TY  - JOUR
AU  - Campi Santos, Patricia
AU  - Santos, Daniel Assis
AU  - Secchim Ribeiro, Lucas
AU  - Fagundes, Caio Tavares
AU  - de Paula, Talles Prosperi
AU  - Avila, Thiago Vinícius
AU  - Baltazar, Ludmila de Matos
AU  - Madeira, Mila Moreira
AU  - Cruz, Rosana de Carvalho
AU  - Dias, Ana Carolina Fialho
AU  - Machado, Fabiana Simão
AU  - Teixeira, Mauro Martins
AU  - Cisalpino, Patrícia Silva
AU  - Souza, Danielle G.
TI  - The Pivotal Role of 5-Lipoxygenase-Derived LTB4 in Controlling Pulmonary Paracoccidioidomycosis
JO  - PLoS neglected tropical diseases
VL  - 7
IS  - 8
SN  - 1935-2727
CY  - Lawrence, Kan.
PB  - PLoS
M1  - DZNE-2026-00105
SP  - e2390
PY  - 2013
AB  - Leukotrienes (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.
KW  - Animals
KW  - Arachidonate 5-Lipoxygenase: metabolism
KW  - Colony Count, Microbial
KW  - Disease Models, Animal
KW  - Leukotriene B4: metabolism
KW  - Lung: microbiology
KW  - Lung: pathology
KW  - Male
KW  - Mice
KW  - Mice, Knockout
KW  - Paracoccidioides: immunology
KW  - Paracoccidioidomycosis: immunology
KW  - Survival Analysis
KW  - Leukotriene B4 (NLM Chemicals)
KW  - Arachidonate 5-Lipoxygenase (NLM Chemicals)
LB  - PUB:(DE-HGF)16
DO  - DOI:10.1371/journal.pntd.0002390
UR  - https://pub.dzne.de/record/284097
ER  -