Refine
Year of publication
- 2021 (2) (remove)
Document Type
- Article (2)
Language
- English (2)
Has Fulltext
- yes (2)
Is part of the Bibliography
- no (2)
Keywords
- 5 lipoxygenase (1)
- ACE inhibitor (1)
- AT1 receptor antagonist (1)
- KLK5 (1)
- MMP9 (1)
- SARS-CoV-2 (1)
- cell barrier integrity (1)
- neutrophils (1)
- rosacea (1)
- sodium bituminosulfonate (1)
Institute
- Medizin (2)
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)A4, the precursor of LTB4, were both inhibited by SBDS with an IC50 of 7.6 μg/mL and 33 μg/mL, respectively.
Conclusion: Since LTB4 induces LL-37 which, in turn, promotes increased intracellular calcium levels and thereby, ROS/VEGF/elastase release, SBDS possibly regulates the LTB4/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.
Blood-pressure-lowering drugs are proposed to foster SARS-CoV-2 infection by pharmacological upregulation of angiotensin-converting enzyme 2 (ACE2), the binding partner of the virus spike (S) protein, located on the surface of the host cells. Conversely, it is postulated that angiotensin–renin system antagonists may prevent lung damage caused by SARS-CoV-2 infection, by reducing angiotensin II levels, which can induce permeability of lung endothelial barrier via its interaction with the AT1 receptor (AT1R). Methods: We have investigated the influence of the ACE inhibitors (lisinopril, captopril) and the AT1 antagonists (telmisartan, olmesartan) on the level of ACE2 mRNA and protein expression as well as their influence on the cytopathic effect of SARS-CoV-2 and on the cell barrier integrity in a Caco-2 cell model. Results: The drugs revealed no effect on ACE2 mRNA and protein expression. ACE inhibitors and AT1R antagonist olmesartan did not influence the infection rate of SARS-CoV-2 and were unable to prevent the SARS-CoV-2-induced cell barrier disturbance. A concentration of 25 µg/mL telmisartan significantly reduced the virus replication rate. Conclusion: ACE inhibitors and AT1R antagonist showed neither beneficial nor detrimental effects on SARS-CoV-2-infection and cell barrier integrity in vitro at pharmacologically relevant concentrations.