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Pulmonary Vascular Remodeling Correlates with Lung Eggs and Cytokines in Murine Schistosomiasis

¹ Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital; ² Department of Pathology, University of Cambridge; ³ Department of Pathology, Papworth Hospital, Cambridge, United Kingdom; ⁴ University of Giessen Lung Centre, Giessen, Germany; ⁵ Max-Planck Institute for Heart and Lung Research, Munich, Germany; and ⁶ University of Kent, Canterbury, United Kingdom

Correspondence and requests for reprints should be addressed to Nicholas W. Morrell, Ph.D., M.D., Division of Respiratory Medicine, Department of Medicine, University of Cambridge School of Clinical Medicine, Box 157, Addenbrooke's Hospital Hills Road, Cambridge CB2 2QQ, UK. E-mail: nwm23{at}cam.ac.uk

Rationale: Schistosomiasis is considered to be the most common worldwide cause of pulmonary hypertension. At present there is no well-characterized animal model to study the pathobiology of this important condition.

Objectives: To develop a mouse model of schistosomiasis, characterize the extent of pulmonary vascular remodeling, and determine the potential role of inflammatory cytokines.

Methods: Mice (C57/Bl6) were infected transcutaneously with a high dose (75–100 cercariae) or a low dose (30 cercariae) of Schistosoma mansoni, and the development of lung and liver pathology was studied in the subacute (high-dose) and chronic (low-dose) settings.

Measurements and Main Results: In the subacute setting, mice showed few eggs in the lungs and no evidence of pulmonary vascular remodeling. In contrast, chronically infected animals had a much greater lung egg burden and developed marked pulmonary vascular remodeling accompanied by perivascular inflammation from 12 weeks onwards. In addition, we observed the presence of plexiform-like lesions in these mice. Lung egg burden correlated with both liver egg burden and right ventricular (RV) index in the chronic group, although significant RV hypertrophy was lacking. Plasma Th1 and Th2 cytokines increased with time in the chronic group and correlated with the degree of pulmonary vascular remodeling.

Conclusions: This study provides evidence for extensive pulmonary vascular remodeling, despite the absence of RV hypertrophy, in a mouse model of schistosomiasis, including the formation of plexiform-like lesions. Inflammatory cytokines and lung egg burden may contribute to vascular lesion formation.

Key Words: pulmonary hypertension • parasites • Schistosoma mansoni

AT A GLANCE COMMENTARY Scientific Knowledge on The Subject Schistosomiasis is believed to be the most common cause of pulmonary hypertension worldwide, but little is known about its pathobiology. What This Study Adds to the Field After chronic Schistosoma mansoni infection via transcutaneous infection, mice develop severe but heterogeneous vascular remodeling, which is characterized by perivascular inflammation, marked medial thickening, and the formation of plexiform-like lesions without significant pulmonary hypertension. The extent of pulmonary vascular remodeling correlated with levels of inflammatory cytokines and lung egg burden.

 

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Th2 Inflammation, Hypoxia-induced Mitogenic Factor/FIZZ1, and Pulmonary Hypertension and Vascular Remodeling in Schistosomiasis

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