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.
Highlights
Ophidic accidents constitute a serious and neglected public health problem in tropical countries [1]
We examined the inflammatory response profile resulting from crude venom (CV)- and MjTX-IIinduced peritonitis
This effect was associated with diminished peritoneal neutrophil recruitment in the MjTX-II group at 24 hours, but no significant effect was observed in the CV group (Fig 1B)
Summary
Ophidic accidents constitute a serious and neglected public health problem in tropical countries [1]. In Brazil, there were 25,302 cases of ophidic envenomation reported in 2013, primarily caused by snakes belonging to the genus Bothrops, [2] of which 0.5% were lethal. Bothrops snake venoms induce a pathophysiological condition characterized by local and systemic effects [3, 4]. The systemic effects result in clotting, cardiovascular and renal alterations, hypovolemic shock and bleeding at sites distant from the bite [4]. Some of the primary components responsible for the pathophysiological effects of bothropic venoms are the phospholipases A2 (PLA2s), which are a family of lipolytic enzymes that play key roles in several cellular processes by regulating the release of arachidonic acid and lysophospholipids from cell membrane phospholipids [8]. PLA2s can be classified into two groups: i) the catalytically active enzymes, such as Asp49-PLA2s and ii) the catalytically inactive PLA2 variants (principally Lys49- and Arg49-PLA2s) [9]
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