Introduction
Methods
Literature search
Inter-reviewer agreement
Data extraction
Results
Search results
Cell-culture studies
Study | Cell type | Treatment | Hours | Main findings |
---|---|---|---|---|
Rasley et al. [25] | C3H/Hej mice EOC13 microglia and neonatal brain microglia | B. burgdorferi exposure (5 µg /ml) | 4, 8, 12 | - COX2 mRNA was significantly elevated following exposure to B. burgdorferi for 8 or 12 h - PGE2 secretion was elevated in both cell types at 12 h post-B. burgdorferi exposure |
Singh et al. [39] | Synovial cells from normal human joint tissue | B. burgdorferi strains: Geho and B31 (MOI 10) | 5 (days) | - COX-1 was upregulated with Geho B. burgdorferi exposure but not B31 B. burgdorferi - PGE2 secretion increased with Geho B. burgdorferi but decreased with B31 B. burgdorferi exposure |
Rasley et al. [26] | Mice neonatal brain microglia | B. burgdorferi strain N40 (1 µg/ml) | 4, 8, 12 | - Stimulation with B. burgdorferi modestly increased COX-2 expression after 8 h (2.2-fold) but not 4 h (1.3 fold), and EP2 expression at 4 h (18-fold) - There was no change in COX-1, PGE2, or EP4 expression |
Ramesh et al. [27] | Rhesus macaques frontal cortex brain tissue | B. burgdorferi strain B31 (10 µg/ml) | 4, 8 | - COX-2 was detected in both astrocytes and microglia in B. burgdorferi-infected cells but not in controls |
Blaho et al. [29] | Splenic B cells from C3H/HeJ mice (wild-type or COX-1−/−) | B. burgdorferi (5 µg/ml); with or without COX-1 and COX-2 inhibitors | 8, 72 | - B. burgdorferi increased expression of COX-1 and COX-2 - B. burgdorferi increased the levels of PGF2a, TXB2, and PGE2, which was attenuated by COX-1 or COX-2 inhibitors - FP and TP receptor expression increased with B. burgdorferi exposure - COX-1−/− mice produced lower levels of PGF1α, TXB2, PGF2α, PGJ2 than WT when exposed to B. burgdorferi |
Ramesh et al. [28] | Primary Rhesus macaque astrocyte and microglia | B. burgdorferi strain B31 (10 µg/ml) with and without Meloxicam (100 µM) | 24 | - B. burgdorferi increased COX-2 levels in microglia, while B. burgdorferi + Meloxicam reduced COX-2 (p < 0.01) - B. burgdorferi had no effect on COX-2 levels in astrocytes |
Zhang et al. [33] | BMDMs and PMNs from C57BL/6J mouse femurs (WT, 5-LOX−/−, BLT1−/−, BLT2−/−, BLT1/2−/−) | B. burgdorferi N40 (MOI 10) | 1, 4 | - 5-LOX−/− and BLT1−/− BMDMs had significantly lower phagocytosis of B. burgdorferi than WT, which was restored with LTB4 addition - LTB4 production was two-to-three times higher in BLT1−/− vs WT BMDMs at 4 h but not 1 h. LTB4 production was ten times higher in PMNs vs. BMDMs but did not differ between BLT1−/− vs wild-type animals |
Study | Species | Treatment | Days | Main findings |
---|---|---|---|---|
Anguita et al. [40] | C3H mice | B. burgdorferi strain N40 (1 × 104 spirochetes); MF-tricyclic COX-2 inhibitor | 0–60 | - COX-2 expression was elevated following B. burgdorferi infection, peaking on day 14 - Mice fed with COX-2 inhibitor showed a reduction in arthritis severity (p < 0.01) compared to control mice on day 14 following B. burgdorferi infection, but there were no differences in levels of IL-2, IFN-γ, IgG, or IgM |
Glasner et al. [41] | C3H/HeJ mice | B. burgdorferi strain N40 (final inoculum: 1 × 105) | 0–25 | - COX-2 expression was significantly elevated, peaking on day 8 post-treatment |
Blaho et al. [42] | C3H/HeJ and DBA2/J (arthritis-resistant) mice | B. burgdorferi strain N40 (final inoculum: 1 × 105); celecoxib (COX-2 inhibitor) | 0–35 | - Celecoxib administration resulted in prolonged Lyme arthritis, with a high concentration of infiltrating neutrophils on day 35 post-treatment - Celecoxib administration did not alter IgG or IgM production, or the number of spirochetes in joints. It lowered the upregulation of cPLA2, PGE2, PGJ2 on days 7, 14, and 21, respectively, seen in WT mice |
Blaho et al. [29] | C3H, DBA, and COX-2−/− mice | B. burgdorferi strain N40 (final inoculum: 1 × 105) | 0–35 | - Eicosanoid levels were generally elevated in C3H mice, while DBA mice followed similar but muted trends in eicosanoid fluctuation - Some eicosanoids, such as LTB4 and PD1 were significantly increased during B. burgdorferi infection in C3H, but not DBA mice - COX-2−/− mice displayed a dramatic reduction in LTC4, LTE4, 5-HETE compared to WT following B. burgdorferi infection |
Blaho et al. [44] | C3H/Hej and 5-LOX−/− mice | B. burgdorferi strain N40 (final inoculum: 1 × 105) | 0–35 | - 5-LOX, FLAP, and LTB4 were upregulated in WT ankle joints on days 7–14 post-B. burgdorferi infection - 5-LOX−/− mice had greater ankle swelling and arthritis scores than WT on days 7–28 and showed a failure to resolve inflammation compared to WT animals - Spirochete clearance and IgM levels were equal in both groups, but 5-LOX−/− mice had lower IgG levels than WT on day 28 post-treatment |
Dumlao et al. [46] | C2H/HeJ mice | B. burgdorferi strain N40 (final inoculum: 1 × 105); SO diet- high in n-6 FA’s vs. FO diet high in n-3 FA’s | 0–25 | - Diet did not have any effect on Lyme arthritis or carditis scores, number of spirochetes, or cellular makeup in day 25 post-treatment - Fish oil (FO) diet resulted in a global shift toward EPA- and DHA-metabolites during B. burgdorferi infection vs. SO (soybean oil) diet which resulted in an increase in AA- and LA-derived metabolites |
Lasky et al. [45] | C3H and 5-LOX−/− mice | B. burgdorferi strain N40 (final inoculum: 1 × 105) | 0–56 | - M2 and rM macrophages were decreased in the ankle joints of 5-LOX−/− mice on day 21, compared to wild-type. There were no differences in the number of M1 macrophages - In the heart tissue, 5-LOX−/− mice had fewer M2 macrophages, but not M1 or rM macrophages, compared to WT on day 21 post-treatment - By day 56, there were no difference in macrophage subset or number |
Animal studies
Human studies
Study | Subjects (n) | Mean concentrations of arachidonic acid metabolite or related activity | Findings | ||
---|---|---|---|---|---|
Metabolite/activity | Patients | Controls | |||
Mayatepek et al. [49] | Lyme meningitis (10) vs. healthy controls (10) | PMNLs LTB4 (ng/106 cells) | 39.3 | 35.2 | - LTB4 concentrations in synovial fluid were significantly higher in patients with Lyme arthritis compared to those with noninflammatory arthropathy (p < 0.05). Moreover, concentrations of PMNL LTB4 and LTC4, and urinary LTE4 did not differ between LB patients and controls |
PMNLs LTC4 (ng/106 cells) | 5.3 | 6.0 | |||
Urine LTE4 (pmol/l) | 273 | 265 | |||
Lyme arthritis (7) vs noninflammatory arthropathy controls (7) | PMNLs LTB4 (ng/106 cells) | 40.0 | 38.4 | ||
PMNLs LTC4 (ng/106 cells) | 4.8 | 4.6 | |||
Synovial LTB4 (ng/ml) | 142 | 46 | |||
Urine LTE4 (pmol/l) | 279 | 262 | |||
Luczaj et al. [47] | Lyme arthritis (57) vs. healthy controls (41) | Plasma free AA (nmol/µl) | 0.203 | 0.166 | - Compared to controls, patients with Lyme arthritis had significantly elevated levels of plasma: free AA, total 8-isoPGF2α, and PLA2 activity, and urinary 8-isoPGF2α. Patients also had significantly lower levels of plasma: phospholipid AA and free 8-isoPGF2α (p < 0.05). After antibiotic treatment, patients had significantly reduced levels of plasma: total 8-isoPGF2α, free 8-isoPGF2α, PLA2 activity, and urinary 8-isoPGF2α, compared to pre-antibiotic treatment (p < 0.05) |
Plasma phospholipid AA (nmol/µl) | 24.11 | 36.86 | |||
Plasma total 8-isoPGF2α (pg/ml) | 52.15 | 18.99 | |||
Plasma free 8-isoPGF2α (pg/ml) | 3.48 | 5.16 | |||
Free 8-isoPGF2α (%) | 7 | 27 | |||
Urine 8-isoPGF2α (pg/mg creatinine) | 206.59 | 37.04 | |||
Plasma PLA2 activity (nmol/min/ml) | 28.68 | 9.00 | |||
Plasma PAF-AH activity (nmol/min/ml) | 24.17 | 25.65 | |||
Lyme arthritis pre-antibiotic treatment (13) vs. Lyme arthritis post-antibiotic treatment (13) | Plasma free AA (nmol/µl) | 0.190 | 0.180 | ||
Plasma phospholipid AA (nmol/µl) | 20.06 | 21.18 | |||
Plasma total 8-isoPGF2α (pg/ml) | 75.43 | 48.56 | |||
Plasma free 8-isoPGF2α (pg/ml) | 3.01 | 2.83 | |||
Free 8-isoPGF2α (%) | 4 | 6 | |||
Urine 8-isoPGF2α (pg/mg creatinine) | 237.42 | 144.24 | |||
Plasma PLA2 activity (nmol/min/ml) | 31.92 | 23.51 | |||
Plasma PAF-AH activity (nmol/min/ml) | 23.14 | 29.85 | |||
Molins et al. [51] | Lyme disease (202) vs healthy controls (158) and other controls (101) | No specific metabolites were reported | – | – | - Compared to controls, lyme disease patients had a shift in the abundance of 49 molecular features, including 6 products of prostaglandin metabolism |