title: Mechanisms of the anti-inflammatory actions of the angiotensin type 1 receptor antagonist losartan in experimental models of arthritis.
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.
authors.affiliation: Immunopharmacology, Department of Biochemistry and Immunology, Institute of Biological Sciences, Brazil.
authors.forename: Kátia D
authors.initials: KD
authors.lastname: Silveira
authors.forename: Fernanda M
authors.initials: FM
authors.lastname: Coelho
authors.forename: Angélica T
authors.initials: AT
authors.lastname: Vieira
authors.forename: Lívia C
authors.initials: LC
authors.lastname: Barroso
authors.forename: Celso M
authors.initials: CM
authors.lastname: Queiroz-Junior
authors.forename: Vívian V
authors.initials: VV
authors.lastname: Costa
authors.forename: Larissa F C
authors.initials: LF
authors.lastname: Sousa
authors.forename: Marilene L
authors.initials: ML
authors.lastname: Oliveira
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.forename: Tarcíla A
authors.initials: TA
authors.lastname: Silva
authors.forename: Robson A S
authors.initials: RA
authors.lastname: Santos
authors.forename: Ana Cristina Simões E
authors.initials: AC
authors.lastname: Silva
authors.forename: Mauro M
authors.initials: MM
authors.lastname: Teixeira
mesh_terms: D000803:Angiotensin I / Q000096:biosynthesis; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D002448:Cell Adhesion / Q000187:drug effects; D054360:Chemokine CXCL1 / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D006930:Hyperalgesia / Q000188:drug therapy; D007249:Inflammation / Q000188:drug therapy; D053583:Interleukin-1beta / Q000096:biosynthesis; D036904:Leukocyte Rolling / Q000187:drug effects; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects; D010446:Peptide Fragments / Q000096:biosynthesis; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000894:Anti-Inflammatory Agents, Non-Steroidal; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D053583:Interleukin-1beta; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; D000803:Angiotensin I; C118790:angiotensin I (1-7); D019808:Losartan
keywords: Arthritis; Cytokines; Hypernociception; Inflammation; Leukocytes; Losartan