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"Researchers at University College London (UCL) have uncovered a key mechanism that helps the body switch off inflammation—a breakthrough that could lead to new treatments for chronic diseases affecting millions worldwide. ...
the study reveals that tiny fat-derived molecules called epoxy-oxylipins act as natural brakes on the immune system. These molecules prevent the overgrowth of certain immune cells, known as intermediate monocytes, that can cause chronic inflammation—linked to tissue damage, illness and disease progression. ...
Both approaches showed that blocking the enzyme sEH with GSK2256294 raised epoxy-oxylipin levels, accelerated pain resolution, and sharply reduced levels of intermediate monocytes in blood and tissue – the immune cells linked to chronic inflammation and disease. Interestingly, the drug did not significantly alter external symptoms, such as redness and swelling.
Further tests revealed that one epoxy-oxylipin, 12,13-EpOME, works by shutting down a protein signal called p38 MAPK, which drives monocyte transformation. This was confirmed in lab experiments and in volunteers given a p38-blocking drug. ..."
From the abstract:
"The role of cytochrome P450-derived epoxy-oxylipins and their metabolites in human inflammation and resolution is unknown. We report that epoxy-oxylipins are present in blood of healthy, male volunteers at baseline and following intradermal injection of UV-killed Escherichia coli, an experimental model of acute resolving inflammation.
At the site of inflammation, cytochrome P450s and epoxide hydrolase (EH) isoforms, which catabolise oxylipins to corresponding diols, are differentially upregulated throughout the inflammatory response, as is the biosynthesis of epoxy-oxylipins. GSK2256294, a selective sEH inhibitor specifically elevates 12,13-EpOME and 14,15-EET. While inhibition of sEH hastens pain resolution, it has no effect on tissue heat, redness and swelling.
GSK2256294, however, significantly reduces numbers of circulating intermediate monocytes that expand during inflammation.
We find that 12,13-EpOME blocks the transition of classical to intermediate monocytes in a p38 MAPK-dependent manner, results that are recapitulated when blocking p38 MAPK in vitro and when administering the p38 MAPK inhibitor losmapimod in vivo to healthy volunteers.
Furthermore, fewer intermediate monocytes are observed at the site of inflammation, accompanied by reduced tissue CD4 T cells.
Hence, we have mapped the expression, activity and function of epoxy-oxylipins in human inflammation revealing new mechanisms of monocyte differentiation and resolution biology."
Scientists discover natural ‘brake’ that could stop harmful inflammation (original news release) "Researchers at UCL have uncovered a key mechanism that helps the body switch off inflammation – a breakthrough that could lead to new treatments for chronic diseases affecting millions worldwide."
Fig. 3: Cytochrome P450-derived lipids are elevated with prophylactic and therapeutic sEH inhibition in plasma.
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