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Loxoscelism: from basic research to the proposal of new therapies.

Denise - Loxoscelismo

Denise V. Tambourgi

 

INTRODUCTION

Loxoscelism is caused by envenomation by spiders from Loxosceles genus. Clinical symptoms only appear a few hours after envenomation and can evolve in local reactions, such as dermonecrosis, and systemic reactions, such as intravascular haemolysis, intravascular coagulation and renal failure. Current therapies are not effective, often not based in scientific research and can be even detrimental. A lack of understanding of the mechanism of action of the venom of the Loxosceles spider had thus far prevented development of effective therapies.

Renal failure is one of the major causes of death after Loxosceles envenomation, and recently we have started to investigate the mechanism of renal dysfunction induced by Loxosceles venom. Similarly as seen in ischaemic renal injury, the histological analysis of kidneys of mice injected with Loxosceles venom show clear symptoms of acute tubular necrosis, signs of epithelial detachment and necrosis, loss of the brush border and collapsing of the glomeruli. The acute tubular necrosis is most likely a secondary effect, and may not be directly induced by the Loxosceles venom.

Complement activation is implicated in ischaemic renal injury and our preliminary experiments using C6-deficient mice suggest that in the case of systemic loxoscelism, Complement activation also contributes to the pathology.

 

AIMS

The aims of this project are to investigate the mechanism of Loxosceles venom induced kidney failure. Using a mouse model of systemic loxoscelism and in vitro cultures of human renal cells the following will be investigated: The role of specific Complement components in kidney failure; The role of membrane bound and fluid phase complement regulators in the systemic reactions; The role of the protein C anti-coagulation cascade; The role of metalloproteinases; The potential application of soluble Complement regulators, activated protein C, polyclonal monospecific antibodies against recombinant Loxosceles toxins and metalloproteinase inhibitors in loxoscelism therapy.

 

EXPECTED RESULTS

There is currently no effective treatment of Loxosceles envenomation and the results of this study will give us a greater understanding of how the Loxosceles venom induces pathology and may open up possibility for effective therapeutic intervention, which could save lives.

 

References

1. Tambourgi et al, Toxicon 56: 1113, 2010;
2. Tambourgi et al, Toxicon 36: 391,1998;
3. Amirlak et al, Nephrol 11: 213,2006;
4. Scheiring et al, Eur J Pediatr 169: 7, 2010;
5. Roumenina et al, J Immunol Methods 365: 8, 2011;
6. van den Berg et al, Immunol 107: 102,2002;
7. Esmon CT, Br J Haematol 131:417, 2005;
8. van den Berg et al, J Thromb Haemost 5:989, 2007.

Team

Denise Vilarinho TambourgiPrincipal Investigator
B. Paul Morgan, Associate Investigator
Masashi MizunoCollaborator
Carmen W. van den BergAssociate Investigator
Cinthya Kimori Okamoto, Collaborator
Gisele Pidde QueirozCollaborator
Priscila Hess LopesPostdoctoral fellow
Ana Tung Ching ChingPostdoctoral fellow
Carlos MedeirosCollaborator 

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