Beneficial effects of the AT2 receptor agonist buloxibutid (C21) against acute alveolar epithelial cell inflammation during anti-viral responses
Beneficial effects of the AT2 receptor agonist buloxibutid (C21) against acute alveolar epithelial cell inflammation during anti-viral responses
Aim: activation of the angiotensin II type 2 receptor (AT2 receptor; encoded by AGTR2) has been shown to be beneficial during tissue injury and repair. Therefore, we aimed to investigate the expression of AT2 receptor in human alveolar type II (ATII) cells, a cell population responsible of lung repair and regeneration and the effect of the AT2 receptor agonist buloxibutid (also known as C21), in an in vitro model of viral infection using primary ATII cells.
Methods: we described the expression of AT2 receptor mRNA using publicly available lung single-cell RNA sequencing datasets. We evaluated the effects of buloxibutid on ATII cell biology at baseline and in response to treatment with double stranded RNA (polyinosinic:polycytidylic acid, a pathogen associated molecular pattern) using MTS cytotoxicity assay, transcriptomic analysis and ELISA.
Results: we found that buloxibutid was well tolerated by ATII cells under all conditions tested. RNA sequencing demonstrated that ATII cells responded to polyinosinic:polycytidylic acid with induction of a characteristic antiviral innate immune response. Gene set enrichment analysis revealed that buloxibutid caused a significant suppression of polyinosinic:polycytidylic acid-induced pro-inflammatory responses whereas it was without effect on the expression of antiviral genes.
Conclusions: our findings suggest that buloxibutid may have therapeutic potential for treatment of respiratory viral pneumonias by limiting excessive pro-inflammatory responses that have the potential to lead to a cytokine storm, while maintaining a protective antiviral response.
Conforti, Franco
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Bell, Joseph
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Ridley, Robert
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Dean, Lareb
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Parkin, James
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Loxham, Matthew
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Alzetani, Aiman
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Jones, Mark G.
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Dalsgaard, Carl-Johan
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Raud, Johan
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Davies, Donna E.
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Conforti, Franco
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Bell, Joseph
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Ridley, Robert
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Dean, Lareb
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Parkin, James
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Loxham, Matthew
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Alzetani, Aiman
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Jones, Mark G.
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Dalsgaard, Carl-Johan
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Raud, Johan
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Davies, Donna E.
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Conforti, Franco, Bell, Joseph, Ridley, Robert, Dean, Lareb, Parkin, James, Loxham, Matthew, Alzetani, Aiman, Jones, Mark G., Dalsgaard, Carl-Johan, Raud, Johan and Davies, Donna E.
(2026)
Beneficial effects of the AT2 receptor agonist buloxibutid (C21) against acute alveolar epithelial cell inflammation during anti-viral responses.
ERJ Open Research.
(doi:10.1183/23120541.00249-2025).
Abstract
Aim: activation of the angiotensin II type 2 receptor (AT2 receptor; encoded by AGTR2) has been shown to be beneficial during tissue injury and repair. Therefore, we aimed to investigate the expression of AT2 receptor in human alveolar type II (ATII) cells, a cell population responsible of lung repair and regeneration and the effect of the AT2 receptor agonist buloxibutid (also known as C21), in an in vitro model of viral infection using primary ATII cells.
Methods: we described the expression of AT2 receptor mRNA using publicly available lung single-cell RNA sequencing datasets. We evaluated the effects of buloxibutid on ATII cell biology at baseline and in response to treatment with double stranded RNA (polyinosinic:polycytidylic acid, a pathogen associated molecular pattern) using MTS cytotoxicity assay, transcriptomic analysis and ELISA.
Results: we found that buloxibutid was well tolerated by ATII cells under all conditions tested. RNA sequencing demonstrated that ATII cells responded to polyinosinic:polycytidylic acid with induction of a characteristic antiviral innate immune response. Gene set enrichment analysis revealed that buloxibutid caused a significant suppression of polyinosinic:polycytidylic acid-induced pro-inflammatory responses whereas it was without effect on the expression of antiviral genes.
Conclusions: our findings suggest that buloxibutid may have therapeutic potential for treatment of respiratory viral pneumonias by limiting excessive pro-inflammatory responses that have the potential to lead to a cytokine storm, while maintaining a protective antiviral response.
Text
ERJOR-00249-2025.R2_Proof_hi FC_merge (002)
- Accepted Manuscript
Text
ERJ Open Res-2026-Conforti-23120541.00249-2025
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Accepted/In Press date: 4 December 2025
e-pub ahead of print date: 22 January 2026
Identifiers
Local EPrints ID: 509080
URI: http://eprints.soton.ac.uk/id/eprint/509080
ISSN: 2312-0541
PURE UUID: 5bbb23ab-2c50-4bbb-84e4-6062fef978e5
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Date deposited: 10 Feb 2026 18:12
Last modified: 11 Feb 2026 03:01
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Contributors
Author:
Franco Conforti
Author:
Joseph Bell
Author:
Robert Ridley
Author:
Lareb Dean
Author:
James Parkin
Author:
Aiman Alzetani
Author:
Carl-Johan Dalsgaard
Author:
Johan Raud
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