observed in several acute and chronic lung diseases. Since glycosaminoglycan side chains of proteoglycans act as chemokine co-receptors in inflammation, we have used a CXCL8-based dominant-negative mutant, dnCXCL8, to displace neutrophil-related chemokines in murine lungs using models of lung inflammation. Treatment with dnCXCL8 resulted in a dose-dependent reduction of neutrophil counts in bronchoalveolar lavage (BAL) of mice exposed to lipopolysaccharide after intravenous, subcutaneous and intratracheal administration. A strong and significant therapeutic effect was achieved already at a dose of 40 µg/kg of dnCXCL8. A similar dose response, but showing a broader spectrum of reduced inflammatory cells and soluble inflammatory markers, was observed in a murine model of tobacco smoke (TS)-induced lung inflammation. The broad spectrum of reduced inflammatory cells and markers can be due to the strong inhibition of neutrophil extravasation into the lung parenchyma, and/or to a relatively broad protein displacement profile of dnCXCL8 which may compete not only with wtCXCL8 for glycosaminoglycan-binding but possibly also with other related glycosaminoglycan-binding pro-inflammatory chemokines. Overall our results demonstrate that antagonizing CXCL8/glycosaminoglycan binding reduces lung inflammation as well as associated lung tissue damage due to LPS and TS and may therefore be a new therapeutic approach for lung pathologies characterized by a neutrophilic inflammatory phenotype. Copyright © 2014 Elsevier B.V. All rights reserved.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Biomarkers - metabolism
- Endothelial Cells - drug effects
- Endothelial Cells - metabolism
- Female -
- Gene Expression Regulation - drug effects
- Glycosaminoglycans - metabolism
- Humans -
- Interleukin-8 - genetics
- Interleukin-8 - metabolism
- Interleukin-8 - pharmacology
- Interleukin-8 - therapeutic use
- Lipopolysaccharides - pharmacology
- Lung - drug effects
- Lung - immunology
- Lung - metabolism
- Male -
- Mice -
- Microvessels - cytology
- Molecular Targeted Therapy - methods
- Neutrophil Infiltration - drug effects
- Pneumonia - drug therapy
- Pneumonia - genetics
- Pneumonia - immunology
- Pneumonia - metabolism
- Protein Engineering -
- Smoke - adverse effects
- Syndecan-4 - genetics
- Tobacco - chemistry
- Find related publications in this database (Keywords)
- Chemokine
- Inflammation
- Glycosaminoglycan
- Heparan sulfate
- Protein engineering
- Neutrophils