Abstract
Defective apoptosis of eosinophils, the main leukocyte in the pathogenesis of asthma, and delay in its removal lead to lung damage and loss of pulmonary function due to failure in the resolution of inflammation. Here, we investigated the ability of angiotensin-(1–7) [Ang-(1–7)], a pivotal peptide of the renin–angiotensin system, to promote resolution of an allergic lung inflammatory response. Balb/c mice were sensitized and challenged with ovalbumin and treated with Ang-(1–7) at the peak of the inflammatory process. Bronchoalveolar lavage (BAL) fluid and lungs were collected 24 h after treatment. Different lung lobes were processed for histology to evaluate inflammatory cell infiltration, airway and pulmonary remodeling, total collagen staining, and measurements of (i) collagen I and III mRNA expression by qRT-PCR; (ii) ERK1/2, IκB-α, and GATA3 protein levels by Western blotting; and (iii) eosinophilic peroxidase activity. Total number of inflammatory cells, proportion of apoptotic eosinophils and immunofluorescence for caspase 3 and NF-κB in leukocytes were evaluated in the BAL. Mas receptor immunostaining was evaluated in mouse and human eosinophils. Engulfment of human polimorphonuclear cells by macrophages, efferocytosis, was evaluated in vivo. Ang-(1–7) reduced eosinophils in the lung and in the BAL, increased the number of apoptotic eosinophils, shown by histology criteria and by increase in caspase 3 immunostaining. Furthermore, Ang-(1–7) decreased NF-kB immunostaining in eosinophils, reduced GATA3, ERK1/2, and IκB-α expression in the lung and decreased pulmonary remodeling and collagen deposition. Importantly, Ang-(1–7) increased efferocytosis. Our results demonstrate, for the first time, Ang-(1–7) activates events that are crucial for resolution of the inflammatory process of asthma and promotion of the return of lung homeostasis, indicating Ang-(1–7) as novel endogenous inflammation-resolving mediator.
Highlights
Resolution of inflammation is an active process that allows cessation of inflammation and re-establishment of tissue homeostasis (1–3)
Mice (8–9 weeks of age, weighing 20–25 g) were randomly assigned to four groups: (i) salinesensitized and saline-challenged, control group (CTRL; n = 15); (ii) ovalbumin (OVA)-sensitized and OVA-challenged group (OVA; n = 15); (iii) OVA-sensitized and OVA-challenged group treated by oral administration of Ang-(1–7)/hydroxypropyl β-cyclodextrin (HPβCD) [OVA + Ang-(1–7); n = 15]; and (iv) OVA-sensitized and OVA-challenged group treated by intranasal administration of Ang-(1–7)/HPβCD [OVA + Ang-(1–7); n = 10]
Considering the majority of Ang-(1–7) actions described to date are mediated by Mas receptor (18, 19), using immunofluorescence, we first showed that Mas receptor is present in both murine (Figure 1A) and human (Figure S1 in Supplementary Material) eosinophils
Summary
Resolution of inflammation is an active process that allows cessation of inflammation and re-establishment of tissue homeostasis (1–3) It is a process characterized by prevention of excessive trafficking of leukocytes to the site of damage, shutdown intracellular signaling molecules associated with cytokine production and leukocyte survival, induction of apoptosis of recruited inflammatory cells, and promotion of clearance of apoptotic leukocytes, i.e., efferocytosis (1–5). In chronic inflammatory diseases, including asthma, failure to resolve the inflammatory process causes a persistent inflammation with consequent tissue destruction and loss of organ function (6). In this context, maintenance of inflammation alters pulmonary homeostasis and culminates with clinical manifestations that affect quality of life of asthmatic patients (7). The large increase in incidence of asthma is becoming a major global health problem and has encouraged studies aimed at increasing the knowledge of the pathophysiology of asthma, as well as development of new treatments to improve clinical management of the disease, mainly to meet asthma patients who do not respond well to current therapies (14)
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