Corticosteroids Impair Intestinal Epithelial Wound Repair Mechanisms In Vitro

Jung, Sandra; Fehr, Susanne; Harder-D'heureuse, Johanna; Wiedenmann, Bertram; Dignaß, Axel

doi:10.1080/003655201750305495

Cited by 52 publications

(24 citation statements)

References 34 publications

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“…In the present study, a dose-dependent inhibition of intestinal epithelial restitution by Dex was observed, consistent with results described for budesonide and prednisolone [18], [19]. Strikingly, neither CpdA nor ZK216348 showed negative effects on intestinal epithelial migration or proliferation.…”

Section: Discussionsupporting

confidence: 92%

“…GCs have been shown to impair intestinal wound healing, thus preventing the full restoration of normal host homeostasis [18], [19], [20]. Usually, after superficial injury, the first step in mucosal healing involves the migration of epithelial cells across the mucosal defect to the wound area, a process termed restitution.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to these side effects, GCs are known inhibitors of wound healing [20], [29], [41], which considerably limits their therapeutic application in various inflammatory conditions. The mechanism behind the inhibitory effect of GCs on tissue repair is mainly subscribed to the ability of GCs to regulate the expression of several key proteins at the wound site [29], but the modulation of a range of other physiological processes such as metabolism, migration, cell proliferation and differentiation also plays an important role [18], [19], [41].…”

Section: Discussionmentioning

confidence: 99%

“…In the context of IBD, one of the major consequences of GC use, is the inhibition of intestinal wound healing [18], [19], [20], which limits their therapeutic application considerably, despite their excellent anti-inflammatory action. The mucosal lining of the intestine consists of fast-renewing epithelial cells which function as a barrier between the luminal environment and the mucosal immune system.…”

Section: Introductionmentioning

confidence: 99%

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Selective Non-Steroidal Glucocorticoid Receptor Agonists Attenuate Inflammation but Do Not Impair Intestinal Epithelial Cell Restitution In Vitro

et al. 2012

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IntroductionDespite the excellent anti-inflammatory and immunosuppressive action of glucocorticoids (GCs), their use for the treatment of inflammatory bowel disease (IBD) still carries significant risks in terms of frequently occurring severe side effects, such as the impairment of intestinal tissue repair. The recently-introduced selective glucocorticoid receptor (GR) agonists (SEGRAs) offer anti-inflammatory action comparable to that of common GCs, but with a reduced side effect profile.MethodsThe in vitro effects of the non-steroidal SEGRAs Compound A (CpdA) and ZK216348, were investigated in intestinal epithelial cells and compared to those of Dexamethasone (Dex). GR translocation was shown by immunfluorescence and Western blot analysis. Trans-repressive effects were studied by means of NF-κB/p65 activity and IL-8 levels, trans-activation potency by reporter gene assay. Flow cytometry was used to assess apoptosis of cells exposed to SEGRAs. The effects on IEC-6 and HaCaT cell restitution were determined using an in vitro wound healing model, cell proliferation by BrdU assay. In addition, influences on the TGF-β- or EGF/ERK1/2/MAPK-pathway were evaluated by reporter gene assay, Western blot and qPCR analysis.ResultsDex, CpdA and ZK216348 were found to be functional GR agonists. In terms of trans-repression, CpdA and ZK216348 effectively inhibited NF-κB activity and IL-8 secretion, but showed less trans-activation potency. Furthermore, unlike SEGRAs, Dex caused a dose-dependent inhibition of cell restitution with no effect on cell proliferation. These differences in epithelial restitution were TGF-β-independent but Dex inhibited the EGF/ERK1/2/MAPK-pathway important for intestinal epithelial wound healing by induction of MKP-1 and Annexin-1 which was not affected by CpdA or ZK216348.ConclusionCollectively, our results indicate that, while their anti-inflammatory activity is comparable to Dex, SEGRAs show fewer side effects with respect to wound healing. The fact that SEGRAs did not have a similar effect on cell restitution might be due to a different modulation of EGF/ERK1/2 MAPK signalling.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Selective Non-Steroidal Glucocorticoid Receptor Agonists Attenuate Inflammation but Do Not Impair Intestinal Epithelial Cell Restitution In Vitro

et al. 2012

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“…The direct effect of S. stercoralis on the small bowel mucosa can be related to the secreted ecdysteroids as discussed by Genta (42) and identified in other parasitic helminths (43). This hormone is structurally similar to some metabolites of human steroids (44) from which corticosteroids are known to induce apoptosis concomitant with inhibition of cell proliferation (45,46).…”

Section: Discussionmentioning

confidence: 97%

Intestinal Damage in Strongyloidiasis: The Imbalance Between Cell Death and Proliferation

et al. 2006

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Strongyloidiasis is an endemic tropical parasitosis caused by Strongyloides stercoralis that also affects immigrants in nontropical countries. The nematode colonizes the duodenum and upper jejunum, inducing mucosal alterations. Because integrity is essential for a functional barrier, we aimed to study apoptosis and proliferation in the small bowel epithelium infected with S. stercoralis. We evaluated 23 patients and 17 controls. Apoptotic cells were detected by TUNEL and M30 immunolabelling, whereas proliferation was scored by Ki67 immunostaining and mitotic counting. Infection increased apoptotic indices in duodenum and jejunum (P < 0.001). Conversely, it decreased cell proliferation in both segments (P < 0.001). Our results showed that intestinal strongyloidiasis promotes an imbalance between cell death and proliferation. This is the first evidence of disruption of the epithelial kinetics with S. stercoralis infection, though the mechanisms remain unclear. Furthermore, our results support the idea that strongyloidiasis disturbs the mucosal integrity and can compromise the intestinal barrier.

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Non‐Targeted Therapeutics for Inflammatory Bowel Diseases

Rogler

2010

Inflammatory Bowel Disease

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Corticosteroids Impair Intestinal Epithelial Wound Repair Mechanisms In Vitro

Cited by 52 publications

References 34 publications

Selective Non-Steroidal Glucocorticoid Receptor Agonists Attenuate Inflammation but Do Not Impair Intestinal Epithelial Cell Restitution In Vitro

Selective Non-Steroidal Glucocorticoid Receptor Agonists Attenuate Inflammation but Do Not Impair Intestinal Epithelial Cell Restitution In Vitro

Intestinal Damage in Strongyloidiasis: The Imbalance Between Cell Death and Proliferation

Non‐Targeted Therapeutics for Inflammatory Bowel Diseases

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