Abstract
The presence of eosinophils and neutrophils in the lungs of asthmatic patients is associated with the severity of the disease and resistance to corticosteroids. Thus, defective resolution of eosinophilic and neutrophilic inflammation is importantly related to exacerbation of asthma. In this study, we investigated a therapeutic action of angiotensin-(1-7) (Ang-(1-7)) in a model of asthma induced by ovalbumin (OVA) and lipopolysaccharide (LPS). Balb-c mice were sensitized and challenged with OVA. Twenty-three hours after the last OVA challenge, experimental groups received LPS, and 1 h and 7 h later, mice were treated with oral formulation of Ang-(1-7). On the next day, 45 h after the last challenge with OVA, mice were subjected to a test of motor and exploratory behavior; 3 h later, lung function was evaluated, and bronchoalveolar lavage fluid (BALF) and lungs were collected. Motor and exploratory activities were lower in OVA + LPS-challenged mice. Treatment with Ang-(1-7) improved these behaviors, normalized lung function, and reduced eosinophil, neutrophil, myeloperoxidase (MPO), eosinophilic peroxidase (EPO), and ERK1/2 phosphorylation (p-ERK1/2) in the lungs. In addition, Ang-(1-7) decreased the deposition of mucus and extracellular matrix in the airways. These results extended those of previous studies by demonstrating that oral administration of Ang-(1-7) at the peak of pulmonary inflammation can be valuable for the treatment of neutrophil- and eosinophil-mediated asthma. Therefore, these findings potentially provide a new drug to reverse the natural history of the disease, unlike the current standards of care that manage the disease symptoms at best.
Highlights
Respiratory infections, most frequently those caused by Gramnegative bacteria, especially Haemophilus influenzae, Mycoplasma pneumoniae, and Chlamydia pneumoniae, are associated with asthma induction, progression, and exacerbation (Kumari et al, 2015; Hadjigol et al, 2020)
Exploratory and locomotor activities were evaluated in control (n 6), ovalbumin (OVA) and LPS challenge (OVA + LPS; n 6), and OVA + LPS mice treated with Ang-(1-7)/HPBCD (60 μg/kg; n 6). *p < 0.05 is relative to the CRTL group, and #p < 0.05 is relative to the OVA + LPS group
OVA + LPS-challenged mice presented marked mucus deposition in the airway compared to CTRL mice (A), which was greatly attenuated by Ang-(1-7) treatment. (D) Quantification of the periodic acid–Schiff (PAS) stain positive area in the lungs (n 5 each). (E) Extracellular matrix deposition in the lung (%; n 5–6). *p < 0.05 is relative to the CRTL group, and #p < 0.05 is relative to the OVA-LPS group
Summary
Respiratory infections, most frequently those caused by Gramnegative bacteria, especially Haemophilus influenzae, Mycoplasma pneumoniae, and Chlamydia pneumoniae, are associated with asthma induction, progression, and exacerbation (Kumari et al, 2015; Hadjigol et al, 2020). Corticosteroid-resistant asthma presented an increase in LPS in the bronchoalveolar lavage fluid (BALF) and inflammatory patterns characteristic of the activation of this endotoxin (Goleva et al, 2008). In this regard, Lowe et al (2015) showed that guinea pigs with eosinophilic pulmonary inflammation induced by ovalbumin (OVA) presented a prolongation of pulmonary inflammation and reduction in corticosteroids sensitivity, after exposure to LPS. In this regard, Lowe et al (2015) showed that guinea pigs with eosinophilic pulmonary inflammation induced by ovalbumin (OVA) presented a prolongation of pulmonary inflammation and reduction in corticosteroids sensitivity, after exposure to LPS. Hadjigol et al (2020) reported that exacerbations in an LPS-induced asthma model are associated with steroid resistance
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