A Functional Variant of Elafin With Improved Anti-inflammatory Activity for Pulmonary Inflammation

Small, D.; Zani, M L; Quinn, Derek J.; Dallet‐Choisy, Sandrine; Glasgow, Arlene; O'Kane, Cecilia M; McAuley, Daniel F.; McNally, Paul; Weldon, Sinéad; Moreau, Thierry; Taggart, Clifford C.

doi:10.1038/mt.2014.162

Cited by 21 publications

(17 citation statements)

References 47 publications

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“…In that study, we found that a more NE-resistant variant of elafin (GG-elafin) could also significantly reduce neutrophil recruitment in a mouse model of LPS-induced lung inflammation compared with WT elafin. 30 However, in contrast to the current SLPI study, we found that GG-elafin did not reduce KC levels. This may be related to the fact that SLPI and elafin have different anti-inflammatory effects.…”

Section: Discussioncontrasting

confidence: 99%

A secretory leukocyte protease inhibitor variant with improved activity against lung infection

et al. 2016

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Secretory leukocyte protease inhibitor (SLPI) is an important respiratory tract host defense protein, which is proteolytically inactivated by excessive neutrophil elastase (NE) during chronic Pseudomonas infection in the cystic fibrosis (CF) lung. We generated two putative NE-resistant variants of SLPI by site-directed mutagenesis, SLPI-A16G and SLPI-S15G-A16G, with a view to improving SLPI's proteolytic stability. Both variants showed enhanced resistance to degradation in the presence of excess NE as well as CF patient sputum compared with SLPI-wild type (SLPI-WT). The ability of both variants to bind bacterial lipopolysaccharides and interact with nuclear factor-κB DNA binding sites was also preserved. Finally, we demonstrate increased anti-inflammatory activity of the SLPI-A16G protein compared with SLPI-WT in a murine model of pulmonary Pseudomonas infection. This study demonstrates the increased stability of these SLPI variants compared with SLPI-WT and their therapeutic potential as a putative anti-inflammatory treatment for CF lung disease.

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Section: Discussioncontrasting

confidence: 99%

A secretory leukocyte protease inhibitor variant with improved activity against lung infection

et al. 2016

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“…It was found that aerosolised administration of these recombinant antiproteases reduced the release of a variety of proteases, pro-inflammatory mediators, and in the case of recombinant hMNEI, enhanced bacterial clearance in murine models infected with P. aeruginosa [89][90][91][92]. Subsequent studies have also investigated the therapeutic potential of functional variants of the endogenous antiproteases, elafin and SLPI, and found that these variants retained their antiprotease properties, blunted the pro-inflammatory response to infection in the lung, and showcased an increased resistance to protease-mediated degradation [93,94].…”

Section: Antiprotease Therapiesmentioning

confidence: 99%

Alpha-1 Antitrypsin—A Target for MicroRNA-Based Therapeutic Development for Cystic Fibrosis

Hunt

Glasgow

Humphreys

et al. 2020

IJMS

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Cystic fibrosis (CF) is an autosomal recessive genetic disorder arising from mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Disruption to normal ion homeostasis in the airway results in impaired mucociliary clearance, leaving the lung more vulnerable to recurrent and chronic bacterial infections. The CF lung endures an excess of neutrophilic inflammation, and whilst neutrophil serine proteases are a crucial part of the innate host defence to infection, a surplus of neutrophil elastase (NE) is understood to create a net destructive effect. Alpha-1 antitrypsin (A1AT) is a key antiprotease in the control of NE protease activity but is ineffective in the CF lung due to the huge imbalance of NE levels. Therapeutic strategies to boost levels of protective antiproteases such as A1AT in the lung remain an attractive research strategy to limit the damage from excess protease activity. microRNAs are small non-coding RNA molecules that bind specific cognate sequences to inhibit expression of target mRNAs. The inhibition of miRNAs which target the SERPINA1 (A1AT-encoding gene) mRNA represents a novel therapeutic approach for CF inflammation. This could involve the delivery of antagomirs that bind and sequester the target miRNA, or target site blockers that bind miRNA recognition elements within the target mRNA to prevent miRNA interaction. Therefore, miRNA targeted therapies offer an alternative strategy to drive endogenous A1AT production and thus supplement the antiprotease shield of the CF lung.

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“…Proteolytic cleavage of elafin may have implications for its efficacy when being used as a therapeutic in vivo . Recent work has shown that mutating key residues at the NE cleavage site in elafin results in a peptide with similar antiprotease activity as the wild-type form but with significantly increased stability and anti-inflammatory activity [ 101 ]. When compared to wild-type, the mutant forms of elafin were shown to have improved LPS neutralizing activity in vitro and increased anti-inflammatory activity when employed in an acute model of pulmonary inflammation induced by P. aeruginosa LPS [ 101 ].…”

Section: Antiprotease Activity In Cfmentioning

confidence: 99%

The Role of Serine Proteases and Antiproteases in the Cystic Fibrosis Lung

Twigg

Brockbank

Lowry

et al. 2015

Mediators of Inflammation

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Cystic fibrosis (CF) lung disease is an inherited condition with an incidence rate of approximately 1 in 2500 new born babies. CF is characterized as chronic infection of the lung which leads to inflammation of the airway. Sputum from CF patients contains elevated levels of neutrophils and subsequently elevated levels of neutrophil serine proteases. In a healthy individual these proteases aid in the phagocytic process by degrading microbial peptides and are kept in homeostatic balance by cognate antiproteases. Due to the heavy neutrophil burden associated with CF the high concentration of neutrophil derived proteases overwhelms cognate antiproteases. The general effects of this protease/antiprotease imbalance are impaired mucus clearance, increased and self-perpetuating inflammation, and impaired immune responses and tissue. To restore this balance antiproteases have been suggested as potential therapeutics or therapeutic targets. As such a number of both endogenous and synthetic antiproteases have been trialed with mixed success as therapeutics for CF lung disease.

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A Functional Variant of Elafin With Improved Anti-inflammatory Activity for Pulmonary Inflammation

Cited by 21 publications

References 47 publications

A secretory leukocyte protease inhibitor variant with improved activity against lung infection

A secretory leukocyte protease inhibitor variant with improved activity against lung infection

Alpha-1 Antitrypsin—A Target for MicroRNA-Based Therapeutic Development for Cystic Fibrosis

The Role of Serine Proteases and Antiproteases in the Cystic Fibrosis Lung

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