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Evaluation of systemic inflammatory response and lung injury induced by Crotalus durissus cascavella venom.

ABSTRACT: This study investigated the systemic inflammatory response and mechanism of pulmonary lesions induced by Crotalus durissus cascavella venom in murine in the state of Bahia. In order to investigate T helper Th1, Th2 and Th17 lymphocyte profiles, we measured interleukin (IL) -2, IL-4, IL-6, IL-10, IL-17, tumor necrosis factor (TNF) and interferon gamma (IFN-?) levels in the peritoneal fluid and macerated lungs of mice and histopathological alterations at the specific time windows of 1h, 3h, 6h, 12h, 24h and 48h after inoculation with Crotalus durissus cascavella venom. The data demonstrated an increase of acute-phase cytokines (IL-6 and TNF) in the first hours after inoculation, with a subsequent increase in IL-10 and IL-4, suggesting immune response modulation for the Th2 profile. The histopathological analysis showed significant morphological alterations, compatible with acute pulmonary lesions, with polymorphonuclear leukocyte (PMN) infiltration, intra-alveolar edema, congestion, hemorrhage and atelectasis. These findings advance our understanding of the dynamics of envenomation and contribute to improve clinical management and antiophidic therapy for individuals exposed to venom.

SUBMITTER: Azevedo E

PROVIDER: S-EPMC7035002 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Evaluation of systemic inflammatory response and lung injury induced by Crotalus durissus cascavella venom.

Azevedo Elen E Figueiredo Ricardo Gassmann RG Pinto Roberto Vieira RV Ramos Tarsila de Carvalho Freitas TCF Sampaio Geraldo Pedral GP Bulhosa Santos Rebeca Pereira RP Guerreiro Marcos Lázaro da Silva MLDS Biondi Ilka I Trindade Soraya Castro SC

PloS one 20200221 2

This study investigated the systemic inflammatory response and mechanism of pulmonary lesions induced by Crotalus durissus cascavella venom in murine in the state of Bahia. In order to investigate T helper Th1, Th2 and Th17 lymphocyte profiles, we measured interleukin (IL) -2, IL-4, IL-6, IL-10, IL-17, tumor necrosis factor (TNF) and interferon gamma (IFN-γ) levels in the peritoneal fluid and macerated lungs of mice and histopathological alterations at the specific time windows of 1h, 3h, 6h, 12 ...[more]

PMID: 32084665

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Project description:Background:In recent decades, snake venom disintegrins have received special attention due to their potential use in anticancer therapy. Disintegrins are small and cysteine-rich proteins present in snake venoms and can interact with specific integrins to inhibit their activities in cell-cell and cell-ECM interactions. These molecules, known to inhibit platelet aggregation, are also capable of interacting with certain cancer-related integrins, and may interfere in important processes involved in carcinogenesis. Therefore, disintegrin from Crotalus durissus collilineatus venom was isolated, structurally characterized and evaluated for its toxicity and ability to interfere with cell proliferation and migration in MDA-MB-231, a human breast cancer cell line. Methods:Based on previous studies, disintegrin was isolated by FPLC, through two chromatographic steps, both on reversed phase C-18 columns. The isolated disintegrin was structurally characterized by Tris-Tricine-SDS-PAGE, mass spectrometry and N-terminal sequencing. For the functional assays, MTT and wound-healing assays were performed in order to investigate cytotoxicity and effect on cell migration in vitro, respectively. Results:Disintegrin presented a molecular mass of 7287.4 Da and its amino acid sequence shared similarity with the disintegrin domain of P-II metalloproteases. Using functional assays, the disintegrin showed low cytotoxicity (15% and 17%, at 3 and 6 ?g/mL, respectively) after 24 h of incubation and in the wound-healing assay, the disintegrin (3 ?g/mL) was able to significantly inhibit cell migration (24%, p?<?0.05), compared to negative control. Conclusion:Thus, our results demonstrate that non-RGD disintegrin from C. d. collilineatus induces low cytotoxicity and inhibits migration of human breast cancer cells. Therefore, it may be a very useful molecular tool for understanding ECM-cell interaction cancer-related mechanisms involved in an important integrin family that highlights molecular aspects of tumorigenesis. Also, non-RGD disintegrin has potential to serve as an agent in anticancer therapy or adjuvant component combined with other anticancer drugs.

Project description:Snake venom serine proteases (SVSPs) represent an essential group of enzymatic toxins involved in several pathophysiological effects on blood homeostasis. Some findings suggest the involvement of this class of enzymatic toxins in inflammation. In this paper, we purified and isolated a new gyroxin isoform from the Crotalus durissus terrificus (Cdt) venom, designated as Cdtsp 2, which showed significant proinflammatory effects in a murine model. In addition, we performed several studies to elucidate the main pathway underlying the edematogenic effect induced by Cdtsp 2. Enzymatic assays and structural analysis (primary structure analysis and three-dimensional modeling) were closely performed with pharmacological assays. The determination of edematogenic activity was performed using Cdtsp 2 isolated from snake venom, and was applied to mice treated with protein kinase C (PKC) inhibitor, phospholipase C (PLC) inhibitor, dexamethasone (Dexa), antagonists for protease-activated receptors (PARs), or saline (negative control). Additionally, we measured the levels of cyclooxygenase 2 (COX-2), malondialdehyde (MDA), and prostaglandin E2 (PGE2). Cdtsp 2 is characterized by an approximate molecular mass of 27 kDa, an isoelectric point (pI) of 4.5, and significant fibrinolytic activity, as well as the ability to hydrolyze N?-benzoyl-l-arginine 4-nitroanilide (BAPNA). Its primary and three-dimensional structures revealed Cdtsp 2 as a typical snake venom serine protease that induces significant edema via the metabolism of arachidonic acid (AA), involving PARs, PKC, PLC, and COX-2 receptors, as well as inducing a significant increase in MDA levels. Our results showed that Cdtsp 2 is a serine protease with significant enzymatic activity, and it may be involved in the degradation of PAR1 and PAR2, which activate PLC and PKC to mobilize AA, while increasing oxidative stress. In this article, we provide a new perspective for the role of SVSPs beyond their effects on blood homeostasis.

Dataset Information

Evaluation of systemic inflammatory response and lung injury induced by Crotalus durissus cascavella venom.

Publications

Evaluation of systemic inflammatory response and lung injury induced by Crotalus durissus cascavella venom.

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