Coumarinic derivatives show anti-inflammatory effects on alveolar macrophages, but their anti-elastase activity is essential to reduce lung inflammation in vivo

Bissonnette, Élyse; Tremblay, Guy M.; Turmel, Véronique; Pirotte, Bernard; Reboud‐Ravaux, Michèle

doi:10.1016/j.intimp.2008.09.009

Cited by 22 publications

(17 citation statements)

References 37 publications

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“…42 In addition, small molecule inhibitors of NE have been shown to significantly reduce MCP-1 levels in the lungs of mice treated with LPS. 43 Therefore, the enhanced stability of GG-elafin compared to WT-elafin may help reduce the NE burden more effectively and impact on NE's ability to upregulate MCP-1 production in target cells. Given their similar K i values, we would expect both elafin variants to reduce the activity of their target proteases such as elastase; however, as indicated by the neutrophil counts and the ELISA results, it appears that the GG-elafin variant possesses a more potent anti-inflammatory activity compared to the WT-elafin due to its increased stability.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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Elafin is a serine protease inhibitor produced by epithelial and immune cells with anti-inflammatory properties. Research has shown that dysregulated protease activity may elicit proteolytic cleavage of elafin, thereby impairing the innate immune function of the protein. The aim of this study was to generate variants of elafin (GG- and QQ-elafin) that exhibit increased protease resistance while retaining the biological properties of wild-type (WT) elafin. Similar to WT-elafin, GG- and QQ-elafin variants retained antiprotease activity and susceptibility to transglutaminase-mediated fibronectin cross-linking. However, in contrast to WT-elafin, GG- and QQ-elafin displayed significantly enhanced resistance to degradation when incubated with bronchoalveolar lavage fluid from patients with cystic fibrosis. Intriguingly, both variants, particularly GG-elafin, demonstrated improved lipopolysaccharide (LPS) neutralization properties in vitro. In addition, GG-elafin showed improved anti-inflammatory activity in a mouse model of LPS-induced acute lung inflammation. Inflammatory cell infiltration into the lung was reduced in lungs of mice treated with GG-elafin, predominantly neutrophilic infiltration. A reduction in MCP-1 levels in GG-elafin treated mice compared to the LPS alone treatment group was also demonstrated. GG-elafin showed increased functionality when compared to WT-elafin and may be of future therapeutic relevance in the treatment of lung diseases characterized by a protease burden.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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“…In this study, elastase inhibitor activity of dihydroxy coumarin derivatives was found to increase dose dependently. The inhibition was increased with increasing dihydroxy coumarin concentration ( 44 . Previous studies have shown that the attachment of various leaving groups (halogen, carboxylate, heterocyclic sulfide, sulfone, methoxy) to the triazole compound yields highly potent inhibitors of human leukocyte elastase 45 .…”

Section: ' -( Et H a N E -1 2 -D I Y L B I S ( P H E N Y L A Z A mentioning

confidence: 99%

Synthesis, antielastase, antioxidant and radical scavenging activities of 4-(aza substituted) methylene substituted dihydroxy coumarines

Sökmen

Aydin

Gumus

et al. 2012

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Moreover, it should be considered that coumarins compounds, as reported in literature, display anti-proteinase activity [55]. For example, serin proteinase is capable to degradate the matrix proteins and is involved in several inflammatory respiratory diseases as CF.…”

Section: Resultsmentioning

confidence: 99%

Bergamot (Citrus bergamia Risso) fruit extracts and identified components alter expression of interleukin 8 gene in cystic fibrosis bronchial epithelial cell lines

et al. 2011

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BackgroundCystic fibrosis (CF) airway pathology is a fatal, autosomal, recessive genetic disease characterized by extensive lung inflammation. After induction by TNF-α, elevated concentrations of several pro-inflammatory cytokines (i.e. IL-6, IL-1β) and chemokines (i.e. IL-8) are released from airway epithelial cells. In order to reduce the excessive inflammatory response in the airways of CF patients, new therapies have been developed and in this respect, medicinal plant extracts have been studied. In this article we have investigated the possible use of bergamot extracts (Citrus bergamia Risso) and their identified components to alter the expression of IL-8 associated with the cystic fibrosis airway pathology.MethodsThe extracts were chemically characterized by 1H-NMR (nuclear magnetic resonance), GC-FID (gas chromatography-flame ionization detector), GC-MS (gas chromatography-mass spectrometry) and HPLC (high pressure liquid chromatography). Both bergamot extracts and main detected chemical constituents were assayed for their biological activity measuring (a) cytokines and chemokines in culture supernatants released from cystic fibrosis IB3-1 cells treated with TNF-α by Bio-Plex cytokine assay; (b) accumulation of IL-8 mRNA by real-time PCR.ResultsThe extracts obtained from bergamot (Citrus bergamia Risso) epicarps contain components displaying an inhibitory activity on IL-8. Particularly, the most active molecules were bergapten and citropten. These effects have been confirmed by analyzing mRNA levels and protein release in the CF cellular models IB3-1 and CuFi-1 induced with TNF-α or exposed to heat-inactivated Pseudomonas aeruginosa.ConclusionsThese obtained results clearly indicate that bergapten and citropten are strong inhibitors of IL-8 expression and could be proposed for further studies to verify possible anti-inflammatory properties to reduce lung inflammation in CF patients.

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Coumarinic derivatives show anti-inflammatory effects on alveolar macrophages, but their anti-elastase activity is essential to reduce lung inflammation in vivo

Cited by 22 publications

References 37 publications

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

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

Synthesis, antielastase, antioxidant and radical scavenging activities of 4-(aza substituted) methylene substituted dihydroxy coumarines

Bergamot (Citrus bergamia Risso) fruit extracts and identified components alter expression of interleukin 8 gene in cystic fibrosis bronchial epithelial cell lines

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