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Background <p>While the renin-angiotensin-aldosterone system (RAAS) is critically involved in pathomechanisms related to SARS-CoV-2 infection, the role of ongoing therapy with angiotensin-converting enzyme 1 inhibitors (ACEi) or Angiotensin-II type 1 receptor (AT<sub>1</sub>R) blockers (ARB) is much less clear. We evaluated the effects of the ACEi enalapril (ENA) and the ARB losartan (LOS) on SARS-CoV-2 infection in human ex vivo-cultured, precision-cut lung slices (PCLS) obtained from normal human lung tissue.</p> Methods <p>PCLS were pre-treated for 5d with vehicle, LOS or ENA (300 µM), followed by mock infection or infection with SARS-CoV-2 and incubation with vehicle, LOS or ENA for 1d or 2d. Thereafter, PCLS were harvested for analysis of viral replication, inflammatory responses, endoplasmic reticulum (ER) stress and apoptosis pathways.</p> Results <p>Both LOS and ENA significantly reduced viral replication in PCLS, with ENA being more potent. LOS was more efficient than ENA in reducing the expression of <i>IL1B</i>, <i>CCL2</i>, <i>CXCL2</i> and <i>TNFA</i>, but not of <i>IL6</i>, whereas ENA preferentially caused a reduction of <i>IL6</i> and <i>CCL2</i> in SARS-CoV-2-infected PCLS. Further, ENA, but not LOS, significantly decreased the expression of viral entry factors, ACE2 and transmembrane serine protease 2 (TMPRSS2), in infected PCLS. Importantly, LOS or ENA did not exert cytotoxic effects. </p> Conclusions <p>RAAS-antagonizing drugs do not seem to exert detrimental effects during SARS-CoV-2 infection. In opposite, in an ex-vivo model of human PCLS, such treatment was found to dampen SARS-CoV-2 infection and consecutive inflammation.</p>

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RAAS antagonists dampen the SARS-CoV-2 infection in ex-vivo cultured human precision-cut lung slices

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月13日

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  • Poornima Mahavadi,
  • Martina Korfei,
  • Christin Müller-Ruttloff,
  • Clemens Ruppert,
  • Ekaterina Krauss,
  • Peter Dorfmüller,
  • Stefan Gattenloehner,
  • Stefanie Dimmeler,
  • Elie El Agha,
  • Saverio Bellusci,
  • Susanne Herold,
  • Biruta Witte,
  • John Ziebuhr,
  • Andreas Guenther

摘要

Background

While the renin-angiotensin-aldosterone system (RAAS) is critically involved in pathomechanisms related to SARS-CoV-2 infection, the role of ongoing therapy with angiotensin-converting enzyme 1 inhibitors (ACEi) or Angiotensin-II type 1 receptor (AT1R) blockers (ARB) is much less clear. We evaluated the effects of the ACEi enalapril (ENA) and the ARB losartan (LOS) on SARS-CoV-2 infection in human ex vivo-cultured, precision-cut lung slices (PCLS) obtained from normal human lung tissue.

Methods

PCLS were pre-treated for 5d with vehicle, LOS or ENA (300 µM), followed by mock infection or infection with SARS-CoV-2 and incubation with vehicle, LOS or ENA for 1d or 2d. Thereafter, PCLS were harvested for analysis of viral replication, inflammatory responses, endoplasmic reticulum (ER) stress and apoptosis pathways.

Results

Both LOS and ENA significantly reduced viral replication in PCLS, with ENA being more potent. LOS was more efficient than ENA in reducing the expression of IL1B, CCL2, CXCL2 and TNFA, but not of IL6, whereas ENA preferentially caused a reduction of IL6 and CCL2 in SARS-CoV-2-infected PCLS. Further, ENA, but not LOS, significantly decreased the expression of viral entry factors, ACE2 and transmembrane serine protease 2 (TMPRSS2), in infected PCLS. Importantly, LOS or ENA did not exert cytotoxic effects.

Conclusions

RAAS-antagonizing drugs do not seem to exert detrimental effects during SARS-CoV-2 infection. In opposite, in an ex-vivo model of human PCLS, such treatment was found to dampen SARS-CoV-2 infection and consecutive inflammation.