Schistosomiasis causes remodeling of pulmonary vessels in the lung in a heterogeneous localized manner: Detailed study

Abstract

Schistosomiasis is a global parasitic disease with high impact on public health in tropical areas. Schistosomiasis is a well-described cause of pulmonary arterial hypertension (PAH). The exact pathogenesis is still unclear, though inflammatory mechanisms are suspected. Another unknown is whether the changes in the pulmonary vasculature are generalized or localized. We studied 13 mice infected with cercariae for 12 weeks compared with 10 control mice. In our model, we observed that the liver was a target during infection and was enlarged more than two-fold after infection. However, right heart hypertrophy as measured by RV/(LV + S) ratio was not observed at this time point. Moreover, we noticed that 72% of the sampled lobes (92% of the lungs) harvested from these animals costained evidence of granulomatous changes, secondary to egg deposition. We systemically mapped the distribution of granulomatous lesions in right lung lobes (n = 43) of infected mice. We observed that the distribution of the granulomatous lesions was heterogeneous. Remodeled pulmonary vessels were seen in 26% of the lobes (46% of the lungs) and were observed only in close proximity to the granuloma. No remodeling was observed in the absence of granulomas. These findings support the view that pulmonary vascular remodeling is caused by the local presence of granulomas in PAH associated with schistosomiasis. The heterogeneous nature of the remodeling partly explains why many patients with schistosomiasis do not develop pulmonary hypertension.

Keywords: experimental models; inflammation; pulmonary hypertension; schistosomiasis.

Figure 1

Lung mapping in 12 weeks Schistosoma infected mice. (A) Example of granuloma deposition and numbering in the single lobe and direction of cutting of the lobe. (B) Representative mapping of granulomas (labelled as 1, 2, and 3, respectively) and associated vessel changes in the single lobe of a single mouse. Scale bar = 20 ìm.

Figure 2

Effect of 12 weeks Schistosoma infection on liver weight and right heart hypertrophy. (A) Liver weight in the lungs 12 weeks postinfection. (B) The right ventricular index in the lungs 12 weeks postinfection as analyzed by measuring the ratio RV/(LV+S), where RV is right ventricle, LV is left ventricle, and S is septum. *P< 0.05; **P< 0.01; ***P< 0.001 versus control.

Figure 3

Adult worms in 12 weeks Schistosoma infected mice. Representative photomicrographs of lung sections. (A, B) Adult worms were localized near granuloma (brown stain), (C) egg surrounded with granuloma (green stain), (D) as well as alone. B and D are represented at original magnification 10×. A and C are represented at original magnification 20×. Scale bar = 20 μm.

Figure 4

Granuloma formation, effect on eggs deposition and deposition in the lung in 12 weeks Schistosoma infected mice. (A) Incidence of granuloma formation by lung lobe, (B) Percentage of eggs deposition according to the size of granulomas, (C) Deposition of granuloma in the lobes of the right lung.

Figure 5

Anatomy of the mouse lung, granuloma deposition, adult worms and vessel remodelling in 2 example lungs in 12 weeks Schistosoma infected mice. The diagrams show there was a heterogeneous distribution of the granulomas.

Figure 6

Vascular remodeling and inflammation in 12 weeks Schistosoma infected mice. Representative photomicrographs of lungs sections from (A) control mouse and (B, C, D, E, F) Schistosoma infected mice co-stained with alpha-smooth muscle actin and von Willebrand Factor. Negative staining (no primary antibody) revealed no signal (data not shown). (A, C, D) are presented at original magnification 10×, (B, E, F) are represented at original magnification 20×. Scale bar = 20

Figure 7

Vascular remodeling and effect of granuloma on vascular remodeling in 12 weeks Schistosoma infected mice. (A) Vascular remodeling, (B) muscularization of the vessels localized near granulomas, (C) correlation between granuloma size and vessel muscularization.