Syk expression and function in the pulmonary vasculature

Abstract

Introduction: In the airways, spleen tyrosine kinase (Syk) promotes inflammation, smooth muscle cell proliferation and contraction (Tabeling, C. et al. Allergy 2017 Jul;72(7):1061-1072). However, little is known about the expression and role of Syk in the vascular compartment of the lung. Here, we analyzed Syk expression and function in the pulmonary vasculature and its possible involvement in the pathogenesis of pulmonary arterial hypertension (PAH). Methods: In human (PAH vs. donor) and murine lungs, Syk expression was assessed by immunofluorescence and spectral confocal microscopy. Syk function was analyzed in human precision-cut lung slices (PCLS) and in isolated perfused lungs of wild-type mice or mice deficient in eNOS, PKCα or mast cells with or without inhibition of Syk, PKC, rho kinase, p38 MAPK and/or NO synthase. Pulmonary vascular hyperresponsiveness was investigated following induction of pulmonary Th2 inflammation. Results: Syk was expressed in pulmonary arterial smooth muscle cells of both control and PAH lungs. 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 preconstricted lungs, Syk inhibition rapidly reversed vasoconstriction in a NO-independent manner. Pulmonary vascular hyperresponsiveness was markedly diminished following Syk inhibition. Inhibition of p38 MAPK reduced pulmonary vasoconstriction 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 regulates pulmonary vasoconstriction, presumably via p38 MAPK, and may be a promising target in PAH therapy.