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Novel disease mechanisms in pulmonary arterial hypertension
S101 Praziquantel prevents progression and reverses pulmonary hypertension and pulmonary vascular remodelling in a mouse model of Schistosomiasis
  1. A Crosby1,
  2. F M Jones1,
  3. E Kakolos2,
  4. M Southwood1,
  5. I Purvis1,
  6. G Butrous2,
  7. D W Dunne1,
  8. N Morrell1
  1. 1Cambridge University, Cambridge, UK
  2. 2University of Kent, Canterbury, UK

Abstract

Introduction Schistosomiasis is the most common world-wide cause of pulmonary hypertension. Praziquantel is the drug of choice and has been shown to reverse the liver pathology associated with Schistosomamansoni in mice. We sought to determine whether praziquantel could reverse established pulmonary vascular remodelling and pulmonary hypertension in a mouse model of Schistosomamansoni.

Methods Mice were infected percutaneously with a low dose of Schistosomamansoni. At 17 weeks post-infection mice were either sacrificed or received praziquantel by oral gavage or a vehicle control. At 17 or 25 weeks post-infection right ventricular systolic pressure (RVSP) and right ventricular (RV) hypertrophy, liver and lung egg counts were measured. Pulmonary vascular remodelling was assessed by morphometry, following immunohistochemistry. A cytokine array was performed and the degree of infectivity was measured by faecal egg counts.

Measurements and main results At 25 weeks post-infection there was a significant increase in RVSP and RV hypertrophy between infected and control mice, which was reversed by Praziquantel treatment. RVSP was elevated in mice at 25 weeks post-infection but had normalised with praziquantel treatment. There was a significant increase in the muscularisation of small pulmonary arteries following 25 weeks of schistosomal infection, which was prevented by with Praziquantel treatment. Liver, lung and faecal egg counts were elevated following 25 weeks of schistosomal infection and substantially reduced with praziquantel treatment.

Conclusions This study has shown that severe pulmonary vascular remodelling accompanied by an increase in RVSP and RV hypertrophy occurs 25 weeks post-infection in a mouse model of S mansoni infection. Importantly, this study has shown that progression of disease can be prevented by two oral doses of praziquantel. The mechanism thought to underlie the dramatic pulmonary vascular remodelling, is a local increase in inflammatory cytokines.

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