title: 2-O, 3-O-desulfated heparin inhibits neutrophil elastase-induced HMGB-1 secretion and airway inflammation.
abstract: Neutrophil elastase (NE) is a major inflammatory mediator in cystic fibrosis (CF) that is a robust predictor of lung disease progression. NE directly causes airway injury via protease activity, and propagates persistent neutrophilic inflammation by up-regulation of neutrophil chemokine expression. Despite its key role in the pathogenesis of CF lung disease, there are currently no effective antiprotease therapies available to patients with CF. Although heparin is an effective antiprotease and anti-inflammatory agent, its anticoagulant activity prohibits its use in CF, due to risk of pulmonary hemorrhage. In this report, we demonstrate the efficacy of a 2-O, 3-O-desulfated heparin (ODSH), a modified heparin with minimal anticoagulant activity, to inhibit NE activity and to block NE-induced airway inflammation. Using an established murine model of intratracheal NE-induced airway inflammation, we tested the efficacy of intratracheal ODSH to block NE-generated neutrophil chemoattractants and NE-triggered airway neutrophilic inflammation. ODSH inhibited NE-induced keratinocyte-derived chemoattractant and high-mobility group box 1 release in bronchoalveolar lavage. ODSH also blocked NE-stimulated high-mobility group box 1 release from murine macrophages in vitro, and inhibited NE activity in functional assays consistent with prior reports of antiprotease activity. In summary, this report suggests that ODSH is a promising antiprotease and anti-inflammatory agent that may be useful as an airway therapy in CF.
authors: 1 Department of Pediatrics, Duke University Medical Center.
authors: Kathryn L
authors: KL
authors: Griffin
authors: Bernard M
authors: BM
authors: Fischer
authors: Apparao B
authors: AB
authors: Kummarapurugu
authors: Shuo
authors: S
authors: Zheng
authors: Thomas P
authors: TP
authors: Kennedy
authors: Narayanam V
authors: NV
authors: Rao
authors: W Michael
authors: WM
authors: Foster
authors: Judith A
authors: JA
authors: Voynow
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D002633:Chemotaxis / Q000187:drug effects; D004195:Disease Models, Animal; D024243:HMGB1 Protein / Q000378:metabolism*; D006493:Heparin / Q000031:analogs & derivatives* / Q000494:pharmacology; D018793:Interleukin-13; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration / Q000187:drug effects; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011480:Protease Inhibitors / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D018793:Interleukin-13; D011480:Protease Inhibitors; C410523:heparin, O-desulfated; D006493:Heparin; D019272:Leukocyte Elastase