کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2531536 1558933 2015 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Targeting glycosaminoglycans in the lung by an engineered CXCL8 as a novel therapeutic approach to lung inflammation
موضوعات مرتبط
علوم زیستی و بیوفناوری علم عصب شناسی علوم اعصاب سلولی و مولکولی
پیش نمایش صفحه اول مقاله
Targeting glycosaminoglycans in the lung by an engineered CXCL8 as a novel therapeutic approach to lung inflammation
چکیده انگلیسی
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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Pharmacology - Volume 748, 5 February 2015, Pages 83-92
نویسندگان
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