Neutrophil elastase (NE) is a major
protease in the airways of patients with
cystic fibrosis (CF) that activates airway
inflammation by several mechanisms. NE stimulates epithelial
toll like receptors (TLR) resulting in
cytokine upregulation and release, upregulates MUC5AC, a major airway
mucin, degrades both phagocytic receptors and
opsonins resulting in both neutrophil and macrophage phagocytic failure, generates oxidative stress via extracellular generation and uptake of
heme free
iron, and activates other
proteases. Altogether, these mechanisms create a significant inflammatory challenge that impairs innate immune function and results in
airway remodeling. Currently, a major gap in our therapeutic approach to CF
lung disease is the lack of an effective therapeutic strategy targeting active NE and its downstream pro-inflammatory sequelae. Polysulfated
glycosaminoglycans (GAGs) are potent anti-
elastase drugs that have additional anti-inflammatory properties.
Heparin is a prototype of a
glycosaminoglycan with both anti-
elastase and anti-inflammatory properties.
Heparin inhibits NE in an allosteric manner with high potency.
Heparin also inhibits
cathepsin G, blocks
P-selectin and
L-selectin, hinders
ligand binding to the
receptor for advanced glycation endproducts, and impedes
histone acetyltransferase activity which dampens
cytokine transcription and High Mobility Group Box 1 release. Furthermore, nebulized
heparin treatment improves outcomes for patients with
chronic obstructive pulmonary disease (
COPD),
asthma,
acute lung injury and
smoke inhalation. However, the
anticoagulant activity of
heparin is a potential
contraindication for this
therapy to be developed for CF
lung disease. Therefore, modified heparins and other GAGs are being developed that retain the anti-
elastase and anti-inflammatory qualities of
heparin with minimal to no
anticoagulant activity. The modified
heparin, 2-O, 3-O desulfated
heparin (ODSH), maintains anti-
elastase and anti-inflammatory activities in vitro and in vivo, and has little residual
anticoagulant activity.
Heparan sulfate with O-
sulfate residues but not N-
sulfate residues blocks allergic asthmatic
inflammation in a murine model. Polysulfated
hyaluronic acid abrogates
allergen- triggered
rhinosinusitis in a murine model. Finally, nonsaccharide
glycosaminoglycan mimetics with specific
sulfate modifications can be designed to inhibit NE activity. Altogether, these novel GAGs or GAG mimetics hold significant promise to address the unmet need for inhaled anti-
elastase and anti-inflammatory
therapy for patients with CF.