Polysulfated Hyaluronan GlycoMira-1111 Inhibits Elastase and Improves Rheology in Cystic Fibrosis Sputum

Kummarapurugu, Apparao B.; Zheng, Shuo; Pulsipher, Abigail; Savage, Justin R.; Ma, Jonathan; Rubin, Bruce K.; Kennedy, Thomas P.; Voynow, Judith A.

doi:10.1165/rcmb.2020-0157oc

Cited by 2 publications

(2 citation statements)

References 32 publications

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“…In one doubleblind, placebo-controlled pilot study, inhalation of unfractionated heparin as a therapeutic for COPD resulted in improved lung function, underscoring the significant promise of GAG therapy for chronic lung diseases [144]. Polysulfated GAGs, including 2-O, 3-O desulfated heparin (ODSH) [145], a polysulfated hyaluronan (GM-1111) [146], and non-saccharide glycosaminoglycan mimetic (NSGM) (G32) [147], are potent anti-elastase drugs that have minimal anticoagulant activity and, therefore, may be advantageous for chronic inhalation. We have demonstrated by in silico modeling and Michealis-Menten kinetics that ODSH functions by an allosteric mechanism, binding to basic amino acid residues outside the NE catalytic domain [145] and competing with sputum DNA for access to that site.…”

Section: Ne Inhibitors and Mechanisms Of Actionmentioning

confidence: 99%

Neutrophil Elastase and Chronic Lung Disease

Voynow

Shinbashi

2021

Biomolecules

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Neutrophil elastase (NE) is a major inflammatory protease released by neutrophils and is present in the airways of patients with cystic fibrosis (CF), chronic obstructive pulmonary disease, non-CF bronchiectasis, and bronchopulmonary dysplasia. Although NE facilitates leukocyte transmigration to the site of infection and is required for clearance of Gram-negative bacteria, it also activates inflammation when released into the airway milieu in chronic inflammatory airway diseases. NE exposure induces airway remodeling with increased mucin expression and secretion and impaired ciliary motility. NE interrupts epithelial repair by promoting cellular apoptosis and senescence and it activates inflammation directly by increasing cytokine expression and release, and indirectly by triggering extracellular trap release and exosome release, which magnify protease activity and inflammation in the airway. NE inhibits innate immune function by digesting opsonins and opsonin receptors, degrading innate immune proteins such as lactoferrin, and inhibiting macrophage phagocytosis. Importantly, NE-directed therapies have not yet been effective in preventing the pathologic sequelae of NE exposure, but new therapies are being developed that offer both direct antiprotease activity and multifunctional anti-inflammatory properties.

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Section: Ne Inhibitors and Mechanisms Of Actionmentioning

confidence: 99%

Neutrophil Elastase and Chronic Lung Disease

Voynow

Shinbashi

2021

Biomolecules

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“…Processing of sputum samples for DNase-1 treatment, followed by measuring NE activity, was performed as described previously ( 49 ). Briefly, frozen sputum samples from CF subjects were thawed on ice, weighed, and mixed with NS alone or NS-containing DNase-1 (0.3 mg/ml) at the ratio of 1:1 (w: v).…”

Section: Methodsmentioning

confidence: 99%