Abstract
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.
Highlights
Chronic airway inflammatory response is characterized by repeating cycles of allergen insults and airway repair leading to structural and functional changes such as airway remodeling, airway obstruction and hyperresponsiveness (AHR) [1, 2]
OVA challenge resulted in a significant (P
The major finding of this study is that the anti-inflammatory effects of Ang-(1–7) in an allergic murine model of asthma are mediated, at least in part, via the inhibition of Src and EGFR phosphorylation and consequent suppression of their downstream signaling effectors such as ERK1/2
Summary
Chronic airway inflammatory response is characterized by repeating cycles of allergen insults and airway repair leading to structural and functional changes such as airway remodeling, airway obstruction and hyperresponsiveness (AHR) [1, 2]. As predicted by “network biology analysis”, to have any significant impact on disease metrics, several “nodes” need to be targeted simultaneously, rather than blockade of individual mediator signaling pathways [8]. This approach is in line with the mechanisms of action of steroids, the most effective asthma therapy, which act to “switch off” many pro-inflammatory signaling pathways simultaneously and is so far the gold standard in asthma therapy [9]
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