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Sodium Bituminosulfonate Used to Treat Rosacea Modulates Generation of Inflammatory Mediators by Primary Human Neutrophils

BACKGROUND: Sodium bituminosulfonate is derived from naturally occurring sulphur-rich oil shale and is used for the treatment of the inflammatory skin disease rosacea. Major molecular players in the development of rosacea include the release of enzymes that process antimicrobial peptides which, toge...

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Autores principales: Schiffmann, Susanne, Gunne, Sandra, Henke, Marina, Ulshöfer, Thomas, Steinhilber, Dieter, Sethmann, Annette, Parnham, Michael J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2021
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215909/
https://www.ncbi.nlm.nih.gov/pubmed/34163212
http://dx.doi.org/10.2147/JIR.S313636
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author Schiffmann, Susanne
Gunne, Sandra
Henke, Marina
Ulshöfer, Thomas
Steinhilber, Dieter
Sethmann, Annette
Parnham, Michael J
author_facet Schiffmann, Susanne
Gunne, Sandra
Henke, Marina
Ulshöfer, Thomas
Steinhilber, Dieter
Sethmann, Annette
Parnham, Michael J
author_sort Schiffmann, Susanne
collection PubMed
description BACKGROUND: Sodium bituminosulfonate is derived from naturally occurring sulphur-rich oil shale and is used for the treatment of the inflammatory skin disease rosacea. Major molecular players in the development of rosacea include the release of enzymes that process antimicrobial peptides which, together with reactive oxygen species (ROS) and vascular endothelial growth factor (VEGF), promote pro-inflammatory processes and angiogenesis. The aim of this study was to address the molecular mechanism(s) underlying the therapeutic benefit of the formulation sodium bituminosulfonate dry substance (SBDS), which is indicated for the treatment of skin inflammation, including rosacea. METHODS: We investigated whether SBDS regulates the expression of cytokines, the release of the antimicrobial peptide LL-37, calcium mobilization, proteases (matrix metalloproteinase, elastase, kallikrein (KLK)5), VEGF or ROS in primary human neutrophils. In addition, activity assays with 5-lipoxygenase (5-LO) and recombinant human MMP9 and KLK5 were performed. RESULTS: We observed that SBDS reduces the release of the antimicrobial peptide LL-37, calcium, elastase, ROS and VEGF from neutrophils. Moreover, KLK5, the enzyme that converts cathelicidin to LL-37, and 5-LO that produces leukotriene (LT)A(4), the precursor of LTB(4), were both inhibited by SBDS with an IC(50) of 7.6 µg/mL and 33 µg/mL, respectively. CONCLUSION: Since LTB(4) induces LL-37 which, in turn, promotes increased intracellular calcium levels and thereby, ROS/VEGF/elastase release, SBDS possibly regulates the LTB(4)/LL-37/calcium – ROS/VEGF/elastase axis by inhibiting 5-LO and KLK5. Additional direct effects on other pro-inflammatory pathways such as ROS generation cannot be ruled out. In summary, SBDS reduces the generation of inflammatory mediators from human neutrophils possibly accounting for its anti-inflammatory effects in rosacea.
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spelling pubmed-82159092021-06-22 Sodium Bituminosulfonate Used to Treat Rosacea Modulates Generation of Inflammatory Mediators by Primary Human Neutrophils Schiffmann, Susanne Gunne, Sandra Henke, Marina Ulshöfer, Thomas Steinhilber, Dieter Sethmann, Annette Parnham, Michael J J Inflamm Res Original Research BACKGROUND: Sodium bituminosulfonate is derived from naturally occurring sulphur-rich oil shale and is used for the treatment of the inflammatory skin disease rosacea. Major molecular players in the development of rosacea include the release of enzymes that process antimicrobial peptides which, together with reactive oxygen species (ROS) and vascular endothelial growth factor (VEGF), promote pro-inflammatory processes and angiogenesis. The aim of this study was to address the molecular mechanism(s) underlying the therapeutic benefit of the formulation sodium bituminosulfonate dry substance (SBDS), which is indicated for the treatment of skin inflammation, including rosacea. METHODS: We investigated whether SBDS regulates the expression of cytokines, the release of the antimicrobial peptide LL-37, calcium mobilization, proteases (matrix metalloproteinase, elastase, kallikrein (KLK)5), VEGF or ROS in primary human neutrophils. In addition, activity assays with 5-lipoxygenase (5-LO) and recombinant human MMP9 and KLK5 were performed. RESULTS: We observed that SBDS reduces the release of the antimicrobial peptide LL-37, calcium, elastase, ROS and VEGF from neutrophils. Moreover, KLK5, the enzyme that converts cathelicidin to LL-37, and 5-LO that produces leukotriene (LT)A(4), the precursor of LTB(4), were both inhibited by SBDS with an IC(50) of 7.6 µg/mL and 33 µg/mL, respectively. CONCLUSION: Since LTB(4) induces LL-37 which, in turn, promotes increased intracellular calcium levels and thereby, ROS/VEGF/elastase release, SBDS possibly regulates the LTB(4)/LL-37/calcium – ROS/VEGF/elastase axis by inhibiting 5-LO and KLK5. Additional direct effects on other pro-inflammatory pathways such as ROS generation cannot be ruled out. In summary, SBDS reduces the generation of inflammatory mediators from human neutrophils possibly accounting for its anti-inflammatory effects in rosacea. Dove 2021-06-16 /pmc/articles/PMC8215909/ /pubmed/34163212 http://dx.doi.org/10.2147/JIR.S313636 Text en © 2021 Schiffmann et al. https://creativecommons.org/licenses/by-nc/3.0/This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/ (https://creativecommons.org/licenses/by-nc/3.0/) ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
Schiffmann, Susanne
Gunne, Sandra
Henke, Marina
Ulshöfer, Thomas
Steinhilber, Dieter
Sethmann, Annette
Parnham, Michael J
Sodium Bituminosulfonate Used to Treat Rosacea Modulates Generation of Inflammatory Mediators by Primary Human Neutrophils
title Sodium Bituminosulfonate Used to Treat Rosacea Modulates Generation of Inflammatory Mediators by Primary Human Neutrophils
title_full Sodium Bituminosulfonate Used to Treat Rosacea Modulates Generation of Inflammatory Mediators by Primary Human Neutrophils
title_fullStr Sodium Bituminosulfonate Used to Treat Rosacea Modulates Generation of Inflammatory Mediators by Primary Human Neutrophils
title_full_unstemmed Sodium Bituminosulfonate Used to Treat Rosacea Modulates Generation of Inflammatory Mediators by Primary Human Neutrophils
title_short Sodium Bituminosulfonate Used to Treat Rosacea Modulates Generation of Inflammatory Mediators by Primary Human Neutrophils
title_sort sodium bituminosulfonate used to treat rosacea modulates generation of inflammatory mediators by primary human neutrophils
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215909/
https://www.ncbi.nlm.nih.gov/pubmed/34163212
http://dx.doi.org/10.2147/JIR.S313636
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