Schistosomiasis-Associated Pulmonary Hypertension

Abstract

Inflammation is likely a critical underlying etiology in many forms of severe pulmonary hypertension (PH), and schistosomiasis-associated PH, one of the most common causes of PH worldwide, is likely driven by the host response to parasite antigens. More than 200 million people are infected with schistosomiasis, the third most common parasitic disease, and approximately 1% of those chronically infected develop PH. Acute cutaneous infection causes inflammation at the site of parasite penetration followed by a subacute immune complex-mediated hypersensitivity response as the parasite migrates through the lungs. Chronic schistosomiasis infection induces a granulomatous inflammation around ova deposited in the tissue. In particular, Schistosoma mansoni migrates to the portal venous system and causes preportal fibrosis in a subset of individuals and appears to be a prerequisite for PH. Portal hypertension facilitates shunting of ova from the portal system to the pulmonary arterial tree, resulting in localized periovular pulmonary granulomas. The pulmonary vascular remodeling is likely a direct consequence of the host inflammatory response, and portopulmonary hypertension may be a significant contributor. New specific therapies available for PH have not been widely tested in patients with schistosomiasis and often are unavailable for those infected in resource-poor areas of the world where schistosomiasis is endemic. Furthermore, the current PH therapies in general target vasodilation rather than vascular remodeling and inflammation. Further research is needed into the pathogenic mechanism by which this parasitic infection results in pulmonary vascular remodeling and PH, which also may be informative regarding the etiology of other types of PH.

Pulmonary vascular remodeling in pulmonary hypertension

“…These early observations led to a large set of new data linking inflammation to the pathobiology of PAH (Dorfmuller et al 2003, Hassoun et al 2009, Soon et al 2010), some of which with a strong correlation with severity of disease (notably interleukin (IL) 6, IL8, IL20, and IL12) (Soon et al 2010). Schistosomiasis-induced PAH is perhaps the paradigmatic entity in which a parasite, S. mansoni, triggers a TH-2 dominant response (Graham et al 2010) and pulmonary vascular lesions identical to those seen in idiopathic PAH. Experimentally, the TH-2 inflammation leads to increased transforming growth factor (TGF)-β1 (Kumar et al 2015), which ultimately trigger pulmonary artery remodeling and PH.…”

Aberrant immune response with consequent vascular and connective tissue remodeling – causal to scleroderma and associated syndromes such as Raynaud phenomenon and other fibrosing syndromes?

“…Schistosomiasis is the third most common parasitic disease affecting about 200 to 300 million people in 74 countries including throughout Africa, Brazil, the Middle East and Southeast Asia [39]. Schistosomiasis is an ancient and chronic disease of humans, mammal, birds, and primates.…”

“…Schistosomiasis is an ancient and chronic disease of humans, mammal, birds, and primates. The first host response to antigens released by these worms is a Th-1 response during acute infection [39]. The host releases tumor necrosis factor (TNF)α, interleukin (IL)-1, IL-6, IL-12[40,41], transforming growth factor (TGF)β and interferon-γ [42–44].…”

“…The Th2 milieu induces tissue-remodeling cytokines such as IL-4 [33–35], IL-13 [33,35], and resistin-like molecule α (RELMα) [34,45,46]. The immune response to the parasite eggs and their antigens together with exacerbated activity of TGF-β induce severe pulmonary arterial remodeling and pulmonary hypertension [35,39,44,47,48] (Fig. 1).…”

Human Immunodeficiency Virus–Associated Pulmonary Arterial Hypertension

“…Observations suggest that chronic HIV-associated inflammation leads to an accumulation of asymmetrical dimethylarginine, which is a well-known endogenous inhibitor of endothelial nitric oxide synthase, and, thus, promotes endothelial dysfunction and vascular smooth muscle cell proliferation. [63][64][65] Additionally, Nef and Tat proteins modulate the release of IL-2 and monocyte chemotactic protein-1 (MCP-1, also known as CCL2), which stimulate pulmonary vascular remodeling, 66,67 particularly in Schistosomiasis infection 68,69 ( Figure 2). Whether overlap in cytokine activation patterns in Schistosomiasis and HIV is responsible for PAH in coinfected patients, however, requires further investigation.…”