Dexamethasone, Remdesivir and Azithromycin modulate ACE2 and IL-6 in Lung Epithelial Cells

Abstract

Background The optimal use of steroids in COVID-19 patients remains challenging. Current S3-guidelines “Recommendations for patients with COVID-19” recommend dexamethasone (DEX) for patients requiring respiratory support, remdesivir (RD) in the early disease phase and azythromycin (AZ) is no longer recommended. We investigated effects of DEX, RD and AZ in a lipopolysaccharide induced inflammation in lung cells in vitro and analyzed publicly available datasets with a focus on the Angiotensin-converting enzyme 2 (ACE2) to better understand drugs’ mechanisms of action.

Methods human bronchial (Calu) and alveolar (A549) lung epithelial cells were treated with DEX, AZ or RDV in the presence of lipopolysaccharides (LPS). Gene expression (GE) of ACE2, IL-6 and the IL-6 protein release were measured. Publicly available GE data from lung tissues of COVID-19 patients and from lung cells treated with DEX were analyzed for the GE of ACE2.

Results DEX increased and RDV and AZ reduced the GE of ACE2 in LPS-stimulated bronchial and alveolar epithelial cells. Only DEX significantly reduced LPS-induced IL-6 releases in alveolar cells substantially. The database analyses showed an, albeit not always significant, increase in ACE2 for lung tissue or cell lines treated with DEX. Lung tissue from patients after COVID-19 infection as well as bronchial cell cultures after COVID-19 infection showed lower GEs of ACE2.

Discussion and Conclusion DEX can increase ACE2 expression in vitro and thereby the portal of entry of SARS-CoV-2 into lung cells during an LPS induced inflammation. Simultaneously the inflammatory marker IL-6 is reduced. Comparative database analyses indicate that these processes can also take place in vivo.

Zusammenfassung

Hintergrund und Fragestellung Der optimale Einsatz von Steroiden bei COVID-19 Patienten bleibt eine Herausforderung. Die aktuelle S3-Leitlinie „Empfehlungen zur Therapie von Patienten mit COVID-19“ empfiehlt Dexamethason (DEX) nur bei invasiv beatmeten Patienten sowie bei Patienten mit Sauerstoffbedarf, während Remdesivir (RD) nur in der Frühphase der Erkrankung und Azythromycin (AZ) nach anfänglichem Einsatz heute nicht mehr empfohlen wird. Wir untersuchten die Wirkungen von DEX, RD und AZ bei einer durch Lipopolysaccharide (LPS) induzierten Entzündung in Lungenzellen in vitro und erstellten Datenbankanalysen, um den Wirkmechanismen der Medikamente, insbesondere hinsichtlich des Angiotensin-converting enzyme 2 (ACE2) besser nachvollziehen zu können.

Methoden Humane bronchiale (Calu) und alveoläre (A549) Lungenepithelzellen wurden in Gegenwart von LPS mit DEX, AZ oder RDV behandelt. Die Genexpression (GE) von ACE2, IL-6 sowie die IL-6-Proteinfreisetzung wurden gemessen. Öffentlich zugängliche GE-Daten von Lungengeweben von COVID-19-Patienten und von mit DEX behandelten Lungenzellen wurden auf die GE von ACE2 hin untersucht.

Ergebnisse DEX erhöhte und RDV und AZ reduzierten die GE von ACE2 in LPS-stimulierten Bronchial- und Alveolarepithelzellen. Nur DEX reduzierte die LPS-induzierte IL-6-Freisetzung in Alveolarzellen erheblich. Die Datenbankanalysen zeigten für die mit DEX behandelten Lungengewebe oder Zelllinien einen, wenn auch nicht immer signifikanten Anstieg von ACE2. Lungengewebe von Patienten nach COVID-19-Infektion sowie bronchiale Zellkulturen nach einer COVID-19 Infektion wiesen niedrigere GEs von ACE2 auf.

Diskussion und Schlussfolgerung/Fazit DEX kann in vitro die ACE2-Genexpression und damit die Eintrittspforte von SARS-CoV-2 in Lungenzellen im Modell einer LPS-induzierten Entzündung erhöhen bei gleichzeitiger Senkung des Entzündungsmarkers IL-6. Vergleichende Datenbankanalysen weisen darauf hin, dass diese Prozesse auch in vivo bei Infektionen des Lungengewebes ablaufen können.

Keywords

SARS-CoV-2 infection - ACE2 expression - alveolar epithelial cells - IL-6 - LPS

Schlüsselwörter

SARS-CoV-2-Infektion - ACE2-Expression - alveolare Epithelzellen - Lungenepithelzellen - IL-6 - LPS

Publication History

Received: 12 March 2024

Accepted after revision: 22 July 2024

Article published online:
16 September 2024

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