title: The role of heparanase in pulmonary cell recruitment in response to an allergic but not non-allergic stimulus.
abstract: Heparanase is an endo-β-glucuronidase that specifically cleaves heparan sulfate proteoglycans in the extracellular matrix. Expression of this enzyme is increased in several pathological conditions including inflammation. We have investigated the role of heparanase in pulmonary inflammation in the context of allergic and non-allergic pulmonary cell recruitment using heparanase knockout (Hpa-/-) mice as a model. Following local delivery of LPS or zymosan, no significant difference was found in the recruitment of neutrophils to the lung between Hpa-/- and wild type (WT) control. Similarly neutrophil recruitment was not inhibited in WT mice treated with a heparanase inhibitor. However, in allergic inflammatory models, Hpa-/- mice displayed a significantly reduced eosinophil (but not neutrophil) recruitment to the airways and this was also associated with a reduction in allergen-induced bronchial hyperresponsiveness, indicating that heparanase expression is associated with allergic reactions. This was further demonstrated by pharmacological treatment with a heparanase inhibitor in the WT allergic mice. Examination of lung specimens from patients with different severity of chronic obstructive pulmonary disease (COPD) found increased heparanase expression. Thus, it is established that heparanase contributes to allergen-induced eosinophil recruitment to the lung and could provide a novel therapeutic target for the development of anti-inflammatory drugs for the treatment of asthma and other allergic diseases.
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, United Kingdom.
authors.forename: Abigail
authors.initials: A
authors.lastname: Morris
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, Uppsala, Sweden.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Box 7011, Uppsala, Sweden.
authors.forename: Ida
authors.initials: I
authors.lastname: Waern
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, United Kingdom.
authors.forename: Radhakrishnan
authors.initials: R
authors.lastname: Venkatasamy
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, United Kingdom.
authors.forename: Clive
authors.initials: C
authors.lastname: Page
authors.affiliation: Program in Translational Lung Research, University of Colorado School of Medicine, Aurora, CO, United States of America.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Schmidt
authors.affiliation: Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Box 7011, Uppsala, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Wernersson
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, Uppsala, Sweden.
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Li
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, United Kingdom.
authors.forename: Domenico
authors.initials: D
authors.lastname: Spina
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D017353:Gene Deletion; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D006967:Hypersensitivity / Q000201:enzymology* / Q000473:pathology*; D007114:Immunization; D007249:Inflammation / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D010047:Ovalbumin; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology / Q000473:pathology; D012129:Respiratory Function Tests; D000099175:Heparanase
chemical_list: D004791:Enzyme Inhibitors; D005966:Glucuronidase; D010047:Ovalbumin; D000099175:Heparanase