Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Anal Clin Toxicol & Bromatol, Ribeirao Preto, SP - Brazil
 Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Bioquim & Imunol, Ribeirao Preto, SP - Brazil
 Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Patol, Ribeirao Preto, SP - Brazil
Total Affiliations: 3
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE;
MAR 1 2020.
Web of Science Citations:
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 PGE(2) 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 PGE(2) levels, enhanced IFN-gamma production and NO release, and increased macrophage phagocytosis of Mtb. The results suggest that a balance between PGE(2)/LTB4 is essential in the pathogenesis process of tuberculosis to prevent severe inflammation. Moreover, optimal levels of PGE(2) 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. (AU)