leukotriene-b4 and Tuberculosis

Pulmonary tuberculosis (TB) inflammation is an underestimated disease complication which anti-inflammatory drugs may alleviate. This study explored the potential use of the COX-2 inhibitors acetylsalicylic acid (ASA) and celecoxib in 12 TB patients and 12 healthy controls using a whole-blood ex vivo model where TNFα, PGE2, and LTB4 plasma levels were quantitated by ELISA; we also measured COX-2, 5-LOX, 12-LOX, and 15-LOX gene expression. We observed a significant TNFα production in response to stimulation with LPS or M. tuberculosis (Mtb). Celecoxib, but not ASA, reduced TNFα and PGE2 production, while increasing LTB4 in patients after infection with Mtb. Gene expression of COX-2 and 5-LOX was higher in controls, while 12-LOX was significantly higher in patients. 15-LOX expression was similar in both groups. We concluded that COX-2 inhibitors downregulate inflammation after Mtb infection, and our methodology offers a straightforward time-efficient approach for evaluating different drugs in this context. Further research is warranted to elucidate the underlying mechanisms and assess the potential clinical benefit.

Topics: Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Humans; Immunity; Inflammation; Leukotriene B4; Mycobacterium tuberculosis; Tuberculosis; Tumor Necrosis Factor-alpha

There is a sex bias in tuberculosis's severity, prevalence, and pathogenesis, and the rates are higher in men. Immunological and physiological factors are fundamental contributors to the development of the disease, and sex-related factors could play an essential role in making women more resistant to severe forms of the disease. In this study, we evaluated sex-dependent differences in inflammatory markers. Serum samples were collected from 34 patients diagnosed with pulmonary TB (19 male and 15 female) and 27 healthy controls (18 male and 9 female). Cytokines IL2, IL4, IL6, IL8, IL10, IFNγ, TNFα, and GM-CSF, and eicosanoids PGE2, LTB4, RvD1, and Mar1 were measured using commercially available immunoassays. The MDA, a product of lipidic peroxidation, was measured by detecting thiobarbituric-acid-reactive substances (TBARS). Differential inflammation patterns between men and women were observed. Men had higher levels of IL6, IL8, and TNFα than women. PGE2 and LTB4 levels were higher in patients than healthy controls, but there were no differences for RvD1 and Mar1. Women had higher RvD1/PGE2 and RvD1/LTB4 ratios among patients. RvD1 plays a vital role in resolving the inflammatory process of TB in women. Men are the major contributors to the typical pro-inflammatory profile observed in the serum of tuberculosis patients.

Topics: Dinoprostone; Eicosanoids; Female; Humans; Inflammation; Interleukin-6; Interleukin-8; Leukotriene B4; Male; Tuberculosis; Tuberculosis, Pulmonary; Tumor Necrosis Factor-alpha

While tuberculosis susceptibility has historically been ascribed to failed inflammation, it is now known that an excess of leukotriene A4 hydrolase (LTA4H), which catalyzes the final step in leukotriene B4 (LTB4) synthesis, produces a hyperinflammatory state and tuberculosis susceptibility. Here we show that the LTB4-inactivating enzyme leukotriene B4 dehydrogenase/prostaglandin reductase 1 (LTB4DH/PTGR1) restricts inflammation and independently confers resistance to tuberculous infection. LTB4DH overexpression counters the susceptibility resulting from LTA4H excess while ltb4dh-deficient animals can be rescued pharmacologically by LTB4 receptor antagonists. These data place LTB4DH as a key modulator of TB susceptibility and suggest new tuberculosis therapeutic strategies.

Topics: Alcohol Oxidoreductases; Amino Acid Sequence; Animals; Humans; Inflammation; Leukotriene B4; Molecular Sequence Data; Mycobacterium Infections; Receptors, Leukotriene B4; Sequence Alignment; Tuberculosis; Zebrafish

There is significant research in the role of interleukins in lung disease, as the cytokines are important mediators in the host response to mycobacterium tuberculosis infection. Plasma from patients with pulmonary tuberculosis (TB) and healthy controls were investigated for their content of granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-6 (IL-6) and leukotriene B4 (LTB4). LTB4 and IL-6 were measured by enzyme immunoassay after lipid extraction in the case of LTB4 while GM-CSF was measured by enzyme amplified sensitive immunoassay. Significantly elevated concentrations of IL-6 were found in far-advanced lesions of pulmonary tuberculosis patients, P < 0.05. However, nonsignificant increases of IL-6 were obtained in moderate lesions and minimal lesions compared to normal healthy subjects. Marked elevations of LTB4 were found in TB patients, the highest values being shown in patients with far-advanced lesions followed by moderately advanced and minimal lesions in relation to the mean value for normal healthy controls, P < 0.001 for all groups. 93% of the tuberculosis patients showed a higher level of LTB4 above the upper limit of the control group. In contrast there was no significant increase of GM-CSF in any of the TB subgroups. These results suggest that LTB4 and the interleukins may play a role in the pathogenesis of mycobacterium tuberculosis infection.

Topics: Adolescent; Adult; Chromatography, High Pressure Liquid; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-6; Leukotriene B4; Leukotriene C4; Tuberculosis