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.