title: Extracellular superoxide dismutase protects against matrix degradation of heparan sulfate in the lung.
abstract: Asbestosis is a form of interstitial lung disease caused by the inhalation of asbestos fibers, leading to inflammation and pulmonary fibrosis. Inflammation and oxidant/antioxidant imbalances are known to contribute to the disease pathogenesis. Extracellular superoxide dismutase (EC-SOD) is an antioxidant enzyme that has been shown to protect the lung from oxidant-mediated damage, inflammation, and interstitial fibrosis. Extracellular matrix (ECM) components, such as collagen and glycosaminoglycans, are known to be sensitive to oxidative fragmentation. Heparan sulfate, a glycosaminoglycan, is highly abundant in the ECM and tightly binds EC-SOD. We investigated the protective role of EC-SOD by evaluating the interaction of EC-SOD with heparan sulfate in the presence of reactive oxygen species (ROS). We found that ROS-induced heparin and heparan sulfate fragments induced neutrophil chemotaxis across a modified Boyden chamber, which was inhibited by the presence of EC-SOD by scavenging oxygen radicals. Chemotaxis in response to oxidatively fragmented heparin was mediated by Toll-like receptor-4. In vivo, bronchoalveolar lavage fluid from EC-SOD knockout mice at 1, 14, and 28 days after asbestos exposure showed increased heparan sulfate shedding from the lung parenchyma. We demonstrate that one mechanism through which EC-SOD inhibits lung inflammation and fibrosis in asbestosis is by protecting heparin/heparan sulfate from oxidative fragmentation.
authors.affiliation: Department of Cellular & Molecular Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Corrine R
authors.initials: CR
authors.lastname: Kliment
authors.forename: Jake M
authors.initials: JM
authors.lastname: Tobolewski
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Manni
authors.forename: Roderick J
authors.initials: RJ
authors.lastname: Tan
authors.forename: Jan
authors.initials: J
authors.lastname: Enghild
authors.forename: Tim D
authors.initials: TD
authors.lastname: Oury
mesh_terms: D000818:Animals; D001195:Asbestosis / Q000517:prevention & control; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000502:physiology*; D006493:Heparin / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D011658:Pulmonary Fibrosis / Q000517:prevention & control; D013482:Superoxide Dismutase / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism
chemical_list: D006493:Heparin; D006497:Heparan Sulfate; D013482:Superoxide Dismutase; D013481:Superoxides