In Vivo Availability of Pro-Resolving Lipid Mediators in Oxazolone Induced Dermal Inflammation in the Mouse

Abstract

The activation and infiltration of polymorphonuclear neutrophils (PMN) are critical key steps in inflammation. PMN-mediated inflammation is limited by anti-inflammatory and pro-resolving mechanisms, including specialized pro-resolving lipid mediators (SPM). We examined the effects of 15-epi-LXA4 on inflammation and the biosynthesis of pro-inflammatory mediators, such as prostaglandins, leukotriene B4 and various hydroxyeicosatetraenoic acids and SPM, in an oxazolone (OXA)-induced hypersensitivity model for dermal inflammation. 15-epi-LXA4 (100 μM, 5 μL subcutaneously injected) significantly (P < 0.05) reduced inflammation in skin, 24 hours after the OXA challenge, as compared to skin treated with vehicle. No significant influence on the biosynthesis of prostaglandins or leukotriene B4 was observed, whereas the level of 15S-hydroxy-eicosatetraenoic acid was significantly (P < 0.05) lower in the skin areas treated with 15-epi-LXA4. In spite of the use of a fully validated analytical procedure, no SPM were detected in the biological samples. To investigate the reason for the lack of analytical signal, we tried to mimic the production of SPM (lipoxins, resolvins, maresin and protectin) by injecting them subcutaneously into the skin of mice and studying the in vivo availability and distribution of the compounds. All analytes showed very little lateral distribution in skin tissue and their levels were markedly decreased (> 95%) 2 hours after injection. However, docosahexaenoic acid derivatives were biologically more stable than SPM derived from arachidonic acid or eicosapentaenoic acid.

Inflammatory pain control by blocking oxidized phospholipid-mediated TRP channel activation

“…This was due to the lack of availability of deuterated oxidized phospholipids, or techniques which allow the absolute quantification of individual phospholipid compounds in complex lipid preparations 54 , 55 . Rapid metabolism has been observed for other lipids in vivo before 58 . In CFA inflammation, OxPAPC species, e.g.…”

COVID‐19—Associated dyslipidemia: Implications for mechanism of impaired resolution and novel therapeutic approaches

“…90 In contrast, endogenous PD1 has been described as a pivotal counterregulatory signal in allergic airway inflammation 41 with overall DHA derivatives reported to be biologically more stable as compared to SPMs from EPA and AA. 91 In addition, EPA-rich fish oil increased ApoM abundance in plasma and HDL versus DHA-rich fish oil supplement. 92 Recently it has been found that ApoE-KO mice consuming an omega-3 fatty acid-deficient diet have significant accumulation of pro-inflammatory eicosanoids in lungs.…”

Synthesis of an electrophilic keto-tetraene 15-oxo-Lipoxin A4 methyl ester via a MIDA boronate

“…1 One class of AA-derived mediators termed lipoxins A 4 and B 4 ((5 S ,6 R ,15 S )-trihydroxy-eicosa-7 E ,9 E ,11 Z ,13 E -tetraenoic acid and (5 S ,14 R ,15 S )-trihydroxy-6 E ,8 Z ,10 E ,12 E -eicosatetraenoic acid, or LXA 4 and LXB 4 ) are trihydroxytetraenes produced by the successive lipoxygenase oxidations of AA 2 (5-LOX and 12/15-LOX) by stimulated leukocytes. When administered as pure synthetic compounds, these species display pleiotropic actions described 3 as anti-inflammatory and pro-resolving and, because of low concentrations and rapid degradation, are difficult to detect 4 , 5 in vivo . They, along with the 15( R )-stereoisomers 6 (15- epi -LXA 4 ), have been investigated as leads 7 for the treatment 8 of several chronic and acute inflammatory conditions.…”