Role of cytokines in the formation and downregulation of hepatic circumoval granulomas and hepatic fibrosis in Schistosoma mansoni-infected mice

Cheever, Allen W.; Janković, Dragana; Yap, George; Kullberg, Marika C.; Sher, Alan; Wynn, Thomas A.

doi:10.1590/s0074-02761998000700004

Cited by 35 publications

(26 citation statements)

References 57 publications

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“…Granuloma formation in schistosomiasis is a manifestation of delayed-type hypersensitivity to antigenic material released by S. mansoni eggs that peaks at 8 weeks postinfection (16). Liver fibrosis is a complex process resulting from increased synthesis and deposition of extracellular matrix components (17).…”

Section: Discussionmentioning

confidence: 99%

Effect of praziquantel administration on hepatic stereology of mice infected with Schistosoma mansoni and fed a low-protein diet

Barros

Costa-Silva

Biolchini

et al. 2009

Braz J Med Biol Res

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A study was undertaken to investigate the effect of administering praziquantel (PZQ), focusing on the liver stereological findings of malnourished mice infected with Schistosoma mansoni. Thirty female Swiss Webster mice (age: 21 days; weight: 8-14 g) were fed either a low-protein diet (8%) or standard chow (22% protein) for 15 days. Five mice in each group were infected with 50 cercariae each of the BH strain (Brazil). PZQ therapy (80 mg/kg body weight, per day) was started on the 50th day of infection and consisted of daily administration for 5 days. Volume density (hepatocytes, sinusoids and hepatic fibrosis) was determined by stereology using a light microscope. Body weight gain and total serum albumin levels were always lower in undernourished mice. Our stereological study demonstrated that treatment increased both volume density of hepatocytes in mice fed standard chow (47.56%, treated group and 12.06%, control) and low-protein chow (30.98%, treated group and 21.44%, control), and hepatic sinusoids [standard chow (12.52%, treated group and 9.06%, control), low-protein chow (14.42%, treated group and 8.46%, control)], while hepatic fibrosis was reduced [standard chow (39.92%, treated group and 78.88%, control) and low-protein chow (54.60%, treated group and 70.10%, control)]. On the other hand, mice fed low-protein chow decreased density volume of hepatocytes and hepatic fibrosis. In conclusion, our findings indicate that treatment with PZQ ameliorates hepatic schistosomiasis pathology even in mice fed a low-protein diet.

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Section: Discussionmentioning

confidence: 99%

Effect of praziquantel administration on hepatic stereology of mice infected with Schistosoma mansoni and fed a low-protein diet

Barros

Costa-Silva

Biolchini

et al. 2009

Braz J Med Biol Res

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“…Given the controversial roles of type 1 and type 2 cytokines in the pathogenesis of schistosomiasis (24,30,31), we examined the regulatory role of IL-10 in mice that manifested extreme Th1-or Th2-producing phenotypes (17). For these studies, IL-10/IL-4-deficient and IL-10/IL-12-deficient mice were infected with 20 -30 S. mansoni cercariae, and disease progression was examined in detail during both the acute and chronic stages of infection and compared with that in WT mice as well as animals exhibiting single cytokine deficiencies.…”

Section: The Egg-induced Cytokine Response In Schistosomiasis Is Regumentioning

confidence: 99%

IL-10 and the Dangers of Immune Polarization: Excessive Type 1 and Type 2 Cytokine Responses Induce Distinct Forms of Lethal Immunopathology in Murine Schistosomiasis

Hoffmann

Cheever

Wynn

2000

The Journal of Immunology

416

374

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To dissect the controversial roles of type 1 and type 2 cytokines to the pathogenesis of schistosomiasis, we generated IL-10/IL-4- and IL-10/IL-12-deficient mice that develop highly polarized type 1 and type 2 cytokine responses, respectively. Interestingly, the Th1-polarized IL-10/IL-4-deficient mice rapidly lost weight at the onset of egg-laying and displayed 100% mortality by wk 9 postinfection. This acute mortality was linked to overexpression of the proinflammatory mediators IFN-γ, TNF-α, and inducible NO and the formation of nonfibrotic granulomas. Elevated serum aspartate transaminase levels confirmed that mortality was in part attributable to acute hepatotoxicity. In contrast, the Th2-polarized IL-10/IL-12-deficient mice developed a progressive wasting disease that correlated with increased hepatic fibrosis, formation of large eosinophil-rich granulomas, a 10-fold increase in IL-4 and IL-13, and significant mortality during the chronic stages of infection. Surprisingly, IL-10-deficient mice displayed pathological features that were characteristic of both extremes, while wild-type mice developed relatively successful long term chronic infections. These data demonstrate that IL-10 significantly suppresses type 1 and type 2 cytokine development in IL-4- and IL-12-deficient mice, respectively, thereby impeding the development of severe egg-induced pathology in the single cytokine-deficient animals. Together, these findings reveal the central regulatory role of IL-10 in the pathogenesis of schistosomiasis and illustrate that excessive type 1 and type 2 cytokine responses trigger distinct, but equally detrimental, forms of pathology following infection.

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“…Therefore, the occurrence of this semi-aquatic rodent in endemic areas is a factor that makes it difficult to control this zoonosis (SOUZA et al, 1992;D'ANDREA et al, 2000;GENTILE et al, 2006). Cheever et al (1998) reported the formation of hepatic granulomas in mice infected by S. mansoni. Likewise, CostaSilva et al (2002), in a comparative study of natural and experimental infection by S. mansoni in N. squamipes, detected the presence of peri-ovular hepatic lesions in pre-granulomatous phases under natural conditions, while experimentally infected rodents showed a limited pattern of granulomas and a strong initial or peri-ovular inflammatory reaction 52 days after being infected.…”

Section: Introductionmentioning

confidence: 99%

Biochemical and histological changes in liver ofNectomys squamipes naturally infected bySchistosoma mansoni

Neto

Alves

et al. 2013

Rev. Bras. Parasitol. Vet.

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The South American water rat Nectomys squamipes is a wild mammal reservoir of Schistosoma mansoni in Brazil. In the present study, wild rodents were collected in the field and categorized into two groups: infected and uninfected by S. mansoni. Blood was collected to analyze changes in the serum glucose level (mg/dL) and liver fragments were used to determine the hepatic glycogen content (mg of glucose/g tissue). The histological examination showed inflammatory granulomatous lesions in different phases of development in the liver of rodents naturally infected with S. mansoni, in some cases with total or partial occlusion of the vascular lumen. Early lesions were characterized by the presence of inflammatory infiltrate around morphologically intact recently deposited eggs. Despite the significance of these histological lesions, the biochemical changes differed in extent. N. squamipes naturally infected by S. mansoni showed no variation in hepatic glycogen reserves. These findings were accompanied by a significant increase in plasma glucose contents, probably as a consequence of amino acids deamination, which are degraded, resulting in the formation of intermediates used as precursors for the glucose formation, without compromising the reserves of liver glycogen. In the wild, naturally infected N. squamipes can maintain S. mansoni infections without undergoing alterations in its carbohydrate metabolism, which minimizes the deleterious effects of S. mansoni.Keywords: Biochemical alterations, rodents, wild reservoirs, alternative model. ResumoNectomys squamipes é um mamífero silvestre reservatório de Schistosoma mansoni no Brasil. No presente estudo, os roedores silvestres, colhidos no campo, foram classificados em dois grupos: infectado e não infectado por S. mansoni. O sangue foi colhido para análise da alteração no nível de glicose sérico (mg/dL) e fragmentos de fígado foram usados para determinar o conteúdo de glicogênio hepático (mg de glicose/g tecido). A análise histológica demonstrou lesões granulomatosas em diferentes fases de desenvolvimento no tecido hepático dos roedores naturalmente infectados com S. mansoni, localizados principalmente na região periportal, com total ou parcial oclusão do lúmen vascular. As lesões foram caracterizadas por presença de infiltrado inflamatório ao redor de ovos morfologicamente intactos recentemente depositados. Apesar da grande significância das lesões histológicas, as alterações bioquímicas não diferiram no mesmo

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Role of cytokines in the formation and downregulation of hepatic circumoval granulomas and hepatic fibrosis in Schistosoma mansoni-infected mice

Cited by 35 publications

References 57 publications

Effect of praziquantel administration on hepatic stereology of mice infected with Schistosoma mansoni and fed a low-protein diet

Effect of praziquantel administration on hepatic stereology of mice infected with Schistosoma mansoni and fed a low-protein diet

IL-10 and the Dangers of Immune Polarization: Excessive Type 1 and Type 2 Cytokine Responses Induce Distinct Forms of Lethal Immunopathology in Murine Schistosomiasis

Biochemical and histological changes in liver ofNectomys squamipes naturally infected bySchistosoma mansoni

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