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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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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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. |
format | Online Article Text |
id | pubmed-10003607 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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