Ang-(1-7)/ MAS1 receptor axis inhibits allergic airway inflammation via blockade of Src-mediated EGFR transactivation in a murine model of asthma

Autoři: Ahmed Z. El-Hashim aff001;  Maitham A. Khajah aff001;  Rhema S. Babyson aff001;  Waleed M. Renno aff002;  Charles I. Ezeamuzie aff003;  Ibrahim F. Benter aff004;  Saghir Akhtar aff005
Působiště autorů: Department of Pharmacology & Therapeutics, Faculty of Pharmacy, Kuwait University, Kuwait City, Kuwait aff001;  Department of Anatomy, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait aff002;  Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait aff003;  Faculty of Medicine, Eastern Mediterranean University, Famagusta, North Cyprus aff004;  College of Medicine, Qatar University, Doha, Qatar aff005
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224163


The angiotensin-(1–7) [Ang-(1–7)]/MAS1 receptor signaling axis is a key endogenous anti-inflammatory signaling pathway. However, the mechanisms by which its mediates the anti-inflammatory effects are not completely understood. Using an allergic murine model of asthma, we investigated whether Ang-1(1–7)/MAS1 receptor axis a): inhibits allergic inflammation via modulation of Src-dependent transactivation of the epidermal growth factor receptor (EGFR) and downstream signaling effectors such as ERK1/2, and b): directly inhibits neutrophil and/or eosinophil chemotaxis ex vivo. Ovalbumin (OVA)-induced allergic inflammation resulted in increased phosphorylation of Src kinase, EGFR, and ERK1/2. In addition, OVA challenge increased airway cellular influx, perivascular and peribronchial inflammation, fibrosis, goblet cell hyper/metaplasia and airway hyperresponsiveness (AHR). Treatment with Ang-(1–7) inhibited phosphorylation of Src kinase, EGFR, ERK1/2, the cellular and histopathological changes and AHR. Ang-(1–7) treatment also inhibited neutrophil and eosinophil chemotaxis ex vivo. These changes were reversed following pre-treatment with A779. These data show that the anti-inflammatory actions of Ang-(1–7)/ MAS1 receptor axis are mediated, at least in part, via inhibition of Src-dependent transactivation of EGFR and downstream signaling molecules such as ERK1/2. This study therefore shows that inhibition of the Src/EGRF/ERK1/2 dependent signaling pathway is one of the mechanisms by which the Ang-(1–7)/ MAS1 receptor axis mediates it anti-inflammatory effects in diseases such as asthma.

Klíčová slova:

Asthma – Cell enumeration techniques – Eosinophils – Chemotaxis – Inflammation – Mouse models – Neutrophils – Phosphorylation


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