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Study of the relationship between inflammasome activation and lipid mediators production with pulmonary inflammation induced by scorpion venom with and without hyaluronidase

Grant number: 14/03332-7
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): September 01, 2014
Effective date (End): August 31, 2017
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Lúcia Helena Faccioli
Grantee:Karina Furlani Zoccal
Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil


The envenomation by Tityus serrulatus induces severe clinical manifestations, especially in children. The respiratory failure secondary to scorpion sting is a major cause of patient death as a result of acute pulmonary edema. However, the pathogenesis of the edema and response inflammatory pulmonary induced by scorpion, still require elucidation. Studies have demonstrated increase of IL-1, IL-6 and IFN-³ in patients with severe pulmonary edema. These same cytokines also have been produced in experimental models of envenomation. However, still nothing is known about the activation of the inflammasome and production of lipid mediators in this process. Our group demonstrated, in peritoneal macrophages obtained from mice, that T. serrulatus venom (TsV) and its major toxin Ts1 , induce the production of inflammatory mediators such as IL-6, TNF-± , PGE2 and LTB4, by activation of NF-ºB and MAPKs via TLR2 and TLR4 receptors. Literature data showed that activation of NF-ºB and MAPKs induce proinflammatory cytokines, chemokines, adhesion molecules and inflammasome activation. Inflammassomses are multi-protein complex responsible for the activation of caspase-1 in response to various stimuli. Recently was shown that bee venom induces inflammasome activation, and ongoing data from our group have shown that the inflammasome is activated in bone marrow macrophages stimulated with TsV and Ts1, generating production of IL-1². Although is known that in the plasma of patients envenomation has large concentration of this cytokine, nothing is known about the activation of the inflammasome in lung after envenomation, both in humans and in experimental animals. Also knows nothing about the production of lipid mediators in the lungs after envenomation by scorpions, and if there is a relation with the activation of the inflammasome. Lipid mediators derived from arachidonic acid metabolism may lead both to induce and regulate the inflammatory response. Recently our group demonstrated that hyaluronidase decreased lung injury and fibrosis induced by bleomycin, and also accelerated the healing of the lesion of mice induced skin damage. Furthermore, in the carrageenan-induced inflammation in air pouch model, the treatment with hyaluronidase inhibited the inflammatory response and production of LTB4. The hyaluronidases are enzymes, also known as scatter factor, which are present in the seminal fluid, plasma and urine of mammals, as well as in animal venoms. Known to that hyaluronidase has important role in the local and systemic envenomation facilitating the spread of the venom. However, there is nothing on the studies described the role of hyaluronidase in the edema pulmonary induced by scorpion. Thus, in this project we have two objectives: (i) to investigate the mechanisms that lead to pulmonary changes in mice inoculated with scorpion venom (TsV), focusing especially on inflammasome activation and its relation to the production of lipid mediators, (ii) to investigate the effect of the presence or absence of hyaluronidase in the venom and its participation in the mechanisms of lung inflammation. It is expected with this project to understand the mediation chemistry of inflammatory response local, and find a new therapeutic tool for the treatment of scorpion. (AU)

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Scientific publications (10)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
ZOCCAL, KARINA F.; GARDINASSI, LUIZ G.; BORDON, KARLA C. F.; ARANTES, ELIANE C.; MARLEAU, SYLVIE; ONG, HUY; FACCIOLI, LUCIA H.. EP80317 Restrains Inflammation and Mortality Caused by Scorpion Envenomation in Mice. FRONTIERS IN PHARMACOLOGY, v. 10, . (14/07125-6, 14/03332-7, 15/00658-1)
PUCCA, MANUELA BERTO; CERNI, FELIPE AUGUSTO; PINHEIRO-JUNIOR, ERNESTO LOPES; ZOCCAL, KARINA FURLANI; FIGUEIREDO BORDON, KARLA DE CASTRO; AMORIM, FERNANDA GOBBI; PEIGNEUR, STEVE; VRIENS, KIM; THEVISSEN, KARIN; ANGELO CAMMUE, BRUNO PHILIPPE; et al. Non-disulfide-bridged peptides from Tityus serrulatus venom: Evidence for proline-free ACE-inhibitors. Peptides, v. 82, p. 44-51, . (13/21342-7, 14/03332-7, 12/13590-8, 13/06380-0, 14/07125-6, 13/21329-0, 11/12317-3)
ZOCCAL, KARINA F.; SORGI, CARLOS A.; HORI, JULIANA I.; PAULA-SILVA, FRANCISCO W. G.; ARANTES, ELIANE C.; SEREZANI, CARLOS H.; ZAMBONI, DARIO S.; FACCIOLI, LUCIA H.. Opposing roles of LTB4 and PGE(2) in regulating the inflammasome-dependent scorpion venom-induced mortality. NATURE COMMUNICATIONS, v. 7, . (14/07125-6, 11/51023-5, 14/03332-7, 14/04684-4)
ZOCCAL, KARINA F.; FERREIRA, GIOVANA Z.; PRADO, MORGANA K. B.; GARDINASSI, LUIZ G.; SAMPAIO, V, SUELY; FACCIOLI, LUCIA H.. LTB4 and PGE(2) modulate the release of MIP-1 alpha and IL-1 beta by cells stimulated with Bothrops snake venoms. Toxicon, v. 150, p. 289-296, . (15/18872-0, 14/07125-6, 14/03332-7)
PUCCA, MANUELA B.; PEIGNEUR, STEVE; COLOGNA, CAMILA T.; CERNI, FELIPE A.; ZOCCAL, KARINA F.; BORDON, KARLA DE C. F.; FACCIOLI, LUCIA H.; TYTGAT, JAN; ARANTES, ELIANE C.. Electrophysiological characterization of the first Tityus serrulatus alpha-like toxin, Ts5: Evidence of a pro-inflammatory toxin on macrophages. Biochimie, v. 115, p. 8-16, . (13/21342-7, 14/03332-7, 13/21329-0, 09/07169-5, 13/26200-6)
CERNI, FELIPE AUGUSTO; PUCCA, MANUELA BERTO; ZOCCAL, KARINA FURLANI; FRANTZ, FABIANI GAI; FACCIOLI, LUCIA HELENA; ARANTES, ELIANE CANDIANI. Expanding biological activities of Ts19 Frag-II toxin: Insights into IL-17 production. Toxicon, v. 134, p. 18-25, . (14/07125-6, 13/21329-0, 14/03332-7, 13/21342-7)
DE OLIVEIRA, ISADORA SOUSA; CARDOSO, IARA AIME; FIGUEIREDO BORDON, KARLA DE CASTRO; IMAI CARONE, SANTE EMMANUEL; BOLDRINI-FRANCA, JOHARA; PUCCA, MANUELA BERTO; ZOCCAL, KARMA FURLANI; FACCIOLI, LUCIA HELENA; SAMPAIO, SUELY VILELA; ROSA, JOSE CESAR; et al. Global proteomic and functional analysis of Crotalus durissus collilineatus individual venom variation and its impact on envenoming. JOURNAL OF PROTEOMICS, v. 191, n. SI, p. 153-165, . (14/16182-3, 11/23236-4, 14/03332-7)
DE ARAUJO MOREIRA, MIRELLA DOS REIS; SALES-CAMPOS, HELIOSWILTON; FONTANARI, CAROLINE; GALVAO MEIRELES, ALYNE FAVERO; BORGES PRADO, MORGANA KELLY; ZOCCAL, KARINA FURLANI; SORGI, CARLOS ARTERIO; DA SILVA, CRISTIANE TEFE; GROPPO, MILTON; FACCIOLI, LUCIA HELENA. The ethanolic extract of Terminalia argentea Mart. & Zucc. bark reduces the inflammation through the modulation of cytokines and nitric oxide mediated by the downregulation of NF-kappa B. Journal of Ethnopharmacology, v. 261, . (14/03332-7, 14/07125-6)
WIEZEL, GISELE A.; RUSTIGUEL, JOANE K.; MORGENSTERN, DAVID; ZOCCAL, KARINA E.; FACCIOLI, LUCIA H.; CRISTINA NONATO, M.; UEBERHEIDE, BEATRIX; ARANTES, ELIANE C.. Insights into the structure, function and stability of bordonein-L, the first L-amino acid oxidase from Crotalus durissus terrificus snake venom. Biochimie, v. 163, p. 33-49, . (14/03332-7, 11/23236-4, 15/24010-0, 14/23285-3, 14/06170-8, 14/07125-6)
ZOCCAL, KARINA F.; GARDINASSI, LUIZ G.; SORGI, CARLOS A.; MEIRELLES, ALYNE F. G.; BORDON, KARLA C. F.; GLEZER, ISAIAS; CUPO, PALMIRA; MATSUNO, ALESSANDRA K.; BOLLELA, VALDES R.; ARANTES, ELIANE C.; et al. CD36 Shunts Eicosanoid Metabolism to Repress CD14 Licensed Interleukin-1 beta Release and Inflammation. FRONTIERS IN IMMUNOLOGY, v. 9, . (13/07937-8, 14/07125-6, 15/00658-1, 14/03332-7)

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