Numerous models (in vitro, ex vivo and in vivo) are used in the lab to study the role of bioactive lipid signaling in inflammatory settings. For instance, we recently set up in vitro models (primary glial cells culture, CNS slices) to study the role of lipids on CNS inflammation. However in this year’s report we put forth our work on colon inflammation.
We developed over the years an expertise in colitis murine models of colitis that mimic either the acute phase or the chronicisation of the disease that are both found in Crohn’s disease and ulcerative colitis. (e.g. Alhouayek et al., FASEB J. 2011; Alhouayek et al., FASEB J. 2015).
Due to our long lasting interest in the endocannabinoid system (Muccioli, DDT, 2010; Alhouayek & Muccioli, TMM, 2012; Alhouayek*, Masquelier* et al. PNAS 2013), we noticed, using
TNBS and DSS colitis models, that the levels of N-palmitoylethanolamine (PEA) were decreased in the inflamed colon. This observation, and the known antiinflammatory effects of this bioactive lipid, prompted us to study the effects of increasing PEA levels during colon inflammation.
When administered to mice having either a TNBS-induced colitis or a DSS-induced colitis, PEA was able to reduce the colitis hallmarks in the colon, as well as central and peripheral inflammation. Because we want to find potential pharmacological targets, we went on to determine which enzyme – FAAH or NAAA – actually controls PEA levels in the colon (Figure 1).
We found that upon FAAH inhibition PEA levels are not increased in the colon and that FAAH inhibition does not recapitulate the effects of PEA when tested in TNBS-induced colitis. Inversely, NAAA inhibition increases PEA levels in the colon, and improves colitis (Alhouayek et al. FASEB J. 2015).
Thus modulating PEA endogenous levels, similarly to other bioactive lipids studied in the laboratory, allows for reducing the signs of colon inflammation (Alhouayek & Muccioli,
TMM, 2012; Alhouayek et al., DDT, 2013) (Figure 2). Because these acute models allow for the study of the most acute part of the disease, we also decided this year to set up a more chronic model of colitis.
This was achieved by administering to the mice repeated cycles of DSS (in the drinking water) followed by plain water (Figure 3). The succession of cycles mimics in mice the flares and remissions observed in Crohns’ disease and ulcerative colitis. The adjunction of a pro-carcinogen results in a model of colitis-induced cancer. The roles of bioactive lipids in these two models are currently being studied in the lab.
|In conclusion, the few examples described here of our current research clearly support the interest in developing both bioanalytical tools and pharmacological approaches in order to increase our understanding of bioactive lipid signaling in inflammation and to put forth novel innovative therapeutic strategies.|