Inactivation of fatty acid amide hydrolase exacerbates experimental fibrosis by enhanced endocannabinoid-mediated activation of CB1

dc.contributor.authorPalumbo-Zerr, Katrin
dc.contributor.authorHorn, Angelika
dc.contributor.authorDistler, Alfiya
dc.contributor.authorZerr, Pawel
dc.contributor.authorDees, Clara
dc.contributor.authorBeyer, Christian
dc.contributor.authorSelvi, Enrico
dc.contributor.authorCravatt, Benjamin F.
dc.contributor.authorDistler, Oliver
dc.contributor.authorSchett, Georg
dc.contributor.authorDistler, Jörg H. W.
dc.date.accessioned2016-11-15
dc.date.available2016-11-08
dc.date.created2012
dc.date.issued2016-11-15
dc.description.abstractBackground: Selective targeting of the cannabinoid receptors CB1 and CB2 by synthetic compounds has revealed opposing roles of both receptors in fibrosis. Objectives: To characterise the role of endogenous cannabinoids (endocannabinoids) and their predominant receptor in fibrosis. Methods: The levels of endocannabinoids in mice were modulated by pharmacological or genetic inactivation of the enzyme fatty acid amide hydrolase (FAAH). The predominant receptor for endocannabinoids was determined by selective inhibition of either CB1 or CB2. The extent of fibrosis upon challenge with bleomycin was determined by quantification of dermal thickness, hydroxyproline content and myofibroblast counts. Results: The expression of FAAH is decreased in systemic sclerosis fibroblasts. FAAH-deficient mice with strongly increased levels of endocannabinoids were more sensitive to bleomycin. Consistently, pharmacological inhibition of FAAH significantly exacerbated bleomycin-induced fibrosis. Inhibition of CB1 completely abrogated the profibrotic effects of FAAH inactivation. In contrast, inhibition of CB2 only modestly enhanced fibrosis, indicating that CB1 is the predominant receptor for endocannabinoids in experimental fibrosis. Conclusions: Increased levels of endocannabinoids induced by inactivation of FAAH worsen experimental fibrosis via activation of CB1. These findings highlight the profibrotic effects of endocannabinoids and suggest that CB1 maybe a more promising candidate for targeted treatments in fibrotic diseases than CB2.en
dc.format.extent2051 - 2054
dc.identifier.citationAnnals of the Rheumatic Diseases 71.12 (2012): S. 2051-2054. <http://ard.bmj.com/content/71/12/2051>
dc.identifier.doihttps://doi.org/10.1136/annrheumdis-2012-201823
dc.identifier.opus-id7837
dc.identifier.urihttps://open.fau.de/handle/openfau/7837
dc.identifier.urnurn:nbn:de:bvb:29-opus4-78376
dc.language.isoen
dc.rights.urihttp://www.gesetze-im-internet.de/urhg/index.html
dc.subject.ddcDDC Classification::6 Technik, Medizin, angewandte Wissenschaften :: 61 Medizin und Gesundheit :: 610 Medizin und Gesundheit
dc.titleInactivation of fatty acid amide hydrolase exacerbates experimental fibrosis by enhanced endocannabinoid-mediated activation of CB1en
dc.typearticle
dcterms.publisherFriedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
local.journal.issue12
local.journal.titleAnnals of the Rheumatic Diseases
local.journal.volume71
local.sendToDnbfree*
local.subject.fakultaetMedizinische Fakultät
local.subject.gnd-
local.subject.sammlungUniversität Erlangen-Nürnberg / Allianzlizenzen: Alle Beiträge sind mit Zustimmung der Rechteinhaber aufgrund einer DFG-geförderten Allianzlizenz frei zugänglich. / Allianzlizenzen 2012
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