C Tabeling1, J Herbert1, A C Hocke1, D J Lamb2, S L Wollin2, K J Erb2, E Boiarina1, H Movassagh3, J Scheffel4, J M Doehn1, S Hippenstiel1, M Maurer4, A S Gounni3, W M Kuebler5,6,7, N Suttorp1, M Witzenrath1. 1. Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Biberach, Germany. 2. Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. 3. Department of Immunology, University of Manitoba, Winnipeg, MB, Canada. 4. Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany. 5. Department of Physiology, Charité - Universitätsmedizin Berlin, Berlin, Germany. 6. The Keenan Research Centre for Biomedical Science of St. Michael's, University of Toronto, Toronto, ON, Canada. 7. Departments of Physiology and Surgery, University of Toronto, Toronto, ON, Canada.
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.
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: Christoph Tabeling; Carla R González Calera; Jasmin Lienau; Jakob Höppner; Thomas Tschernig; Olivia Kershaw; Birgitt Gutbier; Jan Naujoks; Julia Herbert; Bastian Opitz; Achim D Gruber; Berthold Hocher; Norbert Suttorp; Harald Heidecke; Gerd-R Burmester; Gabriela Riemekasten; Elise Siegert; Wolfgang M Kuebler; Martin Witzenrath Journal: Front Immunol Date: 2022-06-09 Impact factor: 8.786