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Plasma LOX-Products and Monocyte Signaling Is Reduced by Adjunctive Cyclooxygenase-2 Inhibitor in a Phase I Clinical

Marthe Jøntvedt Jørgensen1,2, Kristin G Nore1, Hans Christian D Aass3

  • 1Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Frontiers in Cellular and Infection Microbiology
|July 26, 2021
PubMed
Abstract

Insights

Cyclooxygenase 2 inhibitors (COX-2i) may reduce tuberculosis inflammation by affecting lipoxygenase pathways and monocyte signaling. Further research is needed to confirm their role as a host-directed therapy (HDT) strategy.

Area of Science:

  • Immunology
  • Pharmacology
  • Infectious Diseases

Background:

  • Tuberculosis (TB) treatment can be enhanced by targeting host-directed therapies (HDT).
  • Eicosanoids and intracellular signaling pathways are key targets for HDT in TB.
  • Cyclooxygenase 2 inhibitors (COX-2i) are being investigated for their immunomodulatory effects.

Purpose of the Study:

  • To investigate the impact of COX-2 inhibitor (etoricoxib) treatment on eicosanoid levels and monocyte signaling pathways in patients with TB.
  • To assess the potential of COX-2i as an adjunctive therapy for TB.

Main Methods:

  • A randomized phase I clinical trial involving TB patients receiving standard treatment with or without adjunctive COX-2i (etoricoxib).
  • Analysis of plasma eicosanoids (ELISA, LC-MS), cytokines (multiplex), and monocyte signaling (phospho-flow cytometry) at baseline, day 14, and day 56.
  • Comparison of outcomes between the COX-2i group and the control group.

Main Results:

  • Lipoxygenase (LOX)-derived products (LXA4, 12-HETE) and pro-inflammatory cytokines were reduced in the COX-2i group, correlating with TB disease severity.
  • Adjunctive COX-2i therapy potentially accelerated the reduction of these markers.
  • Reduced phosphorylation of p38 MAPK, NFkB, Erk1/2, and Akt in monocytes, along with lower plasma levels of MIG/CXCL9 and procalcitonin, were observed in the COX-2i group.

Conclusions:

  • COX-2i may mitigate excess inflammation in TB through the LOX pathway and by modulating monocyte phosphorylation patterns.
  • The immunomodulatory effects of adjunctive COX-2i in TB warrant further investigation.
  • COX-2i requires additional research before it can be recommended as a host-directed therapy for TB.
Keywords:
cyclooxygenase-2 inhibitorcytokineseicosanoidshost-directed therapy (HDT)innate immunitylipooxygenasemonocytestuberculosis

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