title: The essential role of annexin A1 mimetic peptide in the skin allograft survival.
abstract: Immunosuppressive drugs have a critical role in inhibiting tissue damage and allograft rejection. Studies have demonstrated the anti-inflammatory effects of the annexin A1 (AnxA1) in the regulation of transmigration and apoptosis of leucocytes. In the present study, an experimental skin allograft model was used to evaluate a potential protective effect of AnxA1 in transplantation survival. Mice were used for the skin allograft model and pharmacological treatments were carried out using either the AnxA1 mimetic peptide Ac2-26, with or without cyclosporine A (CsA), starting 3 days before surgery until rejection. Graft survival, skin histopathology, leucocyte transmigration and expression of AnxA1 and AnxA5 post-transplantation were analysed. Pharmacological treatment with Ac2-26 increased skin allograft survival related with inhibition of neutrophil transmigration and induction of apoptosis, thereby reducing the tissue damage compared with control animals. Moreover, AnxA1 and AnxA5 expression increased after Ac2-26 treatment in neutrophils. Interestingly, the combination of Ac2-26 and cyclosporine A showed similar survival of transplants when compared with the cyclosporine A group, which could be attributed to a synergistic effect of both drugs. Investigations in vitro revealed that cyclosporine A inhibited extracellular-signal-regulated kinase (ERK) phosphorylation induced by Ac2-26 in neutrophils. Overall, the results suggest that AnxA1 has an essential role in augmenting the survival of skin allograft, mainly owing to inhibition of neutrophil transmigration and enhancement of apoptosis. This effect may lead to the development of new therapeutic approaches relevant to transplant rejection.
authors.affiliation: Post-Graduation in Structural and Functional Biology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil.
authors.forename: Rodrigo Antonio Parra
authors.initials: RA
authors.lastname: Teixeira
authors.affiliation: Post-Graduation in Structural and Functional Biology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil.
authors.forename: Kallyne Kioko Oliveira
authors.initials: KK
authors.lastname: Mimura
authors.affiliation: Post-Graduation in Structural and Functional Biology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil.
authors.forename: Leandro Pires
authors.initials: LP
authors.lastname: Araujo
authors.affiliation: Department of Surgical Research, Northwick Park Institute for Medical Research - University College London, London, UK.
authors.forename: Karin Vicente
authors.initials: KV
authors.lastname: Greco
authors.affiliation: Post-Graduation in Structural and Functional Biology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil.|Department of Biology, Instituto de Biociências, Letras e Ciências Exatas (IBILCE), São Paulo State University (UNESP), São José do Rio Preto, Brazil.
authors.forename: Sonia Maria
authors.initials: SM
authors.lastname: Oliani
mesh_terms: D064591:Allografts / Q000187:drug effects*; D000818:Animals; D017305:Annexin A1 / Q000494:pharmacology*; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003404:Creatinine / Q000652:urine; D016572:Cyclosporine / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006085:Graft Survival / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology; D016038:Skin Transplantation
chemical_list: D017305:Annexin A1; D017304:Annexin A5; D010455:Peptides; D020011:Protective Agents; C096153:annexin A1 peptide (2-26); D016572:Cyclosporine; D003404:Creatinine; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: annexin A1; cyclosporine A; neutrophils; skin; transplantation