Abstract

IntroductionAsthma is characterized by an imbalance between proteases and their inhibitors. Hence, an attractive therapeutic option could be to interfere with asthma-associated proteases. Here we exploited this option by assessing the impact of nafamostat, a serine protease inhibitor known to neutralize mast cell tryptase. MethodsNafamostat was administered in a mouse model for asthma based on sensitization by house dust mite (HDM) extract, followed by the assessment of effects on airway hyperreactivity, inflammatory parameters and gene expression. ResultsWe show that nafamostat efficiently suppressed the airway hyperreactivity in HDM-sensitized mice. This was accompanied by reduced infiltration of eosinophils and lymphocytes to the airways, and by lower levels of pro-inflammatory compounds within the airway lumen. Further, nafamostat had a dampening impact on goblet cell hyperplasia and smooth muscle layer thickening in the lungs of HDM-sensitized animals. To obtain deeper insight into the underlying mechanisms, a transcriptomic analysis was conducted. This revealed, as expected, that the HDM sensitization caused an upregulated expression of numerous pro-inflammatory genes. Further, the transcriptomic analysis showed that nafamostat suppressed the levels of multiple pro-inflammatory genes, with a particular impact on genes related to asthma. DiscussionTaken together, this study provides extensive insight into the ameliorating effect of nafamostat on experimental asthma, and our findings can thereby provide a basis for the further evaluation of nafamostat as a potential therapeutic agent in human asthma.

Keywords

nafamostat; serine proteases; asthma; house dust mite; cytokines; airway hyperreactivity; inflammation

Published in

Frontiers in Immunology
2023, Volume: 14, article number: 1136780
Publisher: FRONTIERS MEDIA SA

SLU Authors

• Allam, Venkata

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    
  • Uppsala University

• Waern, Ida

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    

• Taha, Sowsan

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    

• Akula, Srinivas

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    

• Wernersson, Sara

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    

UKÄ Subject classification

Pathobiology
Immunology in the medical area


Publication identifier

DOI: https://doi.org/10.3389/fimmu.2023.1136780

Permanent link to this page (URI)

https://res.slu.se/id/publ/122177