Introduction: Spleen tyrosine kinase (Syk) mediates bronchoconstriction. However, its role in pulmonary vasoconstriction and pulmonary vascular hyperresponsiveness is unknown.

Aims and objectives: We hypothesized that intracellular signal transduction via Syk is relevant for pulmonary arterial smooth muscle cell contraction with potential significance for the pathogenesis of pulmonary arterial hypertension (PAH).

Methods: Vascular Syk expression was analyzed by immunofluorescence microscopy in human (PAH patients vs. donors) and mouse lungs. The effects of Syk inhibition (either with BAY 61-3606 or with BI 1002494) on pulmonary vasoconstriction were assessed in human precision-cut lung slices, in analgosedated ventilated pigs as well as in isolated perfused and ventilated mouse lungs. For mechanistic analyses, transgenic murine models (deficient in eNOS, PKC?, or mast cells) were assessed. A model of ovalbumin-induced pulmonary Th2 inflammation was used to study pulmonary vascular hyperresponsiveness.

Results: Syk expression was detected in human and murine pulmonary arterial smooth muscle cells. Syk inhibition reduced pulmonary vasoconstriction in all analyzed species (human, pig, mouse). Syk-mediated vasoconstriction was independent of eNOS, PKC?, or mast cell expression. In vivo, in analgosedated ventilated pigs, Syk inhibitor BI 1002494 largely reduced hypoxic pulmonary vasoconstriction. Both pulmonary vascular hyperresponsiveness and pre-established vasoconstriction were diminished in isolated perfused mouse lungs following Syk inhibition.

Conclusions: Syk is required for (hypoxic) pulmonary vasoconstriction, and may serve as a therapeutic target in PAH.