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

• Published in: PloS one Vol. 10; no. 7; p. e0130803
• Main Authors: Stuqui, Bruna, de Paula-Silva, Marina, Carlos, Carla Patrícia, Ullah, Anwar, Arni, Raghuvir Krishnaswamy, Gil, Cristiane Damas, Oliani, Sonia Maria
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06.07.2015; Public Library of Science (PLoS)
• Subjects: Animals; Annexin A1 - chemistry; Annexin A1 - pharmacology; Biology; Blood; Bothrops; Bothrops moojeni; Crotalid Venoms - toxicity; Disease Models, Animal; Distal tubules; Enzymes; Epithelial cells; Exudates; Exudation; Glucocorticoids; Inflammation; Inflammation - prevention & control; Inflammatory diseases; Inflammatory response; Injection; Interleukin 6; Kidneys; Laboratories; Leukocytes (neutrophilic); Lysine - chemistry; Macrophages; Male; Mast cells; Mesentery; Molecular Mimicry; Nephrons; Neutrophilia; Neutrophils; Peptides; Peptides - pharmacology; Peritoneum; Peritonitis; Phospholipase; Phospholipase A2; Phospholipases A2 - chemistry; Phospholipases A2 - toxicity; Proximal tubules; Rats; Rats, Wistar; Rodents; Snake bites; Venom
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0130803

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.