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DOI: 10.1055/s-0039-1678408
Syk Mediates Pulmonary Vasoconstriction
Publication History
Publication Date:
15 February 2019 (online)
Introduction In the airways, spleen tyrosine kinase (Syk) is a central promoter of inflammation, collagen deposition, smooth muscle cell proliferation and contraction (Tabeling C et al. Allergy 2017; 72: 1061 – 1072). To date, little is known about the role of Syk in the pulmonary vasculature. In this study, we investigated Syk expression and function in the pulmonary vasculature and its possible role in pulmonary arterial hypertension (PAH).
Methods In human (PAH vs. donor) and murine lungs, vascular Syk expression was characterized by immunofluorescence and spectral confocal microscopy. Syk function was assessed in human precision-cut lung slices (PCLS) and in isolated perfused lungs of wild-type mice or mice deficient in endothelial nitric oxide synthase (eNOS), protein kinase C isozyme alpha (PKCα) or mast cells with or without inhibition of Syk, PKC, rho kinase, p38 MAPK and/or NO synthase. Pulmonary vascular hyperresponsiveness was analyzed following induction of pulmonary Th2 inflammation.
Results Syk was expressed in pulmonary arterial smooth muscle cells of both control and PAH lungs as well as in murine lungs. Pharmacological Syk inhibition either with BAY 61-3606 or with BI 1002494 reduced pulmonary vasoconstriction in human PCLS and in isolated mouse lungs independent of eNOS, PKCα or mast cells. In the preconstricted vasculature, Syk inhibition rapidly reversed vasoconstriction independent of NO. Both hypoxic pulmonary vasoconstriction and pulmonary vascular hyperresponsiveness were markedly reduced following Syk inhibition. p38 MAPK inhibition reduced the pulmonary vasopressor response to the same extent as Syk inhibition, and simultaneous inhibition of p38 MAPK and Syk had no additive inhibitory effect when compared to Syk inhibition only.
Conclusions Syk promotes pulmonary vasoconstriction, presumably via p38 MAPK, and Syk inhibition may be a promising therapeutic approach in PAH.