Journal
INTERNATIONAL IMMUNOPHARMACOLOGY
Volume 70, Issue -, Pages 324-337Publisher
ELSEVIER
DOI: 10.1016/j.intimp.2019.02.032
Keywords
Antiparasitic chemotherapy; Experimental pathology; Parasitology; Schistosomiasis
Categories
Funding
- Brazilian agency: Fundacao do Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG) [APQ-01895-16, PPM - 00077-18]
- Brazilian agency: Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [303972/2017-3, 423594/2018-4]
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior - Brasil (CAPES) [001]
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We investigated the effect in vitro and in vivo of doxycycline hyclate (Dx), a broad-spectrum antibiotic inhibitor of matrix metaloproteinases (MMPs), on adult Schistosoma mansoni worms and granulomatous liver inflammation in infected mice. Adult S. mansoni worms in culture treated with different concentrations of Dx (50-180 mu g/mL) were studied for eight days to assess its morphology, eggs production, and mortality. Uninfected mice and those infected with S. mansoni, untreated and treated with praziquantel (Pz; 200 mg/kg) or Dx (50 mg/kg), were evaluated for 60 days. Our results indicated that Dx induced dose-dependent integumentary lesions (bubbles, tubercle collapse, spicule disappearance, peeling, and erosion), reduced mating rate and eggs-laying in adult S. mansoni worms. The effective lethal dose required to kill 50% of worms was 112.0 mu g/mL Dx (DL50). In mice, S. mansoni infection induced hepatomegaly, intense IL-4, IL-10, TNF-alpha and TGF-beta production, granulomatous inflammation and hepatic glycogen depletion. The number and size of the granulomas was similar in untreated and Dx-treated animals. Untreated animals showed a predominance of productive granulomas, and intense MMP-2 and MMP-9 activities. Dx-treated mice exhibited a significant increase in IL-4 levels, tissue inflammation, proportion of involutive granulomas, and hepatic collagenogenesis, as well as attenuated MMP-2 and MMP-9 activities. Our findings indicated that Dx is toxic to adult S. mansoni worms in vitro. However, in vitro beneficial effects were not reproduced in vivo, since Dx treatment increased liver granulomatous inflammation and collagenogenesis in S. mansoni-infected mice by a process potentially associated with Dx-mediated hepatic MMP-2 and MMP-9 inhibition.
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