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Inhibition of Macrophage-Specific CHIT1 as an Approach to Treat Airway Remodeling in Severe Asthma

Chitotriosidase (CHIT1) is an enzyme produced by macrophages that regulates their differentiation and polarization. Lung macrophages have been implicated in asthma development; therefore, we asked whether pharmacological inhibition of macrophage-specific CHIT1 would have beneficial effects in asthma...

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Autores principales: Sklepkiewicz, Piotr, Dymek, Barbara, Mlacki, Michal, Zagozdzon, Agnieszka, Salamon, Magdalena, Siwińska, Anna Maria, Mazurkiewicz, Marcin Piotr, de Souza Xavier Costa, Natalia, Mazur, Marzena, Mauad, Thais, Gołębiowski, Adam, Dzwonek, Karolina, Gołąb, Jakub, Zasłona, Zbigniew
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10003607/
https://www.ncbi.nlm.nih.gov/pubmed/36902148
http://dx.doi.org/10.3390/ijms24054719
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author Sklepkiewicz, Piotr
Dymek, Barbara
Mlacki, Michal
Zagozdzon, Agnieszka
Salamon, Magdalena
Siwińska, Anna Maria
Mazurkiewicz, Marcin Piotr
de Souza Xavier Costa, Natalia
Mazur, Marzena
Mauad, Thais
Gołębiowski, Adam
Dzwonek, Karolina
Gołąb, Jakub
Zasłona, Zbigniew
author_facet Sklepkiewicz, Piotr
Dymek, Barbara
Mlacki, Michal
Zagozdzon, Agnieszka
Salamon, Magdalena
Siwińska, Anna Maria
Mazurkiewicz, Marcin Piotr
de Souza Xavier Costa, Natalia
Mazur, Marzena
Mauad, Thais
Gołębiowski, Adam
Dzwonek, Karolina
Gołąb, Jakub
Zasłona, Zbigniew
author_sort Sklepkiewicz, Piotr
collection PubMed
description Chitotriosidase (CHIT1) is an enzyme produced by macrophages that regulates their differentiation and polarization. Lung macrophages have been implicated in asthma development; therefore, we asked whether pharmacological inhibition of macrophage-specific CHIT1 would have beneficial effects in asthma, as it has been shown previously in other lung disorders. CHIT1 expression was evaluated in the lung tissues of deceased individuals with severe, uncontrolled, steroid-naïve asthma. OATD-01, a chitinase inhibitor, was tested in a 7-week-long house dust mite (HDM) murine model of chronic asthma characterized by accumulation of CHIT1-expressing macrophages. CHIT1 is a dominant chitinase activated in fibrotic areas of the lungs of individuals with fatal asthma. OATD-01 given in a therapeutic treatment regimen inhibited both inflammatory and airway remodeling features of asthma in the HDM model. These changes were accompanied by a significant and dose-dependent decrease in chitinolytic activity in BAL fluid and plasma, confirming in vivo target engagement. Both IL-13 expression and TGFβ1 levels in BAL fluid were decreased and a significant reduction in subepithelial airway fibrosis and airway wall thickness was observed. These results suggest that pharmacological chitinase inhibition offers protection against the development of fibrotic airway remodeling in severe asthma.
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spelling pubmed-100036072023-03-11 Inhibition of Macrophage-Specific CHIT1 as an Approach to Treat Airway Remodeling in Severe Asthma Sklepkiewicz, Piotr Dymek, Barbara Mlacki, Michal Zagozdzon, Agnieszka Salamon, Magdalena Siwińska, Anna Maria Mazurkiewicz, Marcin Piotr de Souza Xavier Costa, Natalia Mazur, Marzena Mauad, Thais Gołębiowski, Adam Dzwonek, Karolina Gołąb, Jakub Zasłona, Zbigniew Int J Mol Sci Article Chitotriosidase (CHIT1) is an enzyme produced by macrophages that regulates their differentiation and polarization. Lung macrophages have been implicated in asthma development; therefore, we asked whether pharmacological inhibition of macrophage-specific CHIT1 would have beneficial effects in asthma, as it has been shown previously in other lung disorders. CHIT1 expression was evaluated in the lung tissues of deceased individuals with severe, uncontrolled, steroid-naïve asthma. OATD-01, a chitinase inhibitor, was tested in a 7-week-long house dust mite (HDM) murine model of chronic asthma characterized by accumulation of CHIT1-expressing macrophages. CHIT1 is a dominant chitinase activated in fibrotic areas of the lungs of individuals with fatal asthma. OATD-01 given in a therapeutic treatment regimen inhibited both inflammatory and airway remodeling features of asthma in the HDM model. These changes were accompanied by a significant and dose-dependent decrease in chitinolytic activity in BAL fluid and plasma, confirming in vivo target engagement. Both IL-13 expression and TGFβ1 levels in BAL fluid were decreased and a significant reduction in subepithelial airway fibrosis and airway wall thickness was observed. These results suggest that pharmacological chitinase inhibition offers protection against the development of fibrotic airway remodeling in severe asthma. MDPI 2023-03-01 /pmc/articles/PMC10003607/ /pubmed/36902148 http://dx.doi.org/10.3390/ijms24054719 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sklepkiewicz, Piotr
Dymek, Barbara
Mlacki, Michal
Zagozdzon, Agnieszka
Salamon, Magdalena
Siwińska, Anna Maria
Mazurkiewicz, Marcin Piotr
de Souza Xavier Costa, Natalia
Mazur, Marzena
Mauad, Thais
Gołębiowski, Adam
Dzwonek, Karolina
Gołąb, Jakub
Zasłona, Zbigniew
Inhibition of Macrophage-Specific CHIT1 as an Approach to Treat Airway Remodeling in Severe Asthma
title Inhibition of Macrophage-Specific CHIT1 as an Approach to Treat Airway Remodeling in Severe Asthma
title_full Inhibition of Macrophage-Specific CHIT1 as an Approach to Treat Airway Remodeling in Severe Asthma
title_fullStr Inhibition of Macrophage-Specific CHIT1 as an Approach to Treat Airway Remodeling in Severe Asthma
title_full_unstemmed Inhibition of Macrophage-Specific CHIT1 as an Approach to Treat Airway Remodeling in Severe Asthma
title_short Inhibition of Macrophage-Specific CHIT1 as an Approach to Treat Airway Remodeling in Severe Asthma
title_sort inhibition of macrophage-specific chit1 as an approach to treat airway remodeling in severe asthma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10003607/
https://www.ncbi.nlm.nih.gov/pubmed/36902148
http://dx.doi.org/10.3390/ijms24054719
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