Abstract 17268: ApoA-I Mimetic Peptide 4F Suppresses the Elevation of Pro-Inflammatory Lipid Mediators in Mouse Models of Inflammatory Bowel Disease

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
David Meriwether ◽  
Carmen Volpe ◽  
Victor Grijalva ◽  
Ellen O’Connor ◽  
Nasrin Dorreh ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Mouse Models ◽  
Inflammatory Mediators ◽  
Bowel Disease ◽  
Ex Vivo ◽  
Early Stage ◽  
Lipid Mediators ◽  
Serosal Side ◽  
Ussing Chambers ◽  
Inflammatory Bowel

Introduction: Inflammatory bowel disease (IBD) has been linked to an increased prevalence of early stage vascular disease. ApoA-I mimetic peptides including 4F are potential therapeutic agents for the treatment of inflammatory diseases including atherosclerosis, and their mechanism of action appears localized to the intestine. We have reported that 4F protects against the development of disease in both the piroxicam-accelerated IL10-/- and myeloid COX2-/- mouse models of IBD. Hypothesis: We previously reported that plasma and lesion levels of oxidized products of linoleic and arachidonic acid correlate with disease in mouse models of atherosclerosis, and that 4F protects against disease in these models while inhibiting accumulation of these pro-inflammatory mediators. We thus sought to determine the complete lipid pro-inflammatory mediator profiles of both the COX2- and IL10-dependent models of IBD, while also determining the effect of 4F on the pro-inflammatory lipid profiles. Methods: We developed and validated a LC-ESI-MS/MS method for determining the levels of 40 lipid inflammatory mediators in both intestinal tissue and plasma, and we analyzed the effects of both disease and 4F upon these mediators in both IBD models. We also employed Ussing chambers to investigate ex vivo the direct effect of 4F on the clearance of pro-inflammatory lipid mediators from intestinal explants and serosal-side lipoproteins. Results: Disease in both models correlated with significantly elevated tissue and plasma levels of multiple lipid pro-inflammatory mediators, while the protective effects of 4F correlated with the significant suppression of most of these mediators. Of interest, 4F inhibited the disease dependent increase of 15HETE, 12HETE, 5HETE, 13HODE, LTB4, 6ketoPGF1α, PGF2α, and TXB2 in the COX2-/- model; and 15HETE, 12HETE, 13HODE, LTB4, and LTE4 in the IL10-/- model. Ex vivo, we showed that 4F could directly clear the pro-inflammatory mediators from inflamed intestinal explants, while also mediating their trans-intestinal efflux from serosal-side lipoproteins. Conclusions: 4F appears to protect against IBD in part by inhibiting the accumulation of pro-inflammatory lipid mediators, through a mechanism that involves the intestinal clearance of these mediators from tissue and plasma.

scholarly journals The food additive EDTA aggravates colitis and colon carcinogenesis in mouse models

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rayko Evstatiev ◽  
Adam Cervenka ◽  
Tina Austerlitz ◽  
Gunther Deim ◽  
Maximilian Baumgartner ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Mouse Models ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Food Additives ◽  
Colorectal Carcinogenesis ◽  
Testing Procedures ◽  
Inflammatory Models ◽  
Inflammatory Bowel

AbstractInflammatory bowel disease is a group of conditions with rising incidence caused by genetic and environmental factors including diet. The chelator ethylenediaminetetraacetate (EDTA) is widely used by the food and pharmaceutical industry among numerous other applications, leading to a considerable environmental exposure. Numerous safety studies in healthy animals have revealed no relevant toxicity by EDTA. Here we show that, in the presence of intestinal inflammation, EDTA is surprisingly capable of massively exacerbating inflammation and even inducing colorectal carcinogenesis at doses that are presumed to be safe. This toxicity is evident in two biologically different mouse models of inflammatory bowel disease, the AOM/DSS and the IL10−/− model. The mechanism of this effect may be attributed to disruption of intercellular contacts as demonstrated by in vivo confocal endomicroscopy, electron microscopy and cell culture studies. Our findings add EDTA to the list of food additives that might be detrimental in the presence of intestinal inflammation, but the toxicity of which may have been missed by regulatory safety testing procedures that utilize only healthy models. We conclude that the current use of EDTA especially in food and pharmaceuticals should be reconsidered. Moreover, we suggest that intestinal inflammatory models should be implemented in the testing of food additives to account for the exposure of this primary organ to environmental and dietary stress.

scholarly journals Ex vivo response to mucosal bacteria and muramyl dipeptide in inflammatory bowel disease

2016 ◽  
Vol 22 (44) ◽  
pp. 9734
Author(s):  
Claudia Loganes ◽  
Erica Valencic ◽  
Alessia Pin ◽  
Elisa Marini ◽  
Stefano Martelossi ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Ex Vivo ◽  
Muramyl Dipeptide ◽  
Inflammatory Bowel

scholarly journals Distinct Effects of p38α Deletion in Myeloid Lineage and Gut Epithelia in Mouse Models of Inflammatory Bowel Disease

2010 ◽  
Vol 138 (4) ◽  
pp. 1255-1265.e9 ◽  
Author(s):  
Motoyuki Otsuka ◽  
Young Jun Kang ◽  
Jianlin Ren ◽  
Huiping Jiang ◽  
Yinbin Wang ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Mouse Models ◽  
Bowel Disease ◽  
Myeloid Lineage ◽  
Inflammatory Bowel

scholarly journals Inflammatory bowel disease-associated ubiquitin ligase RNF183 promotes lysosomal degradation of DR5 and TRAIL-induced caspase activation

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yan Wu ◽  
Yuka Kimura ◽  
Takumi Okamoto ◽  
Koji Matsuhisa ◽  
Rie Asada ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Ubiquitin Ligase ◽  
Bowel Disease ◽  
Early Stage ◽  
Caspase 8 ◽  
Trinitrobenzene Sulfonic Acid ◽  
Death Receptor 5 ◽  
Caspase Activation ◽  
Lysosomal Degradation ◽  
Inflammatory Bowel

AbstractRNF183 is a ubiquitin ligase containing RING-finger and transmembrane domains, and its expression levels are increased in patients with inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, and in 2,4,6-trinitrobenzene sulfonic acid-induced colitis mice. Here, we further demonstrate that RNF183 was induced to a greater degree in the dextran sulfate sodium (DSS)-treated IBD model at a very early stage than were inflammatory cytokines. In addition, fluorescence-activated cell sorting and polymerase chain reaction analysis revealed that RNF183 was specifically expressed in epithelial cells of DSS-treated mice, which suggested that increased levels of RNF183 do not result from the accumulation of immune cells. Furthermore, we identified death receptor 5 (DR5), a member of tumour necrosis factor (TNF)-receptor superfamily, as a substrate of RNF183. RNF183 mediated K63-linked ubiquitination and lysosomal degradation of DR5. DR5 promotes TNF-related apoptosis inducing ligand (TRAIL)-induced apoptosis signal through interaction with caspase-8. Inhibition of RNF183 expression was found to suppress TRAIL-induced activation of caspase-8 and caspase-3. Thus, RNF183 promoted not only DR5 transport to lysosomes but also TRAIL-induced caspase activation and apoptosis. Together, our results provide new insights into potential roles of RNF183 in DR5-mediated caspase activation in IBD pathogenesis.

scholarly journals Acetylsalicylic Acid Reduces the Severity of Dextran Sodium Sulfate-Induced Colitis and Increases the Formation of Anti-Inflammatory Lipid Mediators

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Thomas Köhnke ◽  
Beate Gomolka ◽  
Süleyman Bilal ◽  
Xiangzhi Zhou ◽  
Yanping Sun ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Acetylsalicylic Acid ◽  
Bowel Disease ◽  
Sodium Sulfate ◽  
Lipid Mediators ◽  
Dextran Sodium Sulfate ◽  
Cyclooxygenase Inhibitors ◽  
Omega 3 ◽  
Inflammatory Bowel ◽  
Anti Inflammatory

The role of non-steroidal anti-inflammatory drugs in inflammatory bowel disease is controversial, as they have been implicated in disease aggravation. Different from other cyclooxygenase inhibitors, acetylsalicylic acid (ASA) enhances the formation of anti-inflammatory and proresolution lipoxins derived from arachidonic acid as well as resolvins from omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA). In this study, we examined the effect of ASA on murine dextran sodium sulfate colitis. A mouse magnetic resonance imaging (MRI) protocol and post mortem assessment were used to assess disease severity, and lipid metabolites were measured using liquid chromatography-coupled tandem mass spectrometry. Decreased colitis activity was demonstrated by phenotype and MRI assessment in mice treated with ASA, and confirmed in postmortem analysis. Analysis of lipid mediators showed sustained formation of lipoxin A4 and an increase of DHA-derived 17-hydroxydocosahexaenoic acid (17-HDHA) after treatment with ASA. Furthermore,in vitroexperiments in RAW264.7 murine macrophages demonstrated significantly increased phagocytosis activity after incubation with 17-HDHA, supporting its proresolution effect. These results show a protective effect of ASA in a murine colitis model and could give a rationale for a careful reassessment of ASA therapy in patients with inflammatory bowel disease and particularly ulcerative colitis, possibly combined with DHA supplementation.

scholarly journals Novel Targets for Anti-Inflammatory Therapy in Inflammatory Bowel Disease

1994 ◽  
Vol 8 (6) ◽  
pp. 373-378
Author(s):  
John L Wallace
Keyword(s):  
Drug Delivery ◽  
Inflammatory Bowel Disease ◽  
Drug Development ◽  
Inflammatory Mediators ◽  
Bowel Disease ◽  
Drug Delivery Systems ◽  
Experimental Studies ◽  
Inflammatory Bowel ◽  
Novel Targets ◽  
Anti Inflammatory

Until the cause(s) of inflammatory bowel disease are identified, improvements in therapy will likely come from improved anti-inflammatory therapy or improved drug delivery systems. There are many potential targets for anti-inflammatory therapy, including the synthesis of specific inflammatory mediators. This review focuses on the potential for developing therapy aimed at three targets: nerves and neuropeptides; coagulation and thrombosis; and adhesion molecules. In each case, evidence is presented from clinical and/or experimental studies that supports the hypothesis that these are rational targets for anti-inflammatory drug development.

Sign in / Sign up

Export Citation Format

Share Document