Oral Formulation of Angiotensin-(1-7) Promotes Therapeutic Actions in a Model of Eosinophilic and Neutrophilic Asthma

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.

Keywords: LPS; allergic lung inflammation; eosinophilic inflammation; neutrophilic inflammation; renin–angiotensin system 4; resolution of inflammation.