The functions of eicosanoids, a family of potent biologically active lipid mediators, are not restricted to inflammatory responses and they also act as mediators of the pathogenesis process. However, ...the role of eicosanoids in tuberculosis remains controversial. To investigate the specific role of LTB4 in Mycobacterium tuberculosis (Mtb) infection, we used 5-lipoxygenase-deficient (5-LO−/−) mice and WT (sv129) mice inoculated intranasally with LTB4 (encapsulated in PLGA microspheres). We showed that deficiency of the 5-LO pathway was related to resistance to Mtb infection. LTB4 inoculation increased susceptibility to Mtb in 5-LO−/− mice but not in WT mice, resulting in worsening of lung inflammation and tissue damage. In infected WT mice, most supplementary LTB4 was metabolized to the inactive form 12-oxo-LTB4 in the lung. A high amount of PGE2 was detected during Mtb infection, and pharmacological inhibition of COX-2 induced a significant reduction of bacterial load and an improved innate immune response in the lungs, independently of baseline LTB4 levels. COX-2 inhibition with celecoxib significantly reduced PGE2 levels, enhanced IFN-γ production and NO release, and increased macrophage phagocytosis of Mtb. The results suggest that a balance between PGE2/LTB4 is essential in the pathogenesis process of tuberculosis to prevent severe inflammation. Moreover, optimal levels of PGE2 are required to induce an effective innate response in the early phase of Mtb infection. Thus, pharmacological modulation of eicosanoid production may provide an important host-directed therapy in tuberculosis.
•Susceptibility to M. tuberculosis infection is influenced by the 5-LO pathway.•Optimal levels of PGE2 are required for effective immune response in TB.•LTB4 contributes to the immunopathogenesis of M. tuberculosis infection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Erythropoietin (EPO) is a key hormone involved in red blood cell formation, but its effects on nonerythroid cells, such as macrophages, have not been described. Macrophages are key cells in ...controlling histoplasmosis, a fungal infection caused by Histoplasma capsulatum (Hc). Considering that little is known about EPO’s role during fungal infections and its capacity to activate macrophages, in this study we investigated the impact of EPO pretreatment on the alveolar immune response during Hc infection. The consequence of EPO pretreatment on fungal infection was determined by evaluating animal survival, fungal burden, activation of bronchoalveolar macrophages, inflammatory mediator release, and lung inflammation. Pretreatment with EPO diminished mononuclear cell numbers, increased the recruitment of F4/80+/CD80+ and F4/80+/CD86+ cells to the bronchoalveolar space, induced higher production of IFN-γ, IL-6, MIP-1α, MCP-1, and LTB4, reduced PGE2 concentration, and did not affect fungal burden. As a consequence, we observed an increase in lung inflammation with extensive tissue damage that might account for augmented mouse mortality after infection. Our results demonstrate for the first time that EPO treatment has a deleterious impact on lung immune responses during fungal infection.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The functions of eicosanoids, a family of potent biologically active lipid mediators, are not restricted to inflammatory responses and they also act as mediators of the pathogenesis process. However, ...the role of eicosanoids in tuberculosis remains controversial. To investigate the specific role of LTB
in Mycobacterium tuberculosis (Mtb) infection, we used 5-lipoxygenase-deficient (5-LO
) mice and WT (sv129) mice inoculated intranasally with LTB
(encapsulated in PLGA microspheres). We showed that deficiency of the 5-LO pathway was related to resistance to Mtb infection. LTB
inoculation increased susceptibility to Mtb in 5-LO
mice but not in WT mice, resulting in worsening of lung inflammation and tissue damage. In infected WT mice, most supplementary LTB
was metabolized to the inactive form 12-oxo-LTB
in the lung. A high amount of PGE
was detected during Mtb infection, and pharmacological inhibition of COX-2 induced a significant reduction of bacterial load and an improved innate immune response in the lungs, independently of baseline LTB
levels. COX-2 inhibition with celecoxib significantly reduced PGE
levels, enhanced IFN-γ production and NO release, and increased macrophage phagocytosis of Mtb. The results suggest that a balance between PGE
/LTB
is essential in the pathogenesis process of tuberculosis to prevent severe inflammation. Moreover, optimal levels of PGE
are required to induce an effective innate response in the early phase of Mtb infection. Thus, pharmacological modulation of eicosanoid production may provide an important host-directed therapy in tuberculosis.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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