Targeting glycosaminoglycans in the lung by an engineered CXCL8 as a novel therapeutic approach to lung inflammation

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 40µg/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.