Abstract
Endothelin receptors (ETRs) are activated by vasoactive peptide endothelins and involved in the pathogenesis of hepatic fibrosis. However, less is known about the role of ETRs in Schistosoma (S.) japonicum-induced hepatic fibrosis. Here, we show that the expression of ETRs is markedly enhanced in the liver and spleen tissues of patients with schistosome-induced fibrosis, as well as in murine models. Additional analyses have indicated that the expression levels of ETRs in schistosomiasis patients are highly correlated with the portal vein and spleen thickness diameter, both of which represent the severity of fibrosis. Splenomegaly is a characteristic symptom of schistosome infection, and splenic abnormality may promote the progression of hepatic fibrosis. We further demonstrate that elevated levels of ETRs are predominantly expressed on splenic B cells in spleen tissues during infection. Importantly, using a well-studied model of human schistosomiasis, we demonstrate that endothelin receptor antagonists can partially reverse schistosome-induced hepatic fibrosis by suppressing the activation of splenic B cells characterized by interleukin-10 (IL-10) secretion and regulatory T (Treg) cell-inducing capacity. Our study provides insights into the mechanisms by which ETRs regulate schistosomiasis hepatic fibrosis and highlights the potential of endothelin receptor antagonist as a therapeutic intervention for fibrotic diseases.
Highlights
Schistosomiasis is a serious parasitic disease throughout the world’s tropical regions, affecting more than 200 million people worldwide [1]
To detect the expression of Endothelin receptors (ETRs) and fibrotic molecules in liver specimens, and analyse their correlations with the progression of schistosome-induced hepatic fibrosis, liver biopsy was performed in chronic schistosomiasis (CS) patients, chronic hepatitis B (CHB) patients and control (Cont) patients
Representative photomicrographs revealed that pathological lesions and collagen deposition in liver biopsy samples of patients with CS significantly increased with the aggravation of liver fibrosis compared with S0 (S1A and S1B Fig)
Summary
Schistosomiasis is a serious parasitic disease throughout the world’s tropical regions, affecting more than 200 million people worldwide [1]. Schistosome worms lay their eggs in the mesenteric and portal veins of their human host, and the eggs are trapped in liver sinusoids [2]. Intestinal and hepatic schistosomiasis are the most common forms of chronic disease. Intestinal schistosomiasis is an acute or chronic, specific enteropathy caused by the deposition of schistosome ovum on the colon and rectal walls [4]. The egg-induced hepatic fibrosis, which can lead to portal hypertension and variceal bleeding, is the primary cause of morbidity and mortality associated with this chronic disease [6]. Since anti-fibrotic therapies for schistosomiasis have been neglected, new prospective drugs are urgently required that can reverse the fibrosis
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