Schistosomiasis is a leading cause of
pulmonary hypertension (PH) worldwide. Recent studies reveal that the type-2 immune
cytokines IL-4 and
IL-13, as well as consequent activation of TGF-β, are key factors in the pathogenesis of Schistosoma-PH.
Paclitaxel has been reported to act as an adjuvant for Th2
inflammation while downregulating TGF-β activation. Moreover,
paclitaxel blocks PH in
monocrotaline and SU5416-hypoxia models. We hypothesized that
paclitaxel would augment Th2
inflammation while blocking TGF-β activation and PH after
schistosomiasis exposure. Wild-type mice (C57BL6/J; 6/group) were intraperitoneally (IP) sensitized and then intravenously (IV) challenged with Schistosoma mansoni eggs. One day after IV egg challenge, the mice were treated with a single IP dose of 25 mg/kg
paclitaxel or vehicle. Right ventricular (RV) catheterization was performed and
granuloma volumes and
vascular remodeling were quantified. Lung
cytokines were quantified by ELISA and reverse transcription polymerase chain reaction, and the quantity of active TGF-β was determined using a cell reporter line. We also investigated
hypoxia-induced PH.
Paclitaxel treatment significantly protected mice from Schistosoma-PH, with decreased RV systolic pressure ( P = 0.005) and pulmonary vascular media thickness.
Inflammation was significantly suppressed, contrary to our hypothesis, with decreased
IL-4 and
IL-13 levels, smaller
granulomas, and less active TGF-β following
paclitaxel treatment. There was no change in IFN-γ or FoxO1 or FoxO3 expression.
Paclitaxel did not suppress chronic
hypoxia-induced PH, which is also TGF-β-driven but independent of type-2 immunity.
Paclitaxel protects against Schistosoma-induced PH in mice, although by blocking proximate Th2
inflammation rather than suppressing distal TGF-β activation.