Modifying the Protease, Antiprotease Pattern by Elafin Overexpression Protects Mice From Colitis

Motta, Jean‐Paul; Magne, Laurent; Descamps, Delphyne; Rolland, Corinne; Dale, Camila S.; Rousset, Perrine; Martin, Laurence; Cenac, Nicolas; Balloy, Viviane; Huerre, Michel; Fröhlich, Leopold F.; Jenne, Dieter E.; Wartelle, Julien; Belaaouaj, Abderrazzaq; Mas, Emmanuel; Vinel, Jean–Pierre; Alric, Laurent; Chignard, Michel; Vergnolle, Nathalie; Sallenave, Jean–Michel

doi:10.1053/j.gastro.2010.12.050

Cited by 110 publications

(128 citation statements)

References 32 publications

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“…On day 7, DSS was replaced with normal drinking water for 3 d. PD1 n-3 DPA or vehicle (0.3 μg/100 μL in saline 0.01% EtOH) were administered intraperitoneally daily (from day 5 to day 10). At the end of day 8 or 10, the colon was removed, measured, and examined for the consistency of the stool found within, as well as the gross macroscopic appearance and length, as described previously (37,38). Samples harvested for histology were analyzed by light microscopy and scored (37,38).…”

Section: Methodsmentioning

confidence: 99%

“…At the end of day 8 or 10, the colon was removed, measured, and examined for the consistency of the stool found within, as well as the gross macroscopic appearance and length, as described previously (37,38). Samples harvested for histology were analyzed by light microscopy and scored (37,38). MPO activity was performed as previously described (39).…”

Section: Methodsmentioning

confidence: 99%

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Protectin D1 _{n-3 DPA} and resolvin D5 _{n-3 DPA} are effectors of intestinal protection

Gobbetti

Dalli

Colas

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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143

105

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The resolution of inflammation is an active process orchestrated by specialized proresolving lipid mediators (SPM) that limit the host response within the affected tissue; failure of effective resolution may lead to tissue injury. Because persistence of inflammatory signals is a main feature of chronic inflammatory conditions, including inflammatory bowel diseases (IBDs), herein we investigate expression and functions of SPM in intestinal inflammation. Targeted liquid chromatography-tandem mass spectrometry-based metabololipidomics was used to identify SPMs from n-3 polyunsaturated fatty acids in human IBD colon biopsies, quantifying a significant upregulation of the resolvin and protectin pathway compared with normal gut tissue. Systemic treatment with protectin (PD)1 n-3 DPA or resolvin (Rv)D5 n-3 DPA protected against colitis and intestinal ischemia/reperfusion-induced inflammation in mice. Inhibition of 15-lipoxygenase activity reduced PD1 n-3 DPA and augmented intestinal inflammation in experimental colitis. Intravital microscopy of mouse mesenteric venules demonstrated that PD1 n-3 DPA and RvD5 n-3 DPA decreased the extent of leukocyte adhesion and emigration following ischemia-reperfusion. These data were translated by assessing human neutrophil-endothelial interactions under flow: PD1 n-3 DPA and RvD5 n-3 DPA reduced cell adhesion onto TNF-α-activated human endothelial monolayers. In conclusion, we propose that innovative therapies based on n-3 DPA-derived mediators could be developed to enable antiinflammatory and tissue protective effects in inflammatory pathologies of the gut.inflammation resolution | specialized proresolving mediators | omega-3 fatty acids | intravital microscopy | neutrophils

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Protectin D1 _{n-3 DPA} and resolvin D5 _{n-3 DPA} are effectors of intestinal protection

Gobbetti

Dalli

Colas

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

143

105

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“…The authors proposed that this effect was a mechanism for allowing increased neutrophil transepithelial migration. More recently, in an in vivo mouse model of colitis, it was shown that inhibition of NE by elafin significantly suppresses inflammatory mediators and strengthens the intestinal epithelial barrier functions in colonic tissues from mice as well as in intestinal epithelial cells (34). Given that PAR 2 is believed to be a key player in the pathogenesis of colitis (35,36), it will be interesting to evaluate further the signaling responses and trafficking of the receptor in the colonic epithelial cells to assess the possible relationship to data in this report.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil Elastase Acts as a Biased Agonist for Proteinase-activated Receptor-2 (PAR2)

Ramachandran

Mihara

Chung

et al. 2011

Journal of Biological Chemistry

164

198

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Human neutrophil proteinases (elastase, proteinase-3, and cathepsin-G) are released at sites of acute inflammation. We hypothesized that these inflammation-associated proteinases can affect cell signaling by targeting proteinase-activated receptor-2 (PAR 2 ). The PAR family of G protein-coupled receptors is triggered by a unique mechanism involving the proteolytic unmasking of an N-terminal self-activating tethered ligand (TL). Proteinases can either activate PAR signaling by unmasking the TL sequence or disarm the receptor for subsequent enzyme activation by cleaving downstream from the TL sequence. We found that none of neutrophil elastase, cathepsin-G, and proteinase-3 can activate G q -coupled PAR 2 calcium signaling; but all of these proteinases can disarm PAR 2 , releasing the N-terminal TL sequence, thereby preventing G q -coupled PAR 2 signaling by trypsin. Interestingly, elastase (but neither cathepsin-G nor proteinase-3) causes a TL-independent PAR 2 -mediated activation of MAPK that, unlike the canonical trypsin activation, does not involve either receptor internalization or recruitment of ␤-arrestin. Cleavage of synthetic peptides derived from the extracellular N terminus of PAR 2 , downstream of the TL sequence, demonstrated distinct proteolytic sites for all three neutrophil-derived enzymes. We conclude that in inflammation, neutrophil proteinases can modulate PAR 2 signaling by preventing/disarming the G q /calcium signal pathway and, via elastase, can selectively activate the p44/42 MAPK pathway. Our data illustrate a new mode of PAR regulation that involves biased PAR 2 signaling by neutrophil elastase and a disarming/silencing effect of cathepsin-G and proteinase-3.

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“…Under physiological conditions, colonic trypsin activity is constantly counterbalanced by the presence of trypsin inhibitors [43]. On the contrary, in patients with inflammatory bowel disease (IBD), ulcerative colitis and Crohn's disease, there is a reduction of the expression of the trypsin inhibitor [44] [45] and thus, trypsin activity is increased in IBD patients [46].…”

Section: Endogenous Proteases and Pain Related To Protease-activated mentioning

confidence: 99%

Protease-Activated Receptors as Therapeutic Targets in Visceral Pain

Cenac

2013

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Abstract:The protease-activated receptors (PARs) play a pivotal role in inflammatory and nociceptive processes. PARs have raised considerable interest because of their capacity to regulate numerous aspects of viscera physiology and pathophysiology. The present article summarizes research on PARs and proteases as signalling molecules in visceral pain. In particular, experiments in animal models suggest that PAR 2 is important for visceral hypersensitivity. Moreover, endogenous PAR 2 agonists seem to be released by colonic tissue of patients suffering from irritable bowel syndrome, suggesting a role for this receptor in visceral pain perception. Thus, PARs, together with proteases that activate them, represent exciting targets for therapeutic intervention on visceral pain.

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Modifying the Protease, Antiprotease Pattern by Elafin Overexpression Protects Mice From Colitis

Abstract: The protease inhibitor Elafin prevents intestinal inflammation in mouse models of colitis and might be developed as a therapeutic agent for inflammatory bowel disease.

Cited by 110 publications

References 32 publications

Protectin D1 _{n-3 DPA} and resolvin D5 _{n-3 DPA} are effectors of intestinal protection

Protectin D1 _{n-3 DPA} and resolvin D5 _{n-3 DPA} are effectors of intestinal protection

Neutrophil Elastase Acts as a Biased Agonist for Proteinase-activated Receptor-2 (PAR2)

Protease-Activated Receptors as Therapeutic Targets in Visceral Pain

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Modifying the Protease, Antiprotease Pattern by Elafin Overexpression Protects Mice From Colitis

Abstract: The protease inhibitor Elafin prevents intestinal inflammation in mouse models of colitis and might be developed as a therapeutic agent for inflammatory bowel disease.

Cited by 110 publications

References 32 publications

Protectin D1 n-3 DPA and resolvin D5 n-3 DPA are effectors of intestinal protection

Protectin D1 n-3 DPA and resolvin D5 n-3 DPA are effectors of intestinal protection

Neutrophil Elastase Acts as a Biased Agonist for Proteinase-activated Receptor-2 (PAR2)

Protease-Activated Receptors as Therapeutic Targets in Visceral Pain

Contact Info

Product

Resources

About

Protectin D1 _{n-3 DPA} and resolvin D5 _{n-3 DPA} are effectors of intestinal protection

Protectin D1 _{n-3 DPA} and resolvin D5 _{n-3 DPA} are effectors of intestinal protection