Targeting carboxypeptidase A/B activity with the phosphinic inhibitor C28 reduces the asthmatic response in a mouse model of house dust mite-induced asthma.

IF 4.8 3区 医学 Q2 CELL BIOLOGY
Venkata Sita Rama Raju Allam, David Montpeyó, Fabrice Beau, Sowsan Taha, Ida Waern, Srinivas Akula, Francesc Xavier Avilés, Julia Lorenzo, Laurent Devel, Gunnar Pejler, Sara Wernersson
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Abstract

Objective: Metallo-carboxypeptidases are implicated in several pathological contexts but their role in asthma and their potential as therapeutic targets in asthmatic settings are only partly understood. This study sought to investigate whether inhibition of carboxypeptidase activity of A and B-type could mitigate asthma-like symptoms in a mouse model of allergic airway inflammation.

Methods: BALB/c mice were sensitized and challenged with repeated intranasal instillations of 10 µg house dust mite extract. Prior to each instillation, groups of mice received intraperitoneally from 0.2 to 1 mg/kg of compound 28, a phosphinic inhibitor of A/B-type carboxypeptidases. Manifestations of asthma-like features were assessed, including airway hyperresponsiveness, airway inflammation, lung histopathology and inflammatory markers.

Results: Treatment with compound 28 protected against airway hyperresponsiveness and profoundly reduced the house dust mite-induced inflammation both in airways and in lung tissue. Moreover, compound 28 could mitigate airway smooth muscle and goblet cell remodelling as well as inflammatory gene expression in the lungs.

Conclusions: Compound 28 could suppress multiple features of asthma in a physiologically relevant mouse model, reinforcing the potential of targeting A/B type carboxypeptidases for therapeutic purposes in allergic asthma.

用磷酸抑制剂C28靶向羧肽酶A/B活性可降低屋尘螨诱发哮喘小鼠模型的哮喘反应。
目的:金属羧肽酶与多种病理环境有关,但其在哮喘中的作用及其作为哮喘治疗靶点的潜力仅部分被了解。本研究旨在探讨A型和b型羧肽酶活性的抑制是否可以减轻过敏性气道炎症小鼠模型的哮喘样症状。方法:用10µg房尘螨提取物反复灌胃致敏BALB/c小鼠。在每次注射前,各组小鼠腹腔注射0.2 - 1mg /kg化合物28,a / b型羧肽酶的磷酸抑制剂。评估哮喘样特征的表现,包括气道高反应性、气道炎症、肺组织病理学和炎症标志物。结果:化合物28对气道高反应性有保护作用,并能显著减轻屋尘螨引起的气道和肺组织炎症。此外,化合物28可以减轻气道平滑肌和杯状细胞的重塑以及肺部炎症基因的表达。结论:化合物28可以抑制哮喘的多种生理相关小鼠模型,增强了靶向a /B型羧肽酶治疗过敏性哮喘的潜力。
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来源期刊
Inflammation Research
Inflammation Research 医学-免疫学
CiteScore
9.90
自引率
1.50%
发文量
134
审稿时长
3-8 weeks
期刊介绍: Inflammation Research (IR) publishes peer-reviewed papers on all aspects of inflammation and related fields including histopathology, immunological mechanisms, gene expression, mediators, experimental models, clinical investigations and the effect of drugs. Related fields are broadly defined and include for instance, allergy and asthma, shock, pain, joint damage, skin disease as well as clinical trials of relevant drugs.
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