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Mechanisms induced by leukotrienes in arthritis condition

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Cintia Kazuko Tokuhara
Total Authors: 1
Document type: Doctoral Thesis
Press: Bauru.
Institution: Universidade de São Paulo (USP). Faculdade de Odontologia de Bauru (FOB/SDB)
Defense date:
Examining board members:
Rodrigo Cardoso de Oliveira; Marilia Afonso Rabelo Buzalaf; Flávia Amadeu de Oliveira; Willian Fernando Zambuzzi
Advisor: Rodrigo Cardoso de Oliveira

Rheumatoid arthritis is a chronic, autoimmune inflammatory disease that mainly affects the joints. Clinical manifestations are swelling in the joints, erythema, and pain that, with disease progression, promote important changes in joint architecture and decrease and/or loss of function. Pathologically, occurs hyperplasia of the synovial membrane, formation of pannus, presence of several cells of the immune system, and consequently, the release of chemokines and pro-inflammatory cytokines. On the other hand, leukotrienes are lipid mediators, derived from arachidonic acid metabolism and synthesized by the 5- lipoxygenase (5-LO) pathway playing an important role in the inflammatory tissue response and the defense of the host against various pathogens. Leukotriene B4, for example, is a potent neutrophil chemoattractive, as it promotes adhesion of these cells to the vascular endothelium, promoting or developing arthritis. Thus, the present study aimed to investigate the mechanisms involved by leukotrienes, in arthritis induced in mice knockout for 5- lipoxygenase. Using the CAIA model, wild type and 5-LO KO mice were immunized via the caudal vein, with a cocktail of 5 monoclonal antibodies against type II collagen on day 0, and double intraperitoneal injection of LPS on days 3 and 11. PBS was used as a vehicle in the control groups. On the fourteenth day, the mice were euthanized and the paws were collected for HE staining and Masson trichrome assays, immunoexpression by immunohistochemistry, and immunofluorescence, as well as proteomic analysis. Our results showed that the WT CAIA group developed moderate synovitis, in contrast, the knockout group, KO CAIA, deficient in leukotriene, did not present the disease. The immunoexpression of interleukin IL-1 was positively higher in the WT CAIA group, however, there was no difference for IL-6. In addition, the immunostaining for CD31 was also more expressive in the WT CAIA group compared to the other groups and there was no significant difference for CD34. Regarding the proteomic profile, significant changes were found in the identification of total proteins in the comparison between experimental and control groups, as proteins related to collagen production and present in the inflammatory process. Furthermore, antioxidant proteins exclusive to the 5-LO group were identified, leading us to the hypothesis that these proteins would indeed be involved in the non-development of synovitis in knockout mice. (AU)

FAPESP's process: 16/23736-0 - Mechanisms induced by leukotrienes in arthritis condition.
Grantee:Cintia Kazuko Tokuhara
Support Opportunities: Scholarships in Brazil - Doctorate