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

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art_SKLEPKIEWICZ_Inhibition_of_MacrophageSpecific_CHIT1_as_an_Approach_to_.PDF (3.54 MB)
Citações na Scopus
1
Tipo de produção
article
Data de publicação
2023
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
MDPI
Autores
SKLEPKIEWICZ, Piotr
DYMEK, Barbara
MLACKI, Michal
ZAGOZDZON, Agnieszka
SALAMON, Magdalena
SIWINSKA, Anna Maria
MAZURKIEWICZ, Marcin Piotr
MAZUR, Marzena
Citação
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v.24, n.5, article ID 4719, 16p, 2023
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
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-naive 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 TGF beta 1 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.
Palavras-chave
macrophage, chitotriosidase, asthma
URI
https://observatorio.fm.usp.br/handle/OPI/53098
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Coleções
Artigos e Materiais de Revistas Científicas - FM/MPT
Artigos e Materiais de Revistas Científicas - LIM/05
Artigos e Materiais de Revistas Científicas - LIM/26
Artigos e Materiais de Revistas Científicas - ODS/03