title: Ac2-26 Mimetic Peptide of Annexin A1 Inhibits Local and Systemic Inflammatory Processes Induced by Bothrops moojeni Venom and the Lys-49 Phospholipase A2 in a Rat Model.
abstract: Annexin A1 (AnxA1) is an endogenous glucocorticoid regulated protein that modulates anti-inflammatory process and its therapeutic potential has recently been recognized in a range of systemic inflammatory disorders. The effect of the N-terminal peptide Ac2-26 of AnxA1 on the toxic activities of Bothrops moojeni crude venom (CV) and its myotoxin II (MjTX-II) were evaluated using a peritonitis rat model. Peritonitis was induced by the intraperitoneal injection of either CV or MjTX-II, a Lys-49 phospholipase A2. Fifteen minutes after the injection, the rats were treated with either Ac2-26 or PBS. Four hours later, the CV and MjTX-II-induced peritonitis were characterized by neutrophilia (in the peritoneal exudate, blood and mesentery) and increased number of mesenteric degranulated mast cells and macrophages. At 24 hours post-injection, the local inflammatory response was attenuated in the CV-induced peritonitis while the MjTX-II group exhibited neutrophilia (peritoneal exudates and blood). Ac2-26 treatment prevented the influx of neutrophils in MjTX-II-induced peritonitis and diminished the proportion of mesenteric degranulated mast cells and macrophages in CV-induced peritonitis. Additionally, CV and MjTX-II promoted increased levels of IL-1β and IL-6 in the peritoneal exudates which were significantly reduced after Ac2-26 treatment. At 4 and 24 hours, the endogenous expression of AnxA1 was upregulated in the mesenteric neutrophils (CV and MjTX-II groups) and mast cells (CV group). In the kidneys, CV and MjTX-II administrations were associated with an increased number of macrophages and morphological alterations in the juxtamedullary nephrons in proximal and distal tubules. Ac2-26 promoted significant recovery of the juxtamedullary structures, decreased the number of macrophages and diminished the AnxA1 in epithelial cells from distal tubules and renal capsules. Our results show that Ac2-26 treatment significantly attenuates local and systemic inflammatory processes and indicate this peptide as a potential target for the development of new therapeutic strategies for the snakebite envenomation treatment.
authors.affiliation: Laboratory of Immunomorphology, Department of Biology, São Paulo State University (UNESP), São José do Rio Preto, São Paulo, Brazil.
authors.forename: Bruna
authors.initials: B
authors.lastname: Stuqui
authors.affiliation: Laboratory of Immunomorphology, Department of Biology, São Paulo State University (UNESP), São José do Rio Preto, São Paulo, Brazil.
authors.forename: Marina
authors.initials: M
authors.lastname: de Paula-Silva
authors.affiliation: Laboratory of Immunomorphology, Department of Biology, São Paulo State University (UNESP), São José do Rio Preto, São Paulo, Brazil.
authors.forename: Carla Patrícia
authors.initials: CP
authors.lastname: Carlos
authors.affiliation: Multiuser Center for Biomolecular Innovation, Department of Physics, São Paulo State University (UNESP), São José do Rio Preto, São Paulo, Brazil.
authors.forename: Anwar
authors.initials: A
authors.lastname: Ullah
authors.affiliation: Multiuser Center for Biomolecular Innovation, Department of Physics, São Paulo State University (UNESP), São José do Rio Preto, São Paulo, Brazil.
authors.forename: Raghuvir Krishnaswamy
authors.initials: RK
authors.lastname: Arni
authors.affiliation: Department of Morphology and Genetics, São Paulo Federal University (UNIFESP), São Paulo, Brazil.
authors.forename: Cristiane Damas
authors.initials: CD
authors.lastname: Gil
authors.affiliation: Laboratory of Immunomorphology, Department of Biology, São Paulo State University (UNESP), São José do Rio Preto, São Paulo, Brazil.
authors.forename: Sonia Maria
authors.initials: SM
authors.lastname: Oliani
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000737:chemistry* / Q000494:pharmacology; D017837:Bothrops; D003435:Crotalid Venoms / Q000633:toxicity*; D004195:Disease Models, Animal; D007249:Inflammation / Q000517:prevention & control*; D008239:Lysine / Q000737:chemistry*; D008297:Male; D018716:Molecular Mimicry; D010455:Peptides / Q000494:pharmacology*; D054467:Phospholipases A2 / Q000737:chemistry / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D017305:Annexin A1; D003435:Crotalid Venoms; D010455:Peptides; C096153:annexin A1 peptide (2-26); D054467:Phospholipases A2; D008239:Lysine