Mechanisms of the anti-inflammatory actions of the angiotensin type 1 receptor antagonist losartan in experimental models of arthritis |
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| Affiliation: | 1. Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, São Paulo, Brazil;2. School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil;3. Department of Otorhinolaringology and Head and Neck Surgery, AC Camargo Cancer Center, São Paulo, Brazil;4. Department of Pathology, Dental School, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil;5. Department of Pathology, Dental School, State University of Western Paraná, Cascavel, Paraná, Brazil;6. Department of Oral Pathology and Oral Biology, School of Dentistry, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa;1. Department of Oral Surgery and Pathology, Faculty of Dentistry, Federal University of Minas Gerais, MG, Brazil;2. Department of Orthodontics, Faculty of Dentistry, Pontifical Catholic University, Belo Horizonte, MG, Brazil;3. Department of Food Science, Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil;4. Laboratory of Immunoinflammation, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, SP, Brazil;5. Department of Pediatric Dentistry and Orthodontics, Faculty of Dentistry, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil;6. Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo, Bauru, SP, Brazil;7. Department of Microbiology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil;8. Department of Pharmacological Science, Faculty of Pharmacy, University of São Paulo, Ribeirão Preto, SP, Brazil;9. Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil;10. Department of Immunology, Monash University, Melbourne, Australia |
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| Abstract: | Angiotensin (Ang) II and its AT1 receptors have been implicated in the pathogenesis of rheumatoid arthritis. Activation of the counter-regulatory Ang-(1–7)–Mas receptor axis may contribute to some of the effects of AT1 receptor blockers (ARBs). In this study, we have used losartan, an ARB, to investigate the role of and the mechanisms by which AT1 receptors participated in two experimental models of arthritis: antigen-induced arthritis (AIA) in mice and adjuvant-induced arthritis (AdIA) in rats. Treatment with losartan decreased neutrophil recruitment, hypernociception and the production of TNF-α, IL-1β and chemokine (C–X–C motif) ligand 1 in mice subjected to AIA. Histopathological analysis showed significant reduction of tissue injury and inflammation and decreased proteoglycan loss. In addition to decreasing cytokine production, losartan directly reduced leukocyte rolling and adhesion. Anti-inflammatory effects of losartan were not associated to Mas receptor activation and/or Ang-(1–7) production. Anti-inflammatory effects were reproduced in rats subjected to AdIA. This study shows that ARBs have potent anti-inflammatory effects in animal models of arthritis. Mechanistically, reduction of leukocyte accumulation and of joint damage was associated with local inhibition of cytokine production and direct inhibition of leukocyte–endothelium interactions. The anti-inflammatory actions of losartan were accompanied by functional improvement of the joint, as seen by reduced joint hypernociception. These findings support the use of ARBs for the treatment of human arthritis and provide potential mechanisms for the anti-inflammatory actions of these compounds. |
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| Keywords: | Arthritis Inflammation Leukocytes Losartan Hypernociception Cytokines |
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