In:
Allergy, Wiley, Vol. 72, No. 7 ( 2017-07), p. 1061-1072
Abstract:
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, PKC α‐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 PKC α 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.
Type of Medium:
Online Resource
ISSN:
0105-4538
,
1398-9995
DOI:
10.1111/all.2017.72.issue-7
Language:
English
Publisher:
Wiley
Publication Date:
2017
detail.hit.zdb_id:
2003114-2
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