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

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

doi:10.1590/s2175-97902022e201089

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Brazilian Journal of Pharmaceutical Sciences

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Article • Braz. J. Pharm. Sci. 58 • 2022 • https://doi.org/10.1590/s2175-97902022e201089 copy

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

Authorship SCIMAGO INSTITUTIONS RANKINGS

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.

Keywords:
Protease-activated receptor 2; Lung inflammation; Airway remodeling; Allergic asthma

		Treatment groups
		PBS i.p.	PBS i.p.	ENMD1068 i.p.
		PBS i.n.	OVA 10 μg i.n.
4 h	Eosinophils	0.00 ± 0.00	0.2 ± 0.05***	0.1 ± 0.03^#
	Neutrophils	0.02 ± 0.01	1.8 ± 0.2***	1.5 ± 0.3
	Mononuclear cells	4.0 ± 0.2	2.7 ± 0.2**	2.8 ± 0.3**
	Total	4.1 ± 0.2	4.84 ± 0.4	4.4 ± 0.4
24 h	Eosinophils	0.02 ± 0.01	2.4 ± 0.3***	1.0 ± 0.1^###
	Neutrophils	0.01 ± 0.01	0.4 ± 0.1**	0.4 ± 0.05
	Mononuclear cells	4.4 ± 0.2	3.2 ± 0.3*	3.8 ± 0.4
	Total	4.4 ± 0.2	6.0 ± 0.4*	5.2 ± 0.5

Histopathological Scoring System for Mouse Lungs
Points	Score 1	Score 2	Score 3	Score 4	Score 5	Total
	Airway inflammation	Vascular inflammation	Parenchymal inflammation	Eosinophil infiltrating	Neutrophil infiltrating
0	Lack of inflammatory cells around airways - Absent	Lack of inflammatory cells around vessels - Absent	< 1% affected	No eosinophilic inflammation around airways	No neutrophilic inflammation around airways
1	Some airways have small numbers of cells - Mild	Some vessels have small numbers of cells - Mild	1-9% affected	Few eosinophils around airways	Few neutrophils around airways
2	Some airways have significant inflammation - Moderate	Some vessels have significant inflammation - Moderate	10-29% affected	Some eosinophils in airways	Some neutrophils in airways
3	Majority of airways have some inflammation - Marked	Majority of vessels have some inflammation - Marked	30-49% affected	Many eosinophils in airways	Many neutrophils in airways
4	Majority of airways are significantly inflamed- Severe	Majority of vessels are significantly inflamed - Severe	50-69% affected	Airways are Significantly inflamed	Airways are Significantly inflamed
5	-	-	> 70% affected	-	-
Total	4	4	5	4	4	21

Points	Score 1	Score 2	Score 3	Total
	Epithelium of the airways	Inflammatory cells	Parenchyma
0	Absence of expression in the airway epithelium - Absent	Absence of inflammatory cells with expression - Absent	< 1% affected
1	Low expression in the airway epithelium - Mild	Few cells marked - Mild	1-9% affected
2	Significant marking of airway epithelium - Moderate	Significant expression - Moderate	10-29% affected
3	Most airways are marked - Marked	Most cells express - Marked	30-49% affected
4	Airway epithelium is significantly reactive - Severe	Very intense expression - Severe	50-69% affected
5	-	-	> 70% affected
Total	4	4	5	13

Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br

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[1] *Correspondence: A. Klein. Laboratório de Inflamação e Dor. Departamento de Farmacologia. Instituto de Ciências Biológicas. Universidade Federal de Minas Gerais. Av. Presidente Antônio Carlos, 6627, Pampulha, 31270-010. Belo Horizonte, Minas Gerais, Brasil. Phone: + 55 31 34092711. E-mail: klein@ufmg.br.