Spleen tyrosine kinase inhibition blocks airway constriction and protects from Th2-induced airway inflammation and remodeling.

Abstract

BACKGROUND:

Spleen tyrosine kinase (Syk) is an intracellular nonreceptor tyrosine kinase, which has been implicated as central immune modulator promoting allergic airway inflammation. Syk inhibition has been proposed as a new therapeutic approach in asthma. However, the direct effects of Syk inhibition on airway constriction independent of allergen sensitization remain elusive.

METHODS:

Spectral confocal microscopy of human and murine lung tissue was performed to localize Syk expression. The effects of prophylactic or therapeutic Syk inhibition on allergic airway inflammation, hyperresponsiveness, and airway remodeling were analyzed in allergen-sensitized and airway-challenged mice. The effects of Syk inhibitors BAY 61-3606 or BI 1002494 on airway function were investigated in isolated lungs of wild-type, PKCα-deficient, mast cell-deficient, or eNOS-deficient mice.

RESULTS:

Spleen tyrosine kinase expression was found in human and murine airway smooth muscle cells. Syk inhibition reduced allergic airway inflammation, airway hyperresponsiveness, and pulmonary collagen deposition. In naïve mice, Syk inhibition diminished airway responsiveness independently of mast cells, or PKCα or eNOS expression and rapidly reversed established bronchoconstriction independently of NO. Simultaneous inhibition of Syk and PKC revealed additive dilatory effects, whereas combined inhibition of Syk and rho kinase or Syk and p38 MAPK did not cause additive bronchodilation.

CONCLUSIONS:

Spleen tyrosine kinase inhibition directly attenuates airway smooth muscle cell contraction independent of its protective immunomodulatory effects on allergic airway inflammation, hyperresponsiveness, and airway remodeling. Syk mediates bronchoconstriction in a NO-independent manner, presumably via rho kinase and p38 MAPK, and Syk inhibition might present a promising therapeutic approach in chronic asthma as well as acute asthma attacks.

• Authors: C Tabeling, J Herbert, A C Hocke, D J Lamb, S L Wollin, K J Erb, E Boiarina, H Movassagh, J Scheffel, J M Doehn, S Hippenstiel, M Maurer, A S Gounni, W M Kuebler, N Suttorp, M Witzenrath
• Journal: Allergy (Allergy) Vol. 72 Issue 7 Pg. 1061-1072 (Jul 2017) ISSN: 1398-9995 [Electronic] Denmark
• PMID: 27906453 (Publication Type: Journal Article)
• Copyright: © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• 2-(7-(3,4-dimethoxyphenyl)imidazo(1,2-c)pyrimidin-5-ylamino)nicotinamide
• Allergens
• BI 1002494
• Inflammation Mediators
• Naphthyridines
• Protein Kinase Inhibitors
• Pyrimidines
• Pyrrolidinones
• Niacinamide
• Nitric Oxide
• Nitric Oxide Synthase Type III
• Syk Kinase
• Protein Kinase C-alpha
• G-Protein-Coupled Receptor Kinase 1
• GRK1 protein, human
• p38 Mitogen-Activated Protein Kinases

Topics

• Airway Remodeling (drug effects, immunology)
• Allergens (immunology)
• Animals
• Bronchial Hyperreactivity (drug therapy, etiology, metabolism, pathology)
• Bronchoconstriction (drug effects)
• Cell Proliferation (drug effects, genetics)
• Disease Models, Animal
• Female
• G-Protein-Coupled Receptor Kinase 1 (metabolism)
• Gene Expression
• Humans
• Inflammation Mediators (metabolism)
• Lung (drug effects, immunology, metabolism, pathology)
• Male
• Mice
• Naphthyridines (pharmacology)
• Niacinamide (analogs & derivatives, pharmacology)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type III (genetics, metabolism)
• Protein Kinase C-alpha
• Protein Kinase Inhibitors (pharmacology)
• Pyrimidines (pharmacology)
• Pyrrolidinones (pharmacology)
• Signal Transduction (drug effects)
• Syk Kinase (antagonists & inhibitors, genetics, metabolism)
• Th2 Cells (immunology, metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)