Veröffentlichungen

Background: Spleen tyrosine kinase (Syk) is an intracellular nonreceptor tyrosinekinase, which has been implicated as central immune modulator promoting aller-gic airway inflammation. Syk inhibition has been proposed as a new therapeuticapproach in asthma. However, the direct effects of Syk inhibition on airwayconstriction independent of allergen sensitization remain elusive.

Methods: Spectral confocal microscopy of human and murine lung tissue was per-formed to localize Syk expression. The effects of prophylactic or therapeutic Syk inhi-bition on allergic airway inflammation, hyperresponsiveness, and airway remodelingwere analyzed in allergen-sensitized and airway-challenged mice. The effects of Sykinhibitors BAY 61-3606 or BI 1002494 on airway function were investigated in isolatedlungs of wild-type,PKCa-deficient, mast cell-deficient, oreNOS-deficient mice.

Results: Spleen tyrosine kinase expression was found in human and murine air-way smooth muscle cells. Syk inhibition reduced allergic airway inflammation,airway hyperresponsiveness, and pulmonary collagen deposition. In naıve mice,Syk inhibition diminished airway responsiveness independently of mast cells, orPKCaoreNOSexpression and rapidly reversed established bronchoconstrictionindependently of NO. Simultaneous inhibition of Syk and PKC revealed additivedilatory effects, whereas combined inhibition of Syk and rho kinase or Syk andp38 MAPK did not cause additive bronchodilation.

Conclusions: Spleen tyrosine kinase inhibition directly attenuates airway smoothmuscle cell contraction independent of its protective immunomodulatory effectson allergic airway inflammation, hyperresponsiveness, and airway remodeling.Syk mediates bronchoconstriction in a NO-independent manner, presumably viarho kinase and p38 MAPK, and Syk inhibition might present a promising thera-peutic approach in chronic asthma as well as acute asthma attacks.