The Manipulation of the Lipid Mediator Metabolism as Adjunct Host-Directed Therapy in Tuberculosis

Abstract

Host-directed therapies (HDTs) enhance the host response to tuberculosis (TB) infection to reduce disease severity. For instance, the manipulation of lipid mediator production diminishes the hyperactive immune response which is a known pathological feature of TB that generates lung tissue damage. Non-steroidal anti-inflammatory drugs (NSAIDs) and omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) are examples of such HDTs. In this mini-review, we recapitulate the literature available on the effects of NSAIDs and n-3 LCPUFA in TB as well as the immunological pathways underpinning these effects. Many NSAIDs have a great deal of data describing their effects and safety and in many jurisdictions are inexpensive, and sold over the counter in neighborhood convenience stores and supermarkets. The potential benefits of NSAIDs in TB are well-documented in pre-clinical studies. The reduction of pro-inflammatory lipid mediator production by inhibiting cyclooxygenase (COX) pathways with NSAIDs has been found to improve lung histopathology, bacterial control, and survival. Additionally, n-3 LCPUFA and its novel bioactive metabolites produced by COX and lipoxygenase (LOX) have been identified as safe and effective pro-resolving and antibacterial pharmaconutrients. Nevertheless, heterogeneous results have been reported in pre-clinical TB studies. Recently, the importance of the correct timing of NSAIDs and n-3 LCPUFA administration in TB has also been highlighted. This mini-review will provide a better understanding of the potential contribution of these therapies toward reducing inflammatory lung damage and improving bactericidal activity, especially during later stages of TB infection. It further highlights that clinical trials are required to confirm benefit and safety in TB patients.

Keywords: cyclooxygenase; lipid mediators; lipoxygenase; non-steroidal anti-inflammatory drugs; omega-3 polyunsaturated fatty acids; pharmaconutrition; tuberculosis.

Figure 1

Lipid mediator biosynthesis pathways. In response to infection, polyunsaturated fatty acids are hydrolyzed from membrane phospholipids by phospholipase enzymes to release free fatty acids for lipid mediator production. Arachidonic acid serves as a substrate to form lipoxins, 4-series LTs, 2-series PGs, and TXs. The enzymes 5-LOX, 12-LOX, and 15-LOX produce LTs and lipoxins. Additionally, COX enzymes mediate the production of PGs and TXs. Eicosapentaenoic acid serves as a substrate for the intermediate 18-HPEPE by either COX-2 or CYP450 enzyme activity. From 18-HPEPE the E-series resolvins (RvE1, RvE2, and RvE3) are produced by 5- and 15-LOX. Eicosapentaenoic acid is also converted by 5-LOX to form the less inflammatory LTs. Docosahexaenoic acid is metabolized to form the D-series resolvins and protectins by 5- and 15-LOX and the maresins by 12-LOX. COX, cyclooxygenase; CYP450, cytochrome P450; HDHA, hydroxydocosahexaenoic acid; HpDHA, hydroxyperoxydocosahexaenoic acid; HEPE, hydroxyeicosapentaenoic acid; HpEPE, hydroxyperoxy-eicosapentaenoic acid; LOX, lipoxygenase; LT, leukotriene; PG, prostaglandin; PLA₂, phospholipase A₂; Rv, resolvins; TX, thromboxane.

Figure 2

The effects of non-steroidal anti-inflammatory drugs and omega-3 long-chain polyunsaturated fatty acids in tuberculosis. COX, cyclooxygenase; LCPUFA, long-chain polyunsaturated fatty acid; MDR, multi-drug resistant; NSAID, non-steroidal anti-inflammatory drug; n-3, omega-3; SPMs, specialized pro-resolving lipid mediators.