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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

Light micrographs of rat mesenteries showing AnxA1 immunoreactivity in the mast cells.AnxA1-positive mast cells in the control group (A). After 24 hours, the administration of CV and MjTX-II was associated with intense (B) and low (C) AnxA1 immunoreactivity in mast cells (arrows), respectively. Negative control of reaction (D). Counterstain: hematoxylin. Stained adjacent histological sections with 0.5% toluidine blue confirms that the indicated cells are mast cells (arrows; E-H). Scale bars: 5 μm. Densitometric analysis of mesenteric mast cells immunostained for AnxA1 in CV (I) and MjTX-II (J) groups. The values (arbitrary units) are expressed as the mean ± SEM of sections analyzed from 5 rats /group. ***P < 0.001 vs control.
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pone.0130803.g004: Light micrographs of rat mesenteries showing AnxA1 immunoreactivity in the mast cells.AnxA1-positive mast cells in the control group (A). After 24 hours, the administration of CV and MjTX-II was associated with intense (B) and low (C) AnxA1 immunoreactivity in mast cells (arrows), respectively. Negative control of reaction (D). Counterstain: hematoxylin. Stained adjacent histological sections with 0.5% toluidine blue confirms that the indicated cells are mast cells (arrows; E-H). Scale bars: 5 μm. Densitometric analysis of mesenteric mast cells immunostained for AnxA1 in CV (I) and MjTX-II (J) groups. The values (arbitrary units) are expressed as the mean ± SEM of sections analyzed from 5 rats /group. ***P < 0.001 vs control.

Mentions: Similar results were obtained for mesenteric mast cells in CV-induced peritonitis, and we detected high endogenous levels of AnxA1 in these cells at 4 and 24 hours (Fig 4A and 4B). Following MjTX-II administration, the AnxA1 expression was significantly decreased in mast cells (Fig 4C). Fig 4D presents the section incubated in the absence of the primary antibody to provide a negative control of the reaction. The histological sections, sequential to those obtained for immunohistochemistry (Fig 4E–4H), were stained with toluidine blue (Fig 3F) to confirm that the immunostained cells were mast cells. The densitometric analysis of AnxA1 expression on mast cells corroborates our histological findings (Fig 4I and 4J).


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)

Light micrographs of rat mesenteries showing AnxA1 immunoreactivity in the mast cells.AnxA1-positive mast cells in the control group (A). After 24 hours, the administration of CV and MjTX-II was associated with intense (B) and low (C) AnxA1 immunoreactivity in mast cells (arrows), respectively. Negative control of reaction (D). Counterstain: hematoxylin. Stained adjacent histological sections with 0.5% toluidine blue confirms that the indicated cells are mast cells (arrows; E-H). Scale bars: 5 μm. Densitometric analysis of mesenteric mast cells immunostained for AnxA1 in CV (I) and MjTX-II (J) groups. The values (arbitrary units) are expressed as the mean ± SEM of sections analyzed from 5 rats /group. ***P < 0.001 vs control.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4492549&req=5

pone.0130803.g004: Light micrographs of rat mesenteries showing AnxA1 immunoreactivity in the mast cells.AnxA1-positive mast cells in the control group (A). After 24 hours, the administration of CV and MjTX-II was associated with intense (B) and low (C) AnxA1 immunoreactivity in mast cells (arrows), respectively. Negative control of reaction (D). Counterstain: hematoxylin. Stained adjacent histological sections with 0.5% toluidine blue confirms that the indicated cells are mast cells (arrows; E-H). Scale bars: 5 μm. Densitometric analysis of mesenteric mast cells immunostained for AnxA1 in CV (I) and MjTX-II (J) groups. The values (arbitrary units) are expressed as the mean ± SEM of sections analyzed from 5 rats /group. ***P < 0.001 vs control.
Mentions: Similar results were obtained for mesenteric mast cells in CV-induced peritonitis, and we detected high endogenous levels of AnxA1 in these cells at 4 and 24 hours (Fig 4A and 4B). Following MjTX-II administration, the AnxA1 expression was significantly decreased in mast cells (Fig 4C). Fig 4D presents the section incubated in the absence of the primary antibody to provide a negative control of the reaction. The histological sections, sequential to those obtained for immunohistochemistry (Fig 4E–4H), were stained with toluidine blue (Fig 3F) to confirm that the immunostained cells were mast cells. The densitometric analysis of AnxA1 expression on mast cells corroborates our histological findings (Fig 4I and 4J).

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