The Role of Type 2 Inflammation in Schistosoma-Induced Pulmonary Hypertension

Abstract

Approximately 5% of individuals chronically infected with Schistosoma mansoni develop pulmonary hypertension (PH). The disease is progressive and often fatal, and treatment options are palliative, not curative. Recent studies have unraveled major players of the Th2 inflammation axis in the Schistosoma-induced PH pathology using murine models and studying human samples. TGF-β signaling is a link between the Type 2 inflammation and vascular remodeling, and specifically Thrombospondin-1 (TSP-1) is upregulated by the inflammation and activates TGF-β. Overall, the current model for the pathogenesis of Schistosoma-induced PH is that deposition of Schistosoma mansoni eggs in the pulmonary vasculature results in localized Th2 inflammation, leading to TGF-β activation by TSP-1, and the active TGF-β then results in vascular remodeling and PH.

Keywords: Th2 inflammation; pulmonary hypertension; schistosomiasis; transforming growth factor β (TGF-β); vascular remodeling.

Figure 1

Data from the case example. (A) The patient's electrocardiogram showed evidence of right atrial enlargement (black arrowheads) and right ventricular hypertrophy. Arrows show large R waves, and gray arrowheads show inverted T waves in V1 and V2. (B) The chest radiograph showed severe cardiomegaly. (C,D) Echocardiography revealed severe enlargement of the right atrium and right ventricle, and Doppler examination of the tricuspid valve resulted in an estimated pressure gradient of 120 mm Hg. Pulmonary pathology found on autopsy included (E) plexiform lesions and (F) concentric intimal thickening. Hematoxylin and eosin stain, original magnification × 20. Scale bars are 100 μm [Reprinted with permission from Graham et al. (11)].

Figure 2

Mice exposed to Schistosoma mansoni eggs develop pulmonary hypertension (PH) and vascular remodeling. (A) Mice intraperitoneally sensitized to S mansoni eggs followed by intravenous augmentation have an increase in right ventricular (RV) systolic pressure (RVSP; mean ± SE; n = 5–6 mice per group; rank-sum test, ^****P < 0.001; this experiment was repeated 3 times with similar results). (B) Representative hematoxylin and eosin (H&E) and immunofluorescence staining for α-smooth muscle actin (α-SMA) and thrombomodulin of unexposed and intraperitoneal/ intravenous egg–exposed mouse lungs (scale bars, 50 μm). (C,D) Quantitative fractional thickness of the pulmonary vascular media and intima in unexposed and intraperitoneal/ intravenous egg–exposed mice (mean ± SE; n = 5–6 mice per group; rank-sum test, ^**P < 0.01; P = 0.66 for intima thickness). (E) Fulton index [RV/(LV+S)] of unexposed and intraperitoneal/intravenous egg– exposed mice (mean ± SE; n = 5–6 mice per group; rank-sum test, P = 0.052) [Reprinted with permission from Graham et al. 12].