Fig. 4. TB, arachidonic acid metabolites, and HDTs.

Arachidonic acid metabolites are critical mediators of host defense against Mtb. Candidate HDTs that affect this metabolic pathway are shown in shaded boxes at their site of action on the pathway. (A). In controlled TB disease, the arachidonic acid pathway yields balanced levels of TNF and Type I IFNs, which control infection. (B). In uncontrolled TB disease with elevated levels of LTA4, TNF, and Type I IFNs, eicosanoid signaling is out of balance and favors production of LTA4 at the expense of PGE2. (C). Restoration of equilibrium and control of disease may be achieved with zileuton, which block 5-LO. As a consequence LTA4 levels are reduced and, indirectly, PGE2 levels become elevated, which reduces Type I IFNs and TNF, and permits control of the bacteria. Other drugs such as aspirin or valdecoxib, which inhibit PGE2 production, may be useful when the eicosanoid pathway imbalance favors production of PGE2 at the expense of LTA4. Abbreviations: COX, cyclooxygenase; PGE2, prostaglandin E2; 15LO, 15-lipoxygenase; 5LO, 5-lipoxygenase; LXA4, lipoxin A4; LTA4, leukotriene A4.