{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T23:01:14Z","timestamp":1773356474333,"version":"3.50.1"},"reference-count":56,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,9,14]],"date-time":"2020-09-14T00:00:00Z","timestamp":1600041600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2013\/07467"],"award-info":[{"award-number":["2013\/07467"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2019\/20832-7"],"award-info":[{"award-number":["2019\/20832-7"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["301853\/2017-7"],"award-info":[{"award-number":["301853\/2017-7"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["88882.376316\/2007-01"],"award-info":[{"award-number":["88882.376316\/2007-01"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Bitis arietans is a snake of medical importance, as it is responsible for more accidents in humans and domestic animals than all other African snakes put together. The accidents are characterized by local and systemic alterations, such as inflammation, cardiovascular and hemostatic disturbances, which can lead victims to death or permanent disability. However, little is known about the envenomation mechanism, especially regarding the inflammatory response, which is related to severe clinical conditions triggered by the venom. Therefore, the aim of the present study was to evaluate the inflammatory response related to the B. arietans envenomation using a peritonitis mice model. By pharmacological interventions and use of mice genetically deficient of the 5-lipoxygenase enzyme (5-LO\u2212\/\u2212) or platelet-activating factor (PAF) receptor (PAFR\u2212\/\u2212 the participation of eicosanoids and PAF in this response was also investigated. The obtained results demonstrated that the venom induces an in vivo inflammatory response, characterized by an early increased vascular permeability, followed by an accumulation of polymorphonuclear (PMN) cells in the peritoneal cavity, accompanied by the production of the eicosanoids LTB4, LTC4, TXB2 and PGE2, as well as the local and systemic production of IL-6 and MCP-1. These inflammatory events were attenuated by the pre-treatment with anti-inflammatory drugs that interfere in lipid mediators\u2019 functions. However, 5-LO\u2212\/\u2212 mice did not show a reduction of inflammatory response induced by the venom, while PAFR\u2212\/\u2212 mice showed a reduction in both the PMN leukocytes number and the local and systemic production of IL-6 and MCP-1. This study demonstrated that the Bitis arietans venom contains toxins that trigger an inflammatory process, which is partially dependent on lipid mediators, and may contribute to the envenomation pathology.<\/jats:p>","DOI":"10.3390\/toxins12090594","type":"journal-article","created":{"date-parts":[[2020,9,15]],"date-time":"2020-09-15T10:24:09Z","timestamp":1600165449000},"page":"594","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Bitis arietans Snake Venom Induces an Inflammatory Response Which Is Partially Dependent on Lipid Mediators"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2593-4363","authenticated-orcid":false,"given":"Angela Alice Amadeu","family":"Megale","sequence":"first","affiliation":[{"name":"Immunochemistry Laboratory, Butantan Institute, S\u00e3o Paulo 05503-900, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9582-4699","authenticated-orcid":false,"given":"Fernanda Calheta","family":"Portaro","sequence":"additional","affiliation":[{"name":"Immunochemistry Laboratory, Butantan Institute, S\u00e3o Paulo 05503-900, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wilmar Dias","family":"Da Silva","sequence":"additional","affiliation":[{"name":"Immunochemistry Laboratory, Butantan Institute, S\u00e3o Paulo 05503-900, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kasturiratne, A., Wickremasinghe, A.R., de Silva, N., Gunawardena, N.K., Pathmeswaran, A., Premaratna, R., Savioli, L., Lalloo, D.G., and de Silva, H.J. (2008). The global burden of snakebite: A literature analysis and modelling based on regional estimates of envenoming and deaths. PLoS Med., 5.","DOI":"10.1371\/journal.pmed.0050218"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/j.toxicon.2010.12.022","article-title":"Estimate of the burden of snakebites in sub-Saharan Africa: A meta-analytic approach","volume":"57","author":"Chippaux","year":"2011","journal-title":"Toxicon"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40409-017-0127-6","article-title":"Snakebite envenomation turns again into a neglected tropical disease!","volume":"23","author":"Chippaux","year":"2017","journal-title":"J. Venom. Anim. Toxins Incl. Trop. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1136\/bmj.4.5998.697","article-title":"Bites by puff-adder (Bitis arietans) in Nigeria, and value of antivenom","volume":"4","author":"Warrell","year":"1975","journal-title":"Br. Med. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/S0736-4679(97)00191-1","article-title":"Exotic snakebite: Envenomation by an African puff adder (Bitis arietans)","volume":"15","author":"Bey","year":"1997","journal-title":"J. Emerg. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1111\/vec.12127","article-title":"Myocardial injury in dogs with snake envenomation and its relation to systemic inflammation","volume":"24","author":"Langhorn","year":"2014","journal-title":"J. Vet. Emerg. Crit. Care"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1081\/CLT-120016963","article-title":"Severe puff adder (Bitis arietans) envenomation with coagulopathy","volume":"40","author":"Lavonas","year":"2002","journal-title":"J. Toxicol. Clin. Toxicol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1080\/00034983.1985.11811923","article-title":"Venom antibody levels in a patient bitten by a young puff adder (Bitis arietans) during a world record attempt","volume":"79","author":"Theakston","year":"1985","journal-title":"Ann. Trop. Med. Parasitol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1590\/S0100-879X2002001000016","article-title":"Evaluation of antivenoms in the neutralization of hyperalgesia and edema induced by Bothrops jararaca and Bothrops asper snake venoms","volume":"35","author":"Picolo","year":"2002","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1590\/S0104-79301999000100002","article-title":"The systemic inflammatory response syndrome related to the release of cytokines following severe envenomation","volume":"5","author":"Voronov","year":"1999","journal-title":"J. Venom. Anim. Toxins"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1023\/A:1014465611487","article-title":"Importance of metalloproteinases and macrophages in viper snake envenomation\u2013induced local inflammation","volume":"26","author":"Costa","year":"2002","journal-title":"Inflammation"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1097\/01.CCM.0000050440.87890.92","article-title":"Tumor necrosis factor as a mediator of cardiac toxicity following snake envenomation","volume":"31","author":"Szold","year":"2003","journal-title":"Crit. Care Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/nature07201","article-title":"Origin and physiological roles of inflammation","volume":"454","author":"Medzhitov","year":"2008","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.toxicon.2012.03.004","article-title":"Local inflammatory events induced by Bothrops atrox snake venom and the release of distinct classes of inflammatory mediators","volume":"60","author":"Moreira","year":"2012","journal-title":"Toxicon"},{"key":"ref_15","first-page":"209","article-title":"Inflammatory infiltrate in skeletal muscle injected with Bothrops asper venom","volume":"34","author":"Chaves","year":"1986","journal-title":"Rev. Biol. Trop."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1080\/09629359890866","article-title":"Local inflammation, lethality and cytokine release in mice injected with Bothrops atrox venom","volume":"7","author":"Barros","year":"1998","journal-title":"Mediat. Inflamm."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/S0041-0101(96)00135-3","article-title":"Leukocyte response induced by Bothrops jararaca crude venom: In vivo and in vitro studies","volume":"35","author":"Farsky","year":"1997","journal-title":"Toxicon"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1016\/j.toxicon.2005.08.011","article-title":"Inflammation induced by Bothrops asper venom: Release of proinflammatory cytokines and eicosanoids, and role of adhesion molecules in leukocyte infiltration","volume":"46","author":"Zamuner","year":"2005","journal-title":"Toxicon"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Silva de Fran\u00e7a, F., Villas-Boas, I.M., de Toledo Serrano, S.M., Cogliati, B., de Andrade Chudzinski, S.A., Lopes, P.H., Kitano, E.S., Okamoto, C.K., and Tambourgi, D.V. (2019). Naja annulifera Snake: New insights into the venom components and pathogenesis of envenomation. PLoS Negl. Trop. Dis., 13.","DOI":"10.1371\/journal.pntd.0007017"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1126\/science.294.5548.1871","article-title":"Prostaglandins and leukotrienes: Advances in eicosanoid biology","volume":"294","author":"Funk","year":"2001","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.toxicon.2006.11.006","article-title":"Role of cyclooxygenases in oedema-forming activity of bothropic venoms","volume":"49","author":"Olivo","year":"2007","journal-title":"Toxicon"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.toxicon.2013.01.023","article-title":"Dexamethasone antagonizes the in vivo myotoxic and inflammatory effects of Bothrops venoms","volume":"69","author":"Tomaz","year":"2013","journal-title":"Toxicon"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.toxicon.2014.08.001","article-title":"Bothrops jararacussu snake venom-induces a local inflammatory response in a prostanoid-and neutrophil-dependent manner","volume":"90","author":"Wanderley","year":"2014","journal-title":"Toxicon"},{"key":"ref_24","first-page":"400","article-title":"Pharmacological characterization of rat paw edema induced by Cerastes gasperettii (cerastes) venom","volume":"12","author":"Abdo","year":"2006","journal-title":"J. Venom. Anim. Toxins"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.toxrep.2018.02.011","article-title":"Montivipera bornmuelleri venom has immunomodulatory effects mainly up-regulating pro-inflammatory cytokines in the spleens of mice","volume":"5","author":"Yacoub","year":"2018","journal-title":"Toxicol. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Boda, F., Banfai, K., Garai, K., Curticapean, A., Berta, L., Sipos, E., and Kvell, K. (2018). Effect of Vipera ammodytes ammodytes snake venom on the human cytokine network. Toxins, 10.","DOI":"10.3390\/toxins10070259"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/0041-0101(93)90380-2","article-title":"Biological and biochemical activities of Vipera berus (European viper) venom","volume":"31","author":"Lomonte","year":"1993","journal-title":"Toxicon"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/S0014-5793(00)02374-7","article-title":"Intracellular compartmentalization of leukotriene synthesis: Unexpected nuclear secrets","volume":"487","author":"Brock","year":"2001","journal-title":"FEBS Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2974","DOI":"10.4049\/jimmunol.160.6.2974","article-title":"Segregated coupling of phospholipases A2, cyclooxygenases, and terminal prostanoid synthases in different phases of prostanoid biosynthesis in rat peritoneal macrophages","volume":"160","author":"Naraba","year":"1998","journal-title":"J. Immunol."},{"key":"ref_30","unstructured":"Mallow, D., Ludwig, D., and Nilson, G. (2003). True Vipers: Natural History and Toxinology of Old World Vipers, Krieger Publishing Company."},{"key":"ref_31","unstructured":"Shupe, S. (2013). Generic and Species Descriptions, Skyhorse Publishing."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.toxicon.2012.10.002","article-title":"Ts6 and Ts2 from Tityus serrulatus venom induce inflammation by mechanisms dependent on lipid mediators and cytokine production","volume":"61","author":"Zoccal","year":"2013","journal-title":"Toxicon"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1054\/plef.2001.0276","article-title":"Do human platelets express COX-2?","volume":"64","author":"Reiter","year":"2001","journal-title":"Prostaglandins Leukot. Essent. Fat. Acids"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2546","DOI":"10.1194\/jlr.M026385","article-title":"Investigations of human platelet-type 12-lipoxygenase: Role of lipoxygenase products in platelet activation","volume":"53","author":"Ikei","year":"2012","journal-title":"J. Lipid Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.ejphar.2009.02.023","article-title":"MK-886, an inhibitor of the 5-lipoxygenase-activating protein, inhibits cyclooxygenase-1 activity and suppresses platelet aggregation","volume":"608","author":"Koeberle","year":"2009","journal-title":"Eur. J. Pharm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1042\/bj3560899","article-title":"Inhibition of peroxisome-proliferator-activated receptor (PPAR) \u03b1 by MK886","volume":"356","author":"Kehrer","year":"2001","journal-title":"Biochem. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1074\/jbc.M112.437525","article-title":"Peroxisome proliferator-activated receptor \u03b1 positively regulates complement C3 expression but inhibits tumor necrosis factor \u03b1-mediated activation of C3 gene in mammalian hepatic-derived cells","volume":"288","author":"Mogilenko","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1084\/jem.125.5.921","article-title":"Complement as a mediator of inflammation: II. Biological properties of anaphylatoxin prepared with purified components of human complement","volume":"125","author":"Lepow","year":"1967","journal-title":"J. Exp. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1080\/09629350020025728","article-title":"Bothrops asper snake venom and its metalloproteinase BaP\u20131 activate the complement system. Role in leucocyte recruitment","volume":"9","author":"Farsky","year":"2000","journal-title":"Mediat. Inflamm."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Tanaka, G.D., Pidde-Queiroz, G., Maria de F\u00e1tima, D.F., van den Berg, C., and Tambourgi, D.V. (2012). Micrurus snake venoms activate human complement system and generate anaphylatoxins. BMC Immunol., 13.","DOI":"10.1186\/1471-2172-13-4"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1016\/j.molimm.2010.07.003","article-title":"Human complement activation and anaphylatoxins generation induced by snake venom toxins from Bothrops genus","volume":"47","author":"Filgueiras","year":"2010","journal-title":"Mol. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1084\/jem.184.3.883","article-title":"Selective neutralization of prostaglandin E2 blocks inflammation, hyperalgesia, and interleukin 6 production in vivo","volume":"184","author":"Portanova","year":"1996","journal-title":"J. Exp. Med."},{"key":"ref_43","first-page":"1","article-title":"Kn-Ba: A novel serine protease isolated from Bitis arietans snake venom with fibrinogenolytic and kinin-releasing activities","volume":"24","author":"Megale","year":"2018","journal-title":"J. Venom. Anim. Toxins"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/0003-2697(85)90442-7","article-title":"Measurement of protein using bicinchoninic acid","volume":"150","author":"Smith","year":"1985","journal-title":"Anal. Biochem."},{"key":"ref_45","unstructured":"Zoccal, K.F. (2014). A Pe\u00e7onha do Escorpi\u00e3o Tityus serrulatus \u00e9 Reconhecida por Receptores de Reconhecimento Padr\u00e3o e Induz Ativa\u00e7\u00e3o Celular e Inflama\u00e7\u00e3o. [Ph.D. Thesis, Universidade de S\u00e3o Paulo]."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1016\/j.toxicon.2009.10.006","article-title":"Inhibition of the myotoxic activities of three African Bitis venoms (B. rhinoceros, B. arietans and B. nasicornis) by a polyvalent antivenom","volume":"55","author":"Ponte","year":"2010","journal-title":"Toxicon"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Guidolin, F.R., Caricati, C.P., Marcelino, J.R., and da Silva, W.D. (2016). Development of Equine IgG Antivenoms against Major Snake Groups in Mozambique. PLoS Negl. Trop. Dis., 10.","DOI":"10.1371\/journal.pntd.0004325"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.imbio.2005.08.003","article-title":"Neutrophils regulate the expression of cytokines, chemokines and nitric oxide synthase\/nitric oxide in mice injected with Bothrops atrox venom","volume":"211","author":"Kanashiro","year":"2006","journal-title":"Immunobiology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2\u2212\u0394\u0394CT method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1038\/227680a0","article-title":"Cleavage of structural proteins during the assembly of the head of bacteriophage T4","volume":"227","author":"Laemmli","year":"1970","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4350","DOI":"10.1073\/pnas.76.9.4350","article-title":"Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: Procedure and some applications","volume":"76","author":"Towbin","year":"1979","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1093\/jnci\/90.6.455","article-title":"Expression of cyclooxygenase-1 and cyclooxygenase-2 in human breast cancer","volume":"90","author":"Hwang","year":"1998","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/0090-6980(88)90009-3","article-title":"PAF increases vascular permeability in selected tissues: Effect of BN-52021 and L-655,240","volume":"36","author":"Sirois","year":"1988","journal-title":"Prostaglandins"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/laban0511-155","article-title":"Retro-orbital injections in mice","volume":"40","author":"Yardeni","year":"2011","journal-title":"Lab. Anim."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-017-04498-8","article-title":"A snake venom group IIA PLA2 with immunomodulatory activity induces formation of lipid droplets containing 15-d-PGJ2 in macrophages","volume":"7","author":"Giannotti","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ncomms10760","article-title":"Opposing roles of LTB4 and PGE2 in regulating the inflammasome-dependent scorpion venom-induced mortality","volume":"7","author":"Zoccal","year":"2016","journal-title":"Nat. Commun."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/12\/9\/594\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:09:57Z","timestamp":1760177397000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/12\/9\/594"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,14]]},"references-count":56,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["toxins12090594"],"URL":"https:\/\/doi.org\/10.3390\/toxins12090594","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,14]]}}}