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...

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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/
id UDEA2_f0c443b8370bacf4f8bfd7d988648bdc
oai_identifier_str oai:bibliotecadigital.udea.edu.co:10495/24132
network_acronym_str UDEA2
network_name_str Repositorio UdeA
repository_id_str
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/
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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
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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
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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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