Immune cells and mediators involved in the inflammatory responses induced by a P-I metalloprotease and a phospholipase A2 from Bothrops atrox venom |
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| Institution: | 1. Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil;2. Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil;3. Instituto Nacional de Ciência e Tecnologia de Bioanalítica, Universidade Estadual de Campinas, Campinas, SP, Brazil;1. Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid KM380 PR445, CEP 86057-970, Cx Postal 10.011, Londrina, Paraná, Brazil;2. Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Estadual de Londrina, Avenida Robert Koch, 60, CEP 86039-440, Londrina, Paraná, Brazil;3. Laboratório de Imunopatologia, Instituto Butantan, Secretaria de Saúde, Av. Vital Brazil, 1500, CEP 05503-900, Butantan, São Paulo, São Paulo, Brazil;4. Departamento de Bioquímica e Biotecnologia, Centro de Ciências Exatas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid KM380 PR445, CEP 86057-970, Londrina, Paraná, Brazil;1. Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, 60430-270, Fortaleza, Ceará, Brazil;2. Department of Clinical and Toxicological Analysis, Federal University of Ceará, Fortaleza, Ceará, Brazil;3. Department of Pharmacology, Federal University of São Paulo (UNIFESP/EPM), São Paulo, Brazil;4. São Vicente Unit, Paulista Coastal Campus, São Paulo State University (UNESP), São Paulo, Brazil;5. Department of Medicinal Chemistry, Centro de Investigación Príncipe Felipe, Valencia, Spain;1. Institute of Genetics and Biochemistry, Federal University of Uberlandia, UFU, 38400-902 Uberlandia, MG, Brazil;2. Department of Chemical and Physical, State University of Southwest Bahia (UESB), 45506-210 Jequie, BA, Brazil;3. Ezequiel Dias Foundation, FUNED, 30510-010 Belo Horizonte, MG, Brazil;1. Laboratory of Histology and Regenerative Therapy, Institute of Research and Development (IP&D), Vale do Paraíba University (UNIVAP), Avenida Shishima Hifumi, 2911, Urbanova, 12244-000, São José dos Campos, SP, Brazil;2. Laboratory of Pulmonary and Exercise Immunology (LABPEI), Nove de Julho University (UNINOVE) and Brazilian Institute of Teaching and Research in Pulmonary and Exercise Immunology (IBEPIPE), 01504-000, São Paulo, SP, Brazil;3. Laboratory of Pharmacology and Biochemistry, Institute of Research and Development (IP&D), Vale do Paraíba University (UNIVAP), Avenida Shishima Hifumi, 2911, Urbanova, 12244-000, São Jose dos Campos, SP, Brazil;4. Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, 13083-887, Campinas, SP, Brazil;5. Department of Bioengineering and Biomedical Engineering, Brazil University, Rua Carolina Fonseca, 584/235 (Campus I and II), Vila Santana, 08230-030, Itaquera, São Paulo, SP, Brazil;1. Universidade do Estado do Amazonas, Manaus, Brazil;2. Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil;3. Instituto Federal do Acre, Campus de Cruzeiro do Sul, Cruzeiro do Sul, Brazil;4. Programa de Pós-Graduação Bionorte–Universidade Federal do Acre–UFAC, Campus Universitário–BR 364, Rio Branco, Brazil;5. Hospital Regional do Juruá, Cruzeiro do Sul, Brazil;6. Laboratório de Imunopatologia, Instituto Butantan, São Paulo, Brazil;7. Laboratório de Herpetologia, Centro Multidisciplinar, Campus Floresta, Universidade Federal do Acre, Cruzeiro do Sul, Brazil |
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| Abstract: | Bothrops envenomations can promote severe inflammatory responses by inducing edema, pain, leukocyte recruitment and release of chemical mediators by local cells. In the present study, two toxins from Bothrops atrox venom (the P-I metalloprotease Batroxase and the acidic phospholipase A2 BatroxPLA2) were evaluated in relation to their inflammatory effects induced in vivo and in vitro, mainly focusing on the participation of different immune cells and inflammatory mediators. Both toxins mainly promoted acute inflammatory responses with significant recruitment of neutrophils in the early hours (1–4 h) after administration into the peritoneal cavity of C57BL/6 mice, and increased infiltration of mononuclear cells especially after 24 h. Among the mediators induced by both toxins are IL-6, IL-10 and PGE2, with Batroxase also inducing the release of L-1β, and BatroxPLA2 of LTB4 and CysLTs. These responses pointed to possible involvement of immune cells such as macrophages and mast cells, which were then evaluated in vitro. Mice peritoneal macrophages stimulated with Batroxase produced significant levels of IL-6, IL-1β, PGE2 and LTB4, whereas stimulus with BatroxPLA2 induced increases of IL-6, PGE2 and LTB4. Furthermore, both toxins were able to stimulate degranulation of RBL-2H3 mast cells, but with distinct concentration-dependent effects. Altogether, these results indicated that Batroxase and BatroxPLA2 promoted local and acute inflammatory responses related to macrophages and mast cells and to the production of several mediators. Our findings should contribute for better understanding the different mechanisms of toxicity induced by P-I metalloproteases and phospholipases A2 after snakebite envenomations. |
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| Keywords: | Snake venoms Metalloprotease Inflammation Mediators |
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