Introduction: Inflammation and dysregulation of the immune response have been suggested to play important roles in the development of pulmonary arterial hypertension (PAH). ActRIIA-Fc, a selective trap for activins and growth differentiation factors (GDFs), is currently under evaluation in two phase 2 trials in PAH (PULSAR and SPECTRA). We have recently shown that ActRIIA-Fc reverses vascular remodeling in experimental PAH by rebalancing activin-GDF signaling with bone morphogenetic protein signaling. Here, we hypothesized that ActRIIA-Fc also reduces perivascular inflammation in experimental PAH.
Methods: ActRIIA-Fc was evaluated for effects on perivascular inflammation after therapeutic treatment in a Sugen-hypoxia-normoxia rat model of severe angio-obliterative PAH and after preventive treatment in a monocrotaline rat model of PAH exhibiting a pronounced inflammatory component. Flow cytometry and immunohistochemistry were used to quantify inflammatory cells in lungs and perivascular lesions while qRT-PCR was used to measure pulmonary expression of proinflammatory genes.
Results: Consistent with its disease-reversing effects in the Sugen-hypoxia-normoxia model, ActRIIA-Fc significantly increased the numbers of perivascular CD11b+ and CD68+ cells compared to vehicle (by 96% and 150%, respectively) whereas sildenafil did not. ActRIIA-Fc treatment also blunted the increase in expression of Vcam1 and Sele, markers of endothelial injury and known mediators of leukocyte recruitment. In addition, ActRIIA-Fc treatment reduced pulmonary expression of Il6, Ifng, and Ccl2 compared with those in vehicle (p < 0.01). In the monocrotaline model, preventive treatment with ActRIIA-Fc reduced right ventricular hypertrophy and right ventricular systolic pressure by 45% and 49%, respectively, compared to vehicle (p < 0.0001). ActRIIA-Fc treatment also completely normalized the elevated number of pulmonary CD11b+ cells in this model (p < 0.05).
Conclusions: Our results in two preclinical models of PAH indicate that ActRIIA-Fc significantly reduces pulmonary inflammation. This mechanism of action could potentially translate to clinical benefits beyond those of currently available therapies for PAH treatment.