title: Targeting glycosaminoglycans in the lung by an engineered CXCL8 as a novel therapeutic approach to lung inflammation.
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.
authors.affiliation: ProtAffin Biotechnologie AG, Graz, Austria.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Adage
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Konya
authors.affiliation: ProtAffin Biotechnologie AG, Graz, Austria.
authors.forename: Corinna
authors.initials: C
authors.lastname: Weber
authors.affiliation: ProtAffin Biotechnologie AG, Graz, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Strutzmann
authors.affiliation: ProtAffin Biotechnologie AG, Graz, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fuchs
authors.affiliation: ProtAffin Biotechnologie AG, Graz, Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Zankl
authors.affiliation: ProtAffin Biotechnologie AG, Graz, Austria.
authors.forename: Tanja
authors.initials: T
authors.lastname: Gerlza
authors.affiliation: ProtAffin Biotechnologie AG, Graz, Austria.
authors.forename: Dalibor
authors.initials: D
authors.lastname: Jeremic
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: Akos
authors.initials: A
authors.lastname: Heinemann
authors.affiliation: ProtAffin Biotechnologie AG, Graz, Austria; Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria. Electronic address: andreas.kungl@uni-graz.at.
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Kungl
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006025:Glycosaminoglycans / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D055806:Microvessels / Q000166:cytology; D058990:Molecular Targeted Therapy / Q000379:methods*; D020556:Neutrophil Infiltration / Q000187:drug effects; D011014:Pneumonia / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015202:Protein Engineering; D012906:Smoke / Q000009:adverse effects; D053671:Syndecan-4 / Q000235:genetics
chemical_list: D015415:Biomarkers; D006025:Glycosaminoglycans; D016209:Interleukin-8; D008070:Lipopolysaccharides; D012906:Smoke; D053671:Syndecan-4
keywords: Chemokine; Dexamethasone phosphate disodium salt (CID: 16061); Glycosaminoglycan; Heparan sulfate; Inflammation; Neutrophils; Protein engineering; Roflumilast (CID: 449193); SCH527123 (CID: 9865554)