Inhaled tolafentrine reverses pulmonary vascular remodeling via inhibition of smooth muscle cell migration

The aim of the study was to assess the chronic effects of combined phosphodiesterase 3/4 inhibitor tolafentrine, administered by inhalation, during monocrotaline-induced pulmonary arterial hypertension (MCT-PAH) in rats. Monocrotaline injection provoked severe PAH, cardiac output depression and right heart hypertrophy. The media thickness of the pulmonary arteries and the proportion of muscularization of resistance vessels increased dramatically, and the migratory response of ex-vivo isolated pulmonary artery smooth muscle cells (PASMC) was increased. Micro-arrays and subsequent confirmation with real time PCR demonstrated upregulation of several extracellular matrix and adhesion genes, such as matrixmetalloproteases (MMP) 2, 8, 9, 10, 11, 12, 20, Icam, Itgax, Plat and serpinb2. When chronically nebulized from day 28 to 42, after full establishment of severe pulmonary hypertension, tolafentrine largely reversed all hemodynamic abnormalities and MCT-induced structural lung vascular changes. The upregulation of extracellular matrix regulation and adhesion genes was strongly reduced by inhalation of the tolafentrine. When assessed in vitro, tolafentrine blocked the enhanced PASMC migratory response. In conclusion, we demonstrate for the first time that inhalation of combined PDE3/4 inhibitor reverses PAH fully developed in response to monocrotaline in rats. This „reverse-remodeling“ effect includes structural changes in the lung vascular wall and key molecular pathways of matrix regulation, concomitant with near normalization of hemodynamics. Supported by DFG, SFB547 and Altana Pharma.