Itraconazole in combination with neutrophil depletion reduces the expression of genes related to pulmonary fibrosis in an experimental model of paracoccidioidomycosis
ABSTRACT: Itraconazole (ITC) is the drug of choice for treating paracoccidioidomycosis (PCM); nonetheless, patients with the chronic form of this mycosis develop fibrosis, a residual pulmonary abnormality, even after treatment. Recently, we observed that the depletion of neutrophils with a specific...
- Autores:
-
Puerta Arias, Juan David
Pino Tamayo, Paula Andrea
Arango Rincón, Julián Camilo
Salazar Peláez, Lina María
González Marín, Ángel Augusto
- Tipo de recurso:
- Article of investigation
- Fecha de publicación:
- 2018
- Institución:
- Universidad de Antioquia
- Repositorio:
- Repositorio UdeA
- Idioma:
- eng
- OAI Identifier:
- oai:bibliotecadigital.udea.edu.co:10495/24132
- Acceso en línea:
- http://hdl.handle.net/10495/24132
- Palabra clave:
- Itraconazole
Itraconazol
Paracoccidioidomycosis
Paracoccidioidomicosis
Neutrophils
Neutrófilos
Fibrosis
Fibrosis
Paracoccidioides
- Rights
- openAccess
- License
- http://creativecommons.org/licenses/by-nc/2.5/co/
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UDEA2 |
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|
dc.title.spa.fl_str_mv |
Itraconazole in combination with neutrophil depletion reduces the expression of genes related to pulmonary fibrosis in an experimental model of paracoccidioidomycosis |
title |
Itraconazole in combination with neutrophil depletion reduces the expression of genes related to pulmonary fibrosis in an experimental model of paracoccidioidomycosis |
spellingShingle |
Itraconazole in combination with neutrophil depletion reduces the expression of genes related to pulmonary fibrosis in an experimental model of paracoccidioidomycosis Itraconazole Itraconazol Paracoccidioidomycosis Paracoccidioidomicosis Neutrophils Neutrófilos Fibrosis Fibrosis Paracoccidioides |
title_short |
Itraconazole in combination with neutrophil depletion reduces the expression of genes related to pulmonary fibrosis in an experimental model of paracoccidioidomycosis |
title_full |
Itraconazole in combination with neutrophil depletion reduces the expression of genes related to pulmonary fibrosis in an experimental model of paracoccidioidomycosis |
title_fullStr |
Itraconazole in combination with neutrophil depletion reduces the expression of genes related to pulmonary fibrosis in an experimental model of paracoccidioidomycosis |
title_full_unstemmed |
Itraconazole in combination with neutrophil depletion reduces the expression of genes related to pulmonary fibrosis in an experimental model of paracoccidioidomycosis |
title_sort |
Itraconazole in combination with neutrophil depletion reduces the expression of genes related to pulmonary fibrosis in an experimental model of paracoccidioidomycosis |
dc.creator.fl_str_mv |
Puerta Arias, Juan David Pino Tamayo, Paula Andrea Arango Rincón, Julián Camilo Salazar Peláez, Lina María González Marín, Ángel Augusto |
dc.contributor.author.none.fl_str_mv |
Puerta Arias, Juan David Pino Tamayo, Paula Andrea Arango Rincón, Julián Camilo Salazar Peláez, Lina María González Marín, Ángel Augusto |
dc.subject.decs.none.fl_str_mv |
Itraconazole Itraconazol Paracoccidioidomycosis Paracoccidioidomicosis Neutrophils Neutrófilos Fibrosis Fibrosis Paracoccidioides |
topic |
Itraconazole Itraconazol Paracoccidioidomycosis Paracoccidioidomicosis Neutrophils Neutrófilos Fibrosis Fibrosis Paracoccidioides |
description |
ABSTRACT: Itraconazole (ITC) is the drug of choice for treating paracoccidioidomycosis (PCM); nonetheless, patients with the chronic form of this mycosis develop fibrosis, a residual pulmonary abnormality, even after treatment. Recently, we observed that the depletion of neutrophils with a specific monoclonal antibody (mAb-anti-Ly6G) during the chronic stages of PCM was associated with a decrease in the fungal burden, the inflammatory response and a reduction of fibrosis. Herein, we aimed to evaluate the effect of ITC in combination with the mAb-anti-Ly6G in an experimental model of pulmonary PCM. BALB/c male mice were challenged with Paracoccidioides brasiliensis yeasts and treated with the mAb-anti-Ly6G and/or ITC at 4th week post-infection (p.i.) and then sacrificed at 12th week p.i. to assess neutrophil subpopulations, fungal load, collagen, expression of fibrosis- and pro-inflammatory-related genes and histopathology. We observed that combination of ITC/mAb-anti-Ly6G favored the control of infection and diminished the inflammatory response. Of note, such therapeutic strategy reduced the expression of IL-1β, IL-6, IL-17, IL-10, TNF-α, TGF-β1, TGF-β3, GATA-3, RORc, Ahr, MMP-1α, MMP- 8 MMP-15, TIMP-1, and TIMP-2 genes in an additive manner compared to those mice treated with the mAb or ITC alone. Interestingly, ITC induced an increase of type-II neutrophils even in those mice treated with the mAb-anti-Ly6G. These results indicate that combination ITC/mAb-anti-Ly6G reduced the infection and pulmonary fibrosis through down-regulation of inflammatory and pro-fibrotic genes. Additionally, we confirmed the immunomodulatory properties of this antifungal in vivo. This work emphasizes the importance of exploring new potential combination treatments to treat fungal infections. |
publishDate |
2018 |
dc.date.issued.none.fl_str_mv |
2018 |
dc.date.accessioned.none.fl_str_mv |
2021-11-15T23:10:37Z |
dc.date.available.none.fl_str_mv |
2021-11-15T23:10:37Z |
dc.type.spa.fl_str_mv |
info:eu-repo/semantics/article |
dc.type.coarversion.fl_str_mv |
http://purl.org/coar/version/c_970fb48d4fbd8a85 |
dc.type.hasversion.spa.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.coar.spa.fl_str_mv |
http://purl.org/coar/resource_type/c_2df8fbb1 |
dc.type.redcol.spa.fl_str_mv |
https://purl.org/redcol/resource_type/ART |
dc.type.local.spa.fl_str_mv |
Artículo de investigación |
format |
http://purl.org/coar/resource_type/c_2df8fbb1 |
status_str |
publishedVersion |
dc.identifier.issn.none.fl_str_mv |
1369-3786 |
dc.identifier.uri.none.fl_str_mv |
http://hdl.handle.net/10495/24132 |
dc.identifier.doi.none.fl_str_mv |
10.1093/mmy/myx087 |
dc.identifier.eissn.none.fl_str_mv |
1460-2709 |
identifier_str_mv |
1369-3786 10.1093/mmy/myx087 1460-2709 |
url |
http://hdl.handle.net/10495/24132 |
dc.language.iso.spa.fl_str_mv |
eng |
language |
eng |
dc.relation.ispartofjournalabbrev.spa.fl_str_mv |
Med. Mycol. |
dc.rights.spa.fl_str_mv |
info:eu-repo/semantics/openAccess |
dc.rights.uri.*.fl_str_mv |
http://creativecommons.org/licenses/by-nc/2.5/co/ |
dc.rights.accessrights.spa.fl_str_mv |
http://purl.org/coar/access_right/c_abf2 |
dc.rights.creativecommons.spa.fl_str_mv |
https://creativecommons.org/licenses/by-nc/4.0/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
http://creativecommons.org/licenses/by-nc/2.5/co/ http://purl.org/coar/access_right/c_abf2 https://creativecommons.org/licenses/by-nc/4.0/ |
dc.format.extent.spa.fl_str_mv |
12 |
dc.format.mimetype.spa.fl_str_mv |
application/pdf |
dc.publisher.spa.fl_str_mv |
Oxford University Press |
dc.publisher.group.spa.fl_str_mv |
Grupo de Investigación en Microbiología Básica y Aplicada-Microba Micología Médica y Experimental |
dc.publisher.place.spa.fl_str_mv |
Oxford, Inglaterra |
institution |
Universidad de Antioquia |
bitstream.url.fl_str_mv |
http://bibliotecadigital.udea.edu.co/bitstream/10495/24132/1/GonzalezAngel_2018_ItraconazolePulmonary.pdf http://bibliotecadigital.udea.edu.co/bitstream/10495/24132/2/license_rdf http://bibliotecadigital.udea.edu.co/bitstream/10495/24132/3/license.txt |
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bitstream.checksumAlgorithm.fl_str_mv |
MD5 MD5 MD5 |
repository.name.fl_str_mv |
Repositorio Institucional Universidad de Antioquia |
repository.mail.fl_str_mv |
andres.perez@udea.edu.co |
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1812173075207159808 |
spelling |
Puerta Arias, Juan DavidPino Tamayo, Paula AndreaArango Rincón, Julián CamiloSalazar Peláez, Lina MaríaGonzález Marín, Ángel Augusto2021-11-15T23:10:37Z2021-11-15T23:10:37Z20181369-3786http://hdl.handle.net/10495/2413210.1093/mmy/myx0871460-2709ABSTRACT: Itraconazole (ITC) is the drug of choice for treating paracoccidioidomycosis (PCM); nonetheless, patients with the chronic form of this mycosis develop fibrosis, a residual pulmonary abnormality, even after treatment. Recently, we observed that the depletion of neutrophils with a specific monoclonal antibody (mAb-anti-Ly6G) during the chronic stages of PCM was associated with a decrease in the fungal burden, the inflammatory response and a reduction of fibrosis. Herein, we aimed to evaluate the effect of ITC in combination with the mAb-anti-Ly6G in an experimental model of pulmonary PCM. BALB/c male mice were challenged with Paracoccidioides brasiliensis yeasts and treated with the mAb-anti-Ly6G and/or ITC at 4th week post-infection (p.i.) and then sacrificed at 12th week p.i. to assess neutrophil subpopulations, fungal load, collagen, expression of fibrosis- and pro-inflammatory-related genes and histopathology. We observed that combination of ITC/mAb-anti-Ly6G favored the control of infection and diminished the inflammatory response. Of note, such therapeutic strategy reduced the expression of IL-1β, IL-6, IL-17, IL-10, TNF-α, TGF-β1, TGF-β3, GATA-3, RORc, Ahr, MMP-1α, MMP- 8 MMP-15, TIMP-1, and TIMP-2 genes in an additive manner compared to those mice treated with the mAb or ITC alone. Interestingly, ITC induced an increase of type-II neutrophils even in those mice treated with the mAb-anti-Ly6G. These results indicate that combination ITC/mAb-anti-Ly6G reduced the infection and pulmonary fibrosis through down-regulation of inflammatory and pro-fibrotic genes. Additionally, we confirmed the immunomodulatory properties of this antifungal in vivo. This work emphasizes the importance of exploring new potential combination treatments to treat fungal infections.COL0013709COL012613112application/pdfengOxford University PressGrupo de Investigación en Microbiología Básica y Aplicada-MicrobaMicología Médica y ExperimentalOxford, Inglaterrainfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_2df8fbb1https://purl.org/redcol/resource_type/ARTArtículo de investigaciónhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc/2.5/co/http://purl.org/coar/access_right/c_abf2https://creativecommons.org/licenses/by-nc/4.0/Itraconazole in combination with neutrophil depletion reduces the expression of genes related to pulmonary fibrosis in an experimental model of paracoccidioidomycosisItraconazoleItraconazolParacoccidioidomycosisParacoccidioidomicosisNeutrophilsNeutrófilosFibrosisFibrosisParacoccidioidesMed. Mycol.Medical Mycology579590565ORIGINALGonzalezAngel_2018_ItraconazolePulmonary.pdfGonzalezAngel_2018_ItraconazolePulmonary.pdfArtículo de investigaciónapplication/pdf4224260http://bibliotecadigital.udea.edu.co/bitstream/10495/24132/1/GonzalezAngel_2018_ItraconazolePulmonary.pdfd69b733d65c98c882c793a5a82543f6dMD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8933http://bibliotecadigital.udea.edu.co/bitstream/10495/24132/2/license_rdfc0c92b0ffc8b7d22d9cf56754a416a76MD52LICENSElicense.txtlicense.txttext/plain; charset=utf-81748http://bibliotecadigital.udea.edu.co/bitstream/10495/24132/3/license.txt8a4605be74aa9ea9d79846c1fba20a33MD5310495/24132oai:bibliotecadigital.udea.edu.co:10495/241322022-04-22 10:22:11.876Repositorio Institucional Universidad de Antioquiaandres.perez@udea.edu.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 |