Nintedanib has acute pulmonary vasodilatory effects in transgenic Fra2 mice with spontaneous progressive pulmonary hypertension and lung fibrosis

Abstract

Rationale: Pulmonary hypertension (PH) is common in interstitial lung disease (ILD) and impacts survival. Nintedanib slows disease progression and reduces exacerbations in idiopathic pulmonary fibrosis (IPF). Nintedanib has anti-fibrotic and anti-inflammatory properties, however, its effect on the pulmonary vascular tone is largely unknown. Objective: To test if nintedanib has vasoactive effects on pulmonary arteries. Methods: We used Fra2 overexpressing mice (Fra2), which develop spontaneous PH and ILD. Wire myography was applied in intra-pulmonary arteries (IPA) in Fra2 and wildtype mice (WT). IPA were pre-constricted with U46619. Contributions of the endothelium were checked by investigation of intact and endothelium-denuded vessels ± L-NAME. The flow-induced pressure changes ± nintedanib were assessed in isolated perfused and ventilated Fra2 lungs. Results: Nintedanib induced significant pulmonary arterial relaxation both in Fra2 and WT. The relaxation was more pronounced in Fra2 compared to WT vessels at concentrations of 300nM - 3µM. Maximum relaxation was observed at 3µM in Fra2 and WT (-22% vs -9.5%, p Conclusion: Nintedanib has endothelium-independent acute vasodilatory effects in Fra2 and WT pre-constricted pulmonary arteries. This vasodilation is more pronounced in Fra2 as compared to WT mice. Further exploration of the underlying mechanisms is warranted.