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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.

Stuqui B, de Paula-Silva M, Carlos CP, Ullah A, Arni RK, Gil CD, Oliani SM - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunomorphology, Department of Biology, São Paulo State University (UNESP), São José do Rio Preto, São Paulo, Brazil.

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.

No MeSH data available.


Related in: MedlinePlus

Effect of Ac2-26 treatment on the mesenteric inflammation induced by CV and MjTX-II.Intact mast cells (arrows) in the control mesentery (A). Inflamed mesentery of CV—(B) and MjTX-II-induced peritonitis (C-D) with extravasated neutrophils in the tissue (arrowheads) as observed at 4 and 24 h. Reduced neutrophil influx (arrowheads) after Ac2-26 post-treatment at 4 (E) and 24 h (F) of MjTX-II-induced peritonitis. Vessels (V). Stain: Toluidine blue. Scale bars: 10 μm. Quantitative analysis of extravasated neutrophils in the mesentery after CV- (G) and MjTX-II–induced peritonitis (H). The data represent the mean ± SEM of cell numbers/mm2 (n = 5 animals/group). **P < 0.01 vs control; §P < 0.05 vs MjTX-II-4 h.
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pone.0130803.g002: Effect of Ac2-26 treatment on the mesenteric inflammation induced by CV and MjTX-II.Intact mast cells (arrows) in the control mesentery (A). Inflamed mesentery of CV—(B) and MjTX-II-induced peritonitis (C-D) with extravasated neutrophils in the tissue (arrowheads) as observed at 4 and 24 h. Reduced neutrophil influx (arrowheads) after Ac2-26 post-treatment at 4 (E) and 24 h (F) of MjTX-II-induced peritonitis. Vessels (V). Stain: Toluidine blue. Scale bars: 10 μm. Quantitative analysis of extravasated neutrophils in the mesentery after CV- (G) and MjTX-II–induced peritonitis (H). The data represent the mean ± SEM of cell numbers/mm2 (n = 5 animals/group). **P < 0.01 vs control; §P < 0.05 vs MjTX-II-4 h.

Mentions: In addition, the peritoneal exudates displayed a marked increase in the IL-1β and IL-6 levels 4 hours after CV and MjTX-II administration (Table 1). As expected, the Ac2-26 treatment efficiently reduced the levels of both proinflammatory cytokine levels, although only IL-6 was significantly different between untreated and Ac2-26-treated CV group (Table 1). Similarly, an inflammatory response was detected in the mesenteries 4 hours after CV and MjTX-II injection and was characterized by elevated numbers of extravasated neutrophils and mast cell activation compared to the control animals (Fig 2A–2C, 2G and 2H; Table 2). Additionally, CV triggered a significant increase in the number of macrophages in the mesentery (Table 2) whereas no change was observed in the number of macrophages following MjTX-II administration. At 24 h of peritonitis, no alterations were observed in the inflammatory cell counts (Fig 2D, 2G and 2H; Table 2).


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.

Stuqui B, de Paula-Silva M, Carlos CP, Ullah A, Arni RK, Gil CD, Oliani SM - PLoS ONE (2015)

Effect of Ac2-26 treatment on the mesenteric inflammation induced by CV and MjTX-II.Intact mast cells (arrows) in the control mesentery (A). Inflamed mesentery of CV—(B) and MjTX-II-induced peritonitis (C-D) with extravasated neutrophils in the tissue (arrowheads) as observed at 4 and 24 h. Reduced neutrophil influx (arrowheads) after Ac2-26 post-treatment at 4 (E) and 24 h (F) of MjTX-II-induced peritonitis. Vessels (V). Stain: Toluidine blue. Scale bars: 10 μm. Quantitative analysis of extravasated neutrophils in the mesentery after CV- (G) and MjTX-II–induced peritonitis (H). The data represent the mean ± SEM of cell numbers/mm2 (n = 5 animals/group). **P < 0.01 vs control; §P < 0.05 vs MjTX-II-4 h.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4492549&req=5

pone.0130803.g002: Effect of Ac2-26 treatment on the mesenteric inflammation induced by CV and MjTX-II.Intact mast cells (arrows) in the control mesentery (A). Inflamed mesentery of CV—(B) and MjTX-II-induced peritonitis (C-D) with extravasated neutrophils in the tissue (arrowheads) as observed at 4 and 24 h. Reduced neutrophil influx (arrowheads) after Ac2-26 post-treatment at 4 (E) and 24 h (F) of MjTX-II-induced peritonitis. Vessels (V). Stain: Toluidine blue. Scale bars: 10 μm. Quantitative analysis of extravasated neutrophils in the mesentery after CV- (G) and MjTX-II–induced peritonitis (H). The data represent the mean ± SEM of cell numbers/mm2 (n = 5 animals/group). **P < 0.01 vs control; §P < 0.05 vs MjTX-II-4 h.
Mentions: In addition, the peritoneal exudates displayed a marked increase in the IL-1β and IL-6 levels 4 hours after CV and MjTX-II administration (Table 1). As expected, the Ac2-26 treatment efficiently reduced the levels of both proinflammatory cytokine levels, although only IL-6 was significantly different between untreated and Ac2-26-treated CV group (Table 1). Similarly, an inflammatory response was detected in the mesenteries 4 hours after CV and MjTX-II injection and was characterized by elevated numbers of extravasated neutrophils and mast cell activation compared to the control animals (Fig 2A–2C, 2G and 2H; Table 2). Additionally, CV triggered a significant increase in the number of macrophages in the mesentery (Table 2) whereas no change was observed in the number of macrophages following MjTX-II administration. At 24 h of peritonitis, no alterations were observed in the inflammatory cell counts (Fig 2D, 2G and 2H; Table 2).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunomorphology, Department of Biology, São Paulo State University (UNESP), São José do Rio Preto, São Paulo, Brazil.

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.

No MeSH data available.


Related in: MedlinePlus