Angiotensin-(1-7) inhibits allergic inflammation, via the MAS1 receptor, through suppression of ERK1/2- and NF-κB-dependent pathways

Br J Pharmacol. 2012 Jul;166(6):1964-76. doi: 10.1111/j.1476-5381.2012.01905.x.

Abstract

BACKGROUND AND PURPOSE Angiotensin-(1-7) [Ang-(1-7)] has anti-inflammatory effects in models of cardiovascular disease and arthritis, but its effects in asthma are unknown. We investigated whether Ang-(1-7) has anti-inflammatory actions in a murine model of asthma. EXPERIMENTAL APPROACH The effects of Ang-(1-7) alone or in combination with the MAS1 receptor antagonist, A779, were evaluated over a 4 day period in an ovalbumin-challenged mouse model of allergic asthma. On day 5, bronchoalveolar lavage was performed, and lungs were sectioned and assessed histologically for quantification of goblet cells, perivascular and peribronchial inflammation and fibrosis. Biochemical analysis of the pro-inflammatory ERK1/2 and IκB-α was assessed. In addition, the effect of Ang-(1-7) on proliferation of human peripheral blood mononuclear cells (HPBMC) was investigated. KEY RESULTS Ang-(1-7) attenuated ovalbumin-induced increases in total cell counts, eosinophils, lymphocytes and neutrophils. Ang-(1-7) also decreased the ovalbumin-induced perivascular and peribronchial inflammation, fibrosis and goblet cell hyper/metaplasia. Additionally, Ang-(1-7) reduced the ovalbumin-induced increase in the phosphorylation of ERK1/2 and IκB-α. These effects of Ang-(1-7) were reversed by the MAS1 receptor antagonist A779. Furthermore, Ang-(1-7) inhibited phytohaemagglutinin (PHA)-induced HPBMC proliferation. CONCLUSION AND IMPLICATIONS Ang-(1-7), via its MAS1 receptor, acts as an anti-inflammatory pathway in allergic asthma, implying that activation of the MAS1 receptor may represent a novel approach to asthma therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allergens / administration & dosage
  • Angiotensin I / pharmacology*
  • Angiotensin II / analogs & derivatives
  • Angiotensin II / pharmacology
  • Animals
  • Asthma / immunology*
  • Asthma / pathology
  • Bronchoalveolar Lavage Fluid / cytology
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Humans
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology
  • MAP Kinase Signaling System / drug effects
  • Male
  • Mice
  • Mice, Inbred BALB C
  • NF-kappa B / immunology
  • Ovalbumin / administration & dosage
  • Peptide Fragments / pharmacology*
  • Phytohemagglutinins / pharmacology
  • Pneumonia / immunology*
  • Pneumonia / pathology
  • Proto-Oncogene Proteins / immunology*
  • Receptors, G-Protein-Coupled / immunology*

Substances

  • 7-Ala-angiotensin (1-7)
  • Allergens
  • NF-kappa B
  • Peptide Fragments
  • Phytohemagglutinins
  • Proto-Oncogene Proteins
  • Receptors, G-Protein-Coupled
  • proto-oncogene proteins c-mas-1
  • Angiotensin II
  • Ovalbumin
  • Angiotensin I
  • angiotensin I (1-7)