Pharmacological blockade of protease-Activated Receptor 2 improves airway remodeling and lung inflammation in experimental allergic asthma

Natália Alves Matos; Diego Carlos  Reis; Lucas Kraemer Rocha; Matheus Silvério Mattos; Geovanni Dantas  Cassali; Remo Castro Russo; Andrea Castro Perez; André Klein

doi:10.1590/s2175-97902022e201089

Authors

Natália Alves Matos Department of Biological Sciences, Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil; Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
Diego Carlos Reis Department of General Pathology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
Lucas Kraemer Rocha Laboratory of Pulmonary Immunology and Mechanics, Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
Matheus Silvério Mattos Laboratory of Pulmonary Immunology and Mechanics, Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
Geovanni Dantas Cassali Department of General Pathology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
Remo Castro Russo Laboratory of Pulmonary Immunology and Mechanics, Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
Andrea Castro Perez Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
André Klein Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil https://orcid.org/0000-0001-9788-4647

DOI:

https://doi.org/10.1590/s2175-97902022e201089

Keywords:

Protease-activated receptor 2, Lung inflammation, Airway remodeling, Allergic asthma

Abstract

Protease-activated receptors (PARs) are metabotropic G-protein-coupled receptors that are activated via proteolytic cleavage of a specific sequence of amino acids in their N-terminal region. PAR2 has been implicated in mediating allergic airway inflammation. This study aims to study the effect of PAR2 antagonist ENMD1068in lung inflammation and airway remodeling in experimental asthma. Allergic lung inflammation was induced in sensitized BALB/c mice through intranasal instillations of ovalbumin (OVA), and mice were pretreated with ENMD1068 1 hour before each OVA challenge. Bronchoalveolar lavage fluid (BALF) was collected, and the lungs were removed at different time intervals after OVA challenge to analyze inflammation, airway remodeling and airway hyperresponsiveness. Ovalbumin promoted leukocyte infiltration into BALF in a PAR2-dependent manner. ENMD1068 impaired eosinophil peroxidase (EPO) and myeloperoxidase (MPO) activity in the lung parenchyma into BALF and reduced the loss of dynamic pulmonary compliance, lung resistance in response to methacholine, mucus production, collagen deposition and chemokine (C-C motif) ligand 5 expression compared to those in OVA-challenged mice. We propose that proteases released after an allergen challenge may be crucial to the development of allergic asthma in mice, and PAR2 blockade may be useful as a new pharmacological approach for the treatment of airway allergic diseases.

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