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000284097 1001_ $$0P:(DE-2719)9003461$$aCampi Santos, Patricia$$b0$$udzne
000284097 245__ $$aThe Pivotal Role of 5-Lipoxygenase-Derived LTB4 in Controlling Pulmonary Paracoccidioidomycosis
000284097 260__ $$aLawrence, Kan.$$bPLoS$$c2013
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000284097 520__ $$aLeukotrienes (LTs) produced from arachidonic acid by the action of 5-lipoxygenase (5-LO) are classical mediators of inflammatory responses. However, studies published in the literature regarding these mediators are contradictory and it remains uncertain whether these lipid mediators play a role in host defense against the fungal pathogen Paracoccidioides brasiliensis. To determine the involvement of LTs in the host response to pulmonary infection, wild-type and LT-deficient mice by targeted disruption of the 5-lipoxygenase gene (knockout mice) were studied following intratracheal challenge with P. brasiliensis yeasts. The results showed that infection is uniformly fatal in 5-LO-deficient mice and the mechanisms that account for this phenotype are an exacerbated lung injury and higher fungal pulmonary burden. Genetic ablation or pharmacological inhibition of LTs resulted in lower phagocytosis and fungicidal activity of macrophages in vitro, suggesting that deficiency in fungal clearance seems to be secondary to the absence of activation in 5-LO(-/-) macrophages. Exogenous LTB4 restored phagocytosis and fungicidal activity of 5-LO(-/-) macrophages. Moreover, P. brasiliensis killing promoted by LTB4 was dependent on nitric oxide (NO) production by macrophages. Taken together, these results reveal a fundamental role for 5-LO-derived LTB4 in the protective response to P. brasiliensis infection and identify relevant mechanisms for the control of fungal infection during the early stages of the host immune response.
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000284097 650_7 $$01HGW4DR56D$$2NLM Chemicals$$aLeukotriene B4
000284097 650_7 $$0EC 1.13.11.34$$2NLM Chemicals$$aArachidonate 5-Lipoxygenase
000284097 650_2 $$2MeSH$$aAnimals
000284097 650_2 $$2MeSH$$aArachidonate 5-Lipoxygenase: metabolism
000284097 650_2 $$2MeSH$$aColony Count, Microbial
000284097 650_2 $$2MeSH$$aDisease Models, Animal
000284097 650_2 $$2MeSH$$aLeukotriene B4: metabolism
000284097 650_2 $$2MeSH$$aLung: microbiology
000284097 650_2 $$2MeSH$$aLung: pathology
000284097 650_2 $$2MeSH$$aMale
000284097 650_2 $$2MeSH$$aMice
000284097 650_2 $$2MeSH$$aMice, Knockout
000284097 650_2 $$2MeSH$$aParacoccidioides: immunology
000284097 650_2 $$2MeSH$$aParacoccidioidomycosis: immunology
000284097 650_2 $$2MeSH$$aSurvival Analysis
000284097 7001_ $$aSantos, Daniel Assis$$b1
000284097 7001_ $$0P:(DE-2719)9001782$$aSecchim Ribeiro, Lucas$$b2$$udzne
000284097 7001_ $$aFagundes, Caio Tavares$$b3
000284097 7001_ $$ade Paula, Talles Prosperi$$b4
000284097 7001_ $$aAvila, Thiago Vinícius$$b5
000284097 7001_ $$aBaltazar, Ludmila de Matos$$b6
000284097 7001_ $$aMadeira, Mila Moreira$$b7
000284097 7001_ $$aCruz, Rosana de Carvalho$$b8
000284097 7001_ $$aDias, Ana Carolina Fialho$$b9
000284097 7001_ $$aMachado, Fabiana Simão$$b10
000284097 7001_ $$aTeixeira, Mauro Martins$$b11
000284097 7001_ $$aCisalpino, Patrícia Silva$$b12
000284097 7001_ $$aSouza, Danielle G.$$b13
000284097 773__ $$0PERI:(DE-600)2429704-5$$a10.1371/journal.pntd.0002390$$gVol. 7, no. 8, p. e2390 -$$n8$$pe2390$$tPLoS neglected tropical diseases$$v7$$x1935-2727$$y2013
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