The AGC kinase inhibitor H89 attenuates airway inflammation in mouse models of asthma

PLoS One. 2012;7(11):e49512. doi: 10.1371/journal.pone.0049512. Epub 2012 Nov 26.

Abstract

Background: H89 is a potent inhibitor of Protein Kinase A (PKA) and Mitogen- and Stress-Activated protein Kinase 1 (MSK1) with some inhibitory activity on other members of the AGC kinase family. H89 has been extensively used in vitro but its anti-inflammatory potential in vivo has not been reported to date. To assess the anti-inflammatory properties of H89 in mouse models of asthma.

Methodology/principal findings: Mice were sensitized intraperitoneally (i.p.) to ovalbumin (OVA) with or without alum, and challenged intranasally with OVA. H89 (10 mg/kg) or vehicle was given i.p. two hours before each OVA challenge. Airway hyperresponsiveness (AHR) was assessed by whole-body barometric plethysmography. Inflammation was assessed by the total and differential cell counts and IL-4 and IL-5 levels in bronchoalveolar lavage (BAL) fluid. Lung inflammation, mucus production and mast cell numbers were analyzed after histochemistry. We show that treatment with H89 reduces AHR, lung inflammation, mast cell numbers and mucus production. H89 also inhibits IL-4 and IL-5 production and infiltration of eosinophils, neutrophils and lymphocytes in BAL fluid.

Conclusions/significance: Taken together, our findings implicate that blockade of AGC kinases may have therapeutic potential for the treatment of allergic airway inflammation.

MeSH terms

  • Animals
  • Asthma / chemically induced
  • Asthma / drug therapy
  • Asthma / immunology
  • Asthma / metabolism*
  • Bronchoalveolar Lavage Fluid / cytology
  • Bronchoalveolar Lavage Fluid / immunology
  • Cytokines / biosynthesis
  • Disease Models, Animal
  • Immunoglobulin E / blood
  • Immunoglobulin E / immunology
  • Immunoglobulin G / blood
  • Immunoglobulin G / immunology
  • Inflammation / drug therapy
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / pathology
  • Isoquinolines / administration & dosage
  • Isoquinolines / pharmacology*
  • Lung / drug effects
  • Lung / immunology
  • Lung / metabolism
  • Lung / pathology
  • Male
  • Mast Cells / drug effects
  • Mast Cells / immunology
  • Mice
  • Mucus / drug effects
  • Mucus / metabolism
  • Ovalbumin / adverse effects
  • Ovalbumin / immunology
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacology*
  • Sulfonamides / administration & dosage
  • Sulfonamides / pharmacology*
  • Th2 Cells / drug effects
  • Th2 Cells / immunology

Substances

  • Cytokines
  • Immunoglobulin G
  • Isoquinolines
  • Protein Kinase Inhibitors
  • Sulfonamides
  • Immunoglobulin E
  • Ovalbumin
  • N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide

Grant support

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.