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Thomas Carion, Matthew Greenwood, Karsten Gronert, Elizabeth A Berger; Lipid Mediator Pathways in the Pathogenesis of Bacterial Keratitis. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5870.
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© ARVO (1962-2015); The Authors (2016-present)
Though prostaglandins and leukotrienes (LTs) primarily derived from the COX-2 and 5-lipoxygenase (LOX) pathways are essential potent mediators of inflammation, endogenous small pro-resolving molecules (SPMs) such as lipoxins/resolvins/protectins act as robust agonists of resolution. To this end, SPM biosynthesis can occur through the conversion of AA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) primarily via the 12/15-LOX pathway. While LOX activity has been reported in the cornea, the role of lipid mediators, notably SPMs, during bacterial keratitis remains largely unknown and is the focus of the study described herein.
Bacterial keratitis was induced in BALB/c and B6 mice using P. aeruginosa 19660. Lipidomic analysis, real-time RT-PCR, ELISA and IHC were used to assess biosynthetic pathways associated with both pro-inflammatory lipid mediator and SPM production in corneas over time. In addition, lipid mediator expression in B6- and BALB/c-derived PMNs was similarly examined.
Significant increases in PUFA (ω-3, ω-6)-derived lipid mediators - AA, EPA and DHA - were detected in B6 vs BALB/c mice post-infection. Results also showed elevated LTB4 via a predominance of the 5-LOX pathway in B6 mice. In contrast, BALB/c mice demonstrated a more effective balance between 5-LOX/12-LOX/15-LOX enzymatic pathways. Furthermore, LTB4 receptors (LTB4R1/BLT1 and LTB4R2/BLT2) mRNA levels were significantly higher in B6 vs BALB/c corneas. Similar trends in LOX levels were observed in B6- and BALB/c-derived PMNs after stimulation, as well.
As the first study to examine lipid mediators in a model of bacterial keratitis, our results suggest that an imbalance of the LOX enzymatic pathways contribute to susceptibility as observed in the B6 mouse, which has been characterized in large part by an overwhelming persistence of activated PMNs. In this respect, inflammation is driven by elevated levels of LTB4, which is known to promote PMN chemotaxis, degranulation and superoxide generation; while deficient SPM formation prolongs inflammation by failing to adequately transition towards resolution. BALB/c, however, demonstrate a well-balanced axis of 5-LOX/12-LOX/15-LOX pathways resulting in sufficient SPM formation. In addition, preliminary studies suggest that the neuropeptide, VIP, increases mRNA levels of 12-/15-LOX, which could offer a therapeutic point of intervention for enhancing SPM formation.
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