Schistosome infection and its effect on pulmonary circulation

Abstract

Schistosomiasis is the most common parasitic disease associated with pulmonary hypertension. It induces remodelling via complex inflammatory processes, which eventually produce the clinical manifestation of pulmonary hypertension. The pulmonary hypertension shows clinical signs and symptoms that are not distinguishable from other forms of pulmonary arterial hypertension.

Figure 1.. A world map showing the geographical distribution of Schistosomiasis with its approximate prevalence.

The yellow bubbles are examples of incidences that increase the prevalence of Schistosomiasis (see text).

Figure 2.. Infographic history of discovery of schistosomiasis from ancient time till the commencement of the 20th century.

Figure 3.. Schistosoma life cycle.

(1) Eggs passed to the fresh water with faeces or urine (depends on the schistosomiasis species ); (2) when eggs hatch Miracidia will be released in the fresh water; (3) Miracida enter intermediary freshwater snails (depends on the schistosomiasis species, see text; (4) after certain gestating period Cercaria are released from the snails to the freshwater; (5) Cercaria enter human venous system (6) after entering the venous system the worn undergo transformation and changed and reside in the target organs (7). The worm will produce many eggs. Some organs trap eggs causing pathological changes, other are released with faeces or urine, and the cycle continues.

Figure 4.. Eggs from the main three human Schistosoma parasite, showing the size and the location of the spine (red arrows) which is one of the main species differentiators.

Figure 5.. Schematic representation showing the development and cellular composition (right panel) of the granuloma around the Schistosoma eggs.

The proportion and types of cells, which comprise granulomas varies depending on the species of infecting schistosome. The process of granuloma development is driven by the egg’s antigens and its growth by cytokines and chemokines released by T lymphocytes. Granuloma formation begins with the initial recruitment of macrophages, eosinophils, and neutrophils around the entrapped egg (Panel 1). These cells cause an inflammatory reaction causing the recruitment of more cells and the development of the granuloma size (Panel 2). Panel (3) shows the final stage of, resolve the granuloma once the antigenic stimulus (mainly the eggs) has been destroyed, resulting in deposition of fibrils of chromatin and collagens, and subsequent collagen degradation and remodelling that contribute to the final tissue fibrosis.

Figure 6.. Schistosomiasis induced granuloma in the lung (mouse model 12 weeks after infection with Schistosoma cercaria).

Panel A shows control normal lung tissue Panel B is showing remodelled arteriole inside a granuloma (black arrow). Panel C shows a peripheral granuloma surrounding an egg (black arrow), with a remodelled arteriole (red arrow) in the periphery of the granuloma. Panel D shows various remodelled vessels nearby a granuloma (red arrows). Staining (alpha-smooth muscle actin and von Willebrand Factor). Scale bar = 20 µm. Source: the author laboratory.

Figure 7.. The mouse model of 12 weeks after infection with Schistosoma cercaria, showed that more than two third of the mouse could be infected with eggs and presence of granulomas (left panel).

However, the right panel shows that only half of the lungs show some form of remodelling pulmonary arteries; but only 15% showed a feature that can be presented as pulmonary hypertension (mainly severe remodelling and presence of right ventricular hypertrophy). (Adopted from the author laboratory data originally published in 90).

Figure 8.. The upper panel shows a hypothetical diagram of a simplified chronological sequence of the T helper cells after the tissue is exposed to schistosome eggs.

Th1 phase is a short and immunologically aggressive initial stage, which starts a longer Th2 phase. The 2 phase helps in suppressing the Th1 activities reducing its the aggressive nature. At the same time a less understood Th17 started and remained for a longer period (see text for more details). During Th2 the most active cytokines (see the lower panel (inflammatory mediators) help in further development and maturation of the granuloma (second panel (granuloma). The major remodelling process of the pulmonary arteries can happen during this stage (Th2) (see the bottom panel) although other staff (ex Th1 and Th17) can play a part. This will be followed the appearance of Treg cells and the predominance of B cells, with the resolution of the granuloma and in most occasion the development of fibrosis.

Figure 9.. Diagrammatic representations of IL-4 and IL13 showing the interaction of IL-13 and IL-4.

These cytokines can affect the remodelling via three possible pathways; that is via TGF-β, Arginase II or RELMα pathways (see text for more details).

Figure 10.. Current understanding of the role of IL-6 and its interaction with TGF-β in the pathogenesis of schistosomiasis pulmonary vascular pathology.

TGF-β can have a complex mechanism as described in the text. In the early stage or short-term exposure to TGF-β (left panel) can stimulate via SMAD3 eNOS and VGEF and thus reduce the remodelling process, and IL-6 can substantiate this. However, with the long chronic exposure to TGF-β (right panel) may lead to a reduction in SMAD3 and with the IL-6 and Th17 cells may cause phenotypic changes in the remodelling process characterised by proliferation and migration in pulmonary smooth muscles and endothelial cells (see text).

Figure 11.. Number of studies (cumulative) assessing prevalence by year, showing a relative gap in research in pulmonary hypertension due to schistosomiasis from 1982 to 1995 and an increase since 1995 (from 293).

Figure 12.. A chest radiograph of a 52-year old man with pulmonary hypertension due to schistosomiasis.

The X ray to the left and right show the dilatation of left and right pulmonary arteries (arrows). the right panel showing the characteristic dilation of both main right and left pulmonary artery in patients with schistosomiasis pulmonary hypertension (images: courtesy of Dr Angela Bandeira).

Figure 13.. CT scan of patient with pulmonary hypertension due to schistosomiasis.

The left panel shows severe pulmonary artery dilatation (X), and in the right panel shows the right ventricular dilatation and hypertrophy. (Images: courtesy of Dr T. Safwat).