Contribution of mast cells and snake venom metalloproteinases to the hyperalgesia induced by Bothrops jararaca venom in rats

Laboratory of Inflammation, Department of Physiology and Pharmacodynamics, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Av. Brasil, CEP 21040-900, 4365 Rio de Janeiro, Brazil.
Toxicon (Impact Factor: 2.49). 07/2006; 47(8):885-93. DOI: 10.1016/j.toxicon.2006.02.017
Source: PubMed


Bothrops jararaca venom (Bjv) is known to induce local inflammation and severe pain. Since, mast cells are able to secrete mediators involved in algesic processes, in this study we examined the putative role of these cells in the hyperalgesia triggered by Bjv in the rat paw. We noted that treatment with mast cell stabilizer sodium cromoglicate as well as with histamine and 5-hydroxytriptamine receptor antagonists meclizine and methysergide, respectively, inhibited the Bjv-induced hyperalgesia. In addition, we showed that stimulation of isolated rat peritoneal mast cells with Bjv in vitro resulted in the release of stored and neo-generated inflammatory mediators such as histamine and leukotriene C(4), respectively. Bjv-induced histamine secretion was clearly sensitive to treatment with sodium cromoglicate and sodium nedocromil. We further observed that metalloproteinase inhibitors 1,10-phenantroline and DM43 inhibited mast cell degranulation in vitro, under conditions where inhibitors of phospholipase A(2) as well as of serine- and cysteine-proteinases were inactive. Altogether, our findings indicate that mast cells seem to contribute to the hyperalgesia caused by Bjv in the rat paw, and also provide evidence that this response might be dependent on the ability of the Bjv to activate directly mast cells.

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Available from: Andre Bonavita, Mar 14, 2014
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    • "In agreement with the role of cytokines in pain, inhibiting NFkB activation also reduces pain (Possebon et al., 2014; Tegeder et al., 2004). Pain is an important clinical component of snakebites (Bonavita et al., 2006; Rocha et al., 2000; Zychar et al., 2010) and the mechanisms underlying B. jararaca snake venom and jararhagininduced pain are incompletely understood. Despite jararhagin induction of TNF-a and IL-1b production in other systems (Clissa et al., 2006; Laing et al., 2003), and the hyperalgesic role of TNF-a and IL-1b, and NFkB (Verri et al., 2006), the contribution of cytokines and NFkB to jararhagin-induced mechanical hyperalgesia remains to be determined. "
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    ABSTRACT: Jararhagin is a hemorrhagic metalloprotease from Bothrops jararaca snake venom. The hyperalgesic mechanisms of jararhagin were investigated focusing on the role of proinflammatory cytokines (TNF-α and IL-1β) and the transcription factor NFκB. Intraplantar administration of jararhagin (1, 10, 100 and 1000 ng/paw) induced mechanical hyperalgesia, and increased TNF-α levels at 1, 3 and 5 h, and IL-1β levels at 0.5, 1 and 3 h after its injection in the paw tissue. Pre-treatment with morphine (2, 6, 12 μg/paw) inhibited jararhagin-induced mechanical hyperagesia. The systemic or local pre-treatment with etanercept (10 mg/kg and 100 μg/paw) and IL-1ra (30 mg/kg and 100 pg/paw) inhibited jararhagin-induced mechanical hyperalgesia. Co-administration of jararhagin (0.1 ng/paw) and TNF-α (0.1 pg/paw) or jararhagin (0.1 ng/paw) and IL-1β (1 pg/paw) enhanced the mechanical hyperalgesia. The systemic or local pre-treatment with PDTC (NFκB inhibitor; 100 mg/kg and 100 μg/paw) inhibited jararhagin-induced mechanical hyperalgesia as well as PDTC decreased the jararhagin-induced production of TNF-α and IL-1β. Thus, these data demonstrate the involvement of pro-inflammatory cytokines TNF-α and IL-1β and nuclear transcription factor NFκB in jararhagin-induced mechanical hyperalgesia indicating that targeting these mechanisms might contribute to reduce the pain induced by B. jararaca snake venom. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Toxicon 06/2015; 103. DOI:10.1016/j.toxicon.2015.06.024 · 2.49 Impact Factor
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    • "Several biological active molecules from Bothrops spp. snake venoms are responsible for stimulating an intense inflammation during envenomation, triggering immunological events, such as prominent leukocyte infiltration, and promoting local and systemic disorders (Bonavita et al. 2006; Carneiro et al. 2008; Teixeira et al. 2009). As an example of these factors within venom, the C-type β-galactoside-binding lectins have been reported to be involved in inflammatory response (Lomonte et al. 1990; Havt et al. 2005; Panunto et al. 2006; Elífio-Esposito et al., 2011). "
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    ABSTRACT: While previous studies suggest that snake venom contains glycan-binding proteins (GBPs), the binding specificity and biological activities of many of these GBPs remains unknown. In order to more fully characterize the glycan binding activity and biological activity of snake venom GBPs, we evaluated the glycan binding specificity of galatrox, a Bothrops atrox snake venom-derived GBP. Glycan microarray analysis indicates that galatrox binds strongly to glycans expressing N-acetyllactosamine (LacNAc), with a significant preference for Galβ1-4GlcNAcβ over Galβ1-3GlcNAcβ compounds. Galatrox also bound immobilized laminin, a LacNAc-dense extracellular matrix component, suggesting that this GBP possess the capacity to recogonize LacNAc bearing glycoproteins. As several endogenous mammalian GBPs utilize a similar binding preference to regulate neutrophil and monocyte activity, we hypothesized that galatrox may, in part, mediate Bothrops atrox toxicity through regulation of leukocyte activity. Indeed, galatrox recognized neutrophils and promoted leukocyte chemotaxis in a carbohydrate-dependent manner. Similarly, galatrox induced significant neutrophil migration and the release of pro-inflammatory cytokines IL-1α and IL-6 into the mouse peritoneal cavity. Exposure of bone marrow-derived macrophages to galatrox produces pro-inflammatory mediators IL-6, TNF-α, and keratinocyte-derived chemokine (KC) mediated by interaction and activation of TLR4- mediated MyD88-dependent signaling pathway, via its carbohydrate recognition domain. These results suggest that galatrox is able to mediate pro-inflammatory activity by interacting with LacNAc bearing glycans on neutrophils, macrophages and extracellular matrix proteins and inducing the release of pro-inflammatory mediators.
    Glycobiology 06/2014; 24(11). DOI:10.1093/glycob/cwu061 · 3.15 Impact Factor
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    ABSTRACT: Various toxins isolated from Bothrops snake venoms induce inflammatory reactions and have been claimed to contribute to the severity of local symptoms present in this envenomation. Notwithstanding, the relative participation of serine proteases, metalloproteases and phospholipases A(2) in the inflammatory reaction produced by crude Bothrops venoms is poorly understood. Herein, crude Bothrops jararaca venom was treated with phenylmethanesulfonyl fluoride (PMSF), 1,10-phenanthroline (oPhe), or p-bromophenacyl-bromide (p-BPB) to inhibit those classes of enzymes, respectively, and inflammatory parameters were evaluated and compared to those induced by the control crude venom. The intensity of edema and hyperalgesia/allodynia was remarkably reduced in animals administered with oPhe-treated venom. Leukocyte-endothelium interactions (LEI), such as adhesion and migration of leukocytes, were also modified at 2h and 24h. Edema and LEI parameters induced by p-BPB-treated venom were similar to those observed with the control venom, but hyperalgesia/allodynia was significantly lower. Inflammatory parameters induced by PMSF-treated venom were similar to those induced by the crude venom, except for a mild reduction in edema intensity. Our results indicate that metalloproteases have a pivotal role in the inflammatory reactions induced by B. jararaca venom, and phospholipases A(2) and serine proteases have a minor role.
    Toxicon 08/2009; 55(2-3):227-34. DOI:10.1016/j.toxicon.2009.07.025 · 2.49 Impact Factor
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