A 5-Lipoxygenase Inhibitor, Zileuton, Modulates Host Immune Responses and Improves Lung Function in a Model of Severe Acute Respiratory Syndrome (SARS) Induced by Betacoronavirus
Exacerbated inflammatory responses are a hallmark of severe coronavirus disease 2019 (COVID-19). Zileuton (Zi) is a selective inhibitor of 5-lipoxygenase, an enzyme involved in the production of several inflammatory/pro-resolving lipid mediators. Herein, we investigated the effect of Zi treatment in a severe acute respiratory syndrome (SARS) model. Mouse hepatitis virus (MHV)3-infected mice treated with Zi significantly improved the clinical score, weight loss, cardiopulmonary function, and survival rates compared with infected untreated animals. The protection observed in Zi-treated mice was associated with a lower inflammatory score, reduced dendritic cell-producing tumor necrosis factor (TNF), and increased neutrophil-producing interleukin (IL)-10 in the lungs three days after infection (dpi). At 5 dpi, the lungs of treated mice showed an increase in Th2-, Treg CD4+-, and Treg CD8+-producing IL-10 and reduced Th1 infiltrating cells. Furthermore, similar results were found upon Zi treatment after SARS-CoV-2 infection in transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2), significantly improving the clinical score, weight loss, and lung inflammatory score compared with untreated animals. Our data suggest that Zi protects against developing severe lung disease during SARS induced by betacoronavirus without affecting the host's capacity to deal with infection.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
|---|---|
| Enthalten in: |
Viruses - 15(2023), 10 vom: 04. Okt. |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Pereira, Rafaela das Dores [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
COVID-19 |
|---|
| Anmerkungen: |
Date Completed 30.10.2023 Date Revised 03.11.2023 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.3390/v15102049 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM36388842X |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM36388842X | ||
| 003 | DE-627 | ||
| 005 | 20231226094308.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.3390/v15102049 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1212.xml |
| 035 | |a (DE-627)NLM36388842X | ||
| 035 | |a (NLM)37896826 | ||
| 035 | |a (PII)2049 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Pereira, Rafaela das Dores |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A 5-Lipoxygenase Inhibitor, Zileuton, Modulates Host Immune Responses and Improves Lung Function in a Model of Severe Acute Respiratory Syndrome (SARS) Induced by Betacoronavirus |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 30.10.2023 | ||
| 500 | |a Date Revised 03.11.2023 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Exacerbated inflammatory responses are a hallmark of severe coronavirus disease 2019 (COVID-19). Zileuton (Zi) is a selective inhibitor of 5-lipoxygenase, an enzyme involved in the production of several inflammatory/pro-resolving lipid mediators. Herein, we investigated the effect of Zi treatment in a severe acute respiratory syndrome (SARS) model. Mouse hepatitis virus (MHV)3-infected mice treated with Zi significantly improved the clinical score, weight loss, cardiopulmonary function, and survival rates compared with infected untreated animals. The protection observed in Zi-treated mice was associated with a lower inflammatory score, reduced dendritic cell-producing tumor necrosis factor (TNF), and increased neutrophil-producing interleukin (IL)-10 in the lungs three days after infection (dpi). At 5 dpi, the lungs of treated mice showed an increase in Th2-, Treg CD4+-, and Treg CD8+-producing IL-10 and reduced Th1 infiltrating cells. Furthermore, similar results were found upon Zi treatment after SARS-CoV-2 infection in transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2), significantly improving the clinical score, weight loss, and lung inflammatory score compared with untreated animals. Our data suggest that Zi protects against developing severe lung disease during SARS induced by betacoronavirus without affecting the host's capacity to deal with infection | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a COVID-19 | |
| 650 | 4 | |a MHV | |
| 650 | 4 | |a SARS-CoV-2 | |
| 650 | 4 | |a viral infection | |
| 650 | 4 | |a zileuton | |
| 650 | 7 | |a Lipoxygenase Inhibitors |2 NLM | |
| 650 | 7 | |a K-18 conjugate |2 NLM | |
| 650 | 7 | |a zileuton |2 NLM | |
| 650 | 7 | |a V1L22WVE2S |2 NLM | |
| 700 | 1 | |a Rabelo, Rayane Aparecida Nonato |e verfasserin |4 aut | |
| 700 | 1 | |a Oliveira, Natália Fernanda de Melo |e verfasserin |4 aut | |
| 700 | 1 | |a Porto, Samuel Luiz Teixeira |e verfasserin |4 aut | |
| 700 | 1 | |a Andrade, Ana Claudia Dos Santos Pereira |e verfasserin |4 aut | |
| 700 | 1 | |a Queiroz-Junior, Celso M |e verfasserin |4 aut | |
| 700 | 1 | |a Barbosa, César Luís Nascimento |e verfasserin |4 aut | |
| 700 | 1 | |a de Souza-Costa, Luiz Pedro |e verfasserin |4 aut | |
| 700 | 1 | |a Santos, Felipe Rocha da Silva |e verfasserin |4 aut | |
| 700 | 1 | |a Oliveira, Fernando Bento Rodrigues |e verfasserin |4 aut | |
| 700 | 1 | |a da Silva, Bárbara Luísa Vieira |e verfasserin |4 aut | |
| 700 | 1 | |a Umezu, Hanna L |e verfasserin |4 aut | |
| 700 | 1 | |a Ferreira, Raquel |e verfasserin |4 aut | |
| 700 | 1 | |a da Silva, Glauber S F |e verfasserin |4 aut | |
| 700 | 1 | |a Cruz, Jader Santos |e verfasserin |4 aut | |
| 700 | 1 | |a Teixeira, Mauro Martins |e verfasserin |4 aut | |
| 700 | 1 | |a Costa, Vivian Vasconcelos |e verfasserin |4 aut | |
| 700 | 1 | |a Machado, Fabiana Simão |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Viruses |d 2009 |g 15(2023), 10 vom: 04. Okt. |w (DE-627)NLM192382764 |x 1999-4915 |7 nnns |
| 773 | 1 | 8 | |g volume:15 |g year:2023 |g number:10 |g day:04 |g month:10 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.3390/v15102049 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 15 |j 2023 |e 10 |b 04 |c 10 | ||