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Anti-inflammatory and anti-fibrotic profile of fish oil emulsions used in parenteral nutrition-associated liver disease.

Pastor-Clerigues A, Marti-Bonmati E, Milara J, Almudever P, Cortijo J - PLoS ONE (2014)

Bottom Line: However, its clinical effectiveness in adults has been scarcely reported.The effect was maintained during the treatment course but impaired when conventional lipid emulsions were reintroduced.Omegaven® improves clinical, anti-inflammatory and anti-fibrotic parameters in adults with long-term home PNALD.

View Article: PubMed Central - PubMed

Affiliation: Hospital Pharmacy, Clinical Nutrition Unit, University General Hospital Consortium, Valencia, Spain.

ABSTRACT
Home parenteral nutrition (PN) is associated with many complications including severe hepatobiliary dysfunction. Commercial ω-6 fatty acid-soybean based-lipid emulsions in PN may mediate long term PN associate liver disease (PNALD) whereas ω-3-fish oil parenteral emulsions have shown to reverse PNALD in children. However, its clinical effectiveness in adults has been scarcely reported. In this work, we study the role of soybean and fish oil lipid commercial emulsions on inflammatory and profibrotic liver markers in adults with long term PNALD and in in vitro cellular models. Inflammatory and profibrotic markers were measured in serum of ten adults with long term PNALD and in culture supernatants of monocytes. Liver epithelial to mesenchymal transition (EMT) was induced by transforming growth factor beta 1 (TGFβ1) to evaluate in vitro liver fibrosis. Omegaven®, a 100% fish oil commercial emulsion, was infused during four months in two patients with severe long term PNALD reversing, at the first month, the inflammatory, profibrotic and clinical parameters of PNALD. The effect was maintained during the treatment course but impaired when conventional lipid emulsions were reintroduced. The other patients under chronic soybean oil-based PN showed elevated inflammatory and profibrotic parameters. In vitro human monocytes stimulated with lipopolysaccharide induced a strong inflammatory response that was suppressed by Omegaven®, but increased by soybean emulsions. In other experiments, TGFβ1 induced EMT that was suppressed by Omegaven® and enhanced by soybean oil lipid emulsions. Omegaven® improves clinical, anti-inflammatory and anti-fibrotic parameters in adults with long-term home PNALD.

No MeSH data available.


Related in: MedlinePlus

Omegaven® inhibits transcription factor an markers related with epithelial to mesenchymal transition induced by TGFβ1.Human liver epithelial cell line THLE-3 was incubated in presence or absence of lipid emulsions Omegaven® 10%, Lipofundin MCT/LCT® 20%, ClinOleic® 20% or SMOFlipid® 20% at different dilutions, for 30 min followed by TGFβ1 5 ng/mL stimulation for additional 72 hours. Expression of mRNA of Snail, Slug, and vimentin. Results are expressed as means ± SEM of six independent experiments. One-way ANOVA was followed by the post hoc Bonferroni test. *p<0.05 related to the control group. #p<0.05 related to the stimulus.
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pone-0115404-g011: Omegaven® inhibits transcription factor an markers related with epithelial to mesenchymal transition induced by TGFβ1.Human liver epithelial cell line THLE-3 was incubated in presence or absence of lipid emulsions Omegaven® 10%, Lipofundin MCT/LCT® 20%, ClinOleic® 20% or SMOFlipid® 20% at different dilutions, for 30 min followed by TGFβ1 5 ng/mL stimulation for additional 72 hours. Expression of mRNA of Snail, Slug, and vimentin. Results are expressed as means ± SEM of six independent experiments. One-way ANOVA was followed by the post hoc Bonferroni test. *p<0.05 related to the control group. #p<0.05 related to the stimulus.

Mentions: The liver epithelial THLE-3 cell line cultured in the absence of TGFβ1 maintained classic cobblestone epithelial morphology as assessed by phase contrast light microscopy (Fig. 8). Liver epithelial cells incubated with ClinOleic® 1/100 and Lipofundin MCT/LCT® 1/100 significantly increased the myofibroblast-like phenotype and markers alpha smooth muscle cell (αSMA) and collagen type I (Col Type I) (Fig. 8 and 9B), whilst Omegaven® 1/100 and SMOFlipid® 1/100 did not modify the epithelial phenotype. A concentration of 5 ng/mL of TGFβ1 (72 h) began to induce morphological changes in liver epithelial cells, characterized by a more mesenchymal fibroblast-like morphology with reduced cell-cell contact (Fig. 9A). Omegaven® (1/100) but not Lipofundin MCT/LCT®, SMOFlipid® or ClinOleic®, preserved the epithelial phenotype. To further study the epithelial to mesenchymal (EMT) process, it was analyzed the distribution and expression of alpha smooth muscle cell (αSMA) and collagen type I (Col Type I) by immunofluorescence. TGFβ1 produced de novo formation of αSMA fibers and Col Type I that were inhibited by Omegaven® (1/100) but not by Lipofundin MCT/LCT®, SMOFlipid® and ClinOleic® (Fig. 9A). Similar results were observed at the level of gene expression. Omegaven® and in a lesser extent SMOFlipid® dose-dependently inhibited the increase of αSMA and Col Type I gene expression induced by TGFβ1 (Fig. 9B). In contrast, Lipofundin MCT/LCT® and ClinOleic® increased the αSMA and Col Type I gene expression per se and in cells stimulated with TGFβ1 (Fig. 9B). According to these observations, TGFβ1 significantly decreased the expression of epithelial markers E-cadherin and ZO-1, both tight and adherent junctions implicated in the epithelial barrier conformation (Figs. 10A and B). Unlike other lipid emulsions studied, Omegaven® was able to increase E-cadherin and ZO-1 expression to control levels (Figs. 10A and B). In other experiments, only Omegaven® was able to decrease vimentin expression as well as mesenchymal transcription factors Snail and Slug increased by TGFβ1 (Fig. 11).


Anti-inflammatory and anti-fibrotic profile of fish oil emulsions used in parenteral nutrition-associated liver disease.

Pastor-Clerigues A, Marti-Bonmati E, Milara J, Almudever P, Cortijo J - PLoS ONE (2014)

Omegaven® inhibits transcription factor an markers related with epithelial to mesenchymal transition induced by TGFβ1.Human liver epithelial cell line THLE-3 was incubated in presence or absence of lipid emulsions Omegaven® 10%, Lipofundin MCT/LCT® 20%, ClinOleic® 20% or SMOFlipid® 20% at different dilutions, for 30 min followed by TGFβ1 5 ng/mL stimulation for additional 72 hours. Expression of mRNA of Snail, Slug, and vimentin. Results are expressed as means ± SEM of six independent experiments. One-way ANOVA was followed by the post hoc Bonferroni test. *p<0.05 related to the control group. #p<0.05 related to the stimulus.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4264955&req=5

pone-0115404-g011: Omegaven® inhibits transcription factor an markers related with epithelial to mesenchymal transition induced by TGFβ1.Human liver epithelial cell line THLE-3 was incubated in presence or absence of lipid emulsions Omegaven® 10%, Lipofundin MCT/LCT® 20%, ClinOleic® 20% or SMOFlipid® 20% at different dilutions, for 30 min followed by TGFβ1 5 ng/mL stimulation for additional 72 hours. Expression of mRNA of Snail, Slug, and vimentin. Results are expressed as means ± SEM of six independent experiments. One-way ANOVA was followed by the post hoc Bonferroni test. *p<0.05 related to the control group. #p<0.05 related to the stimulus.
Mentions: The liver epithelial THLE-3 cell line cultured in the absence of TGFβ1 maintained classic cobblestone epithelial morphology as assessed by phase contrast light microscopy (Fig. 8). Liver epithelial cells incubated with ClinOleic® 1/100 and Lipofundin MCT/LCT® 1/100 significantly increased the myofibroblast-like phenotype and markers alpha smooth muscle cell (αSMA) and collagen type I (Col Type I) (Fig. 8 and 9B), whilst Omegaven® 1/100 and SMOFlipid® 1/100 did not modify the epithelial phenotype. A concentration of 5 ng/mL of TGFβ1 (72 h) began to induce morphological changes in liver epithelial cells, characterized by a more mesenchymal fibroblast-like morphology with reduced cell-cell contact (Fig. 9A). Omegaven® (1/100) but not Lipofundin MCT/LCT®, SMOFlipid® or ClinOleic®, preserved the epithelial phenotype. To further study the epithelial to mesenchymal (EMT) process, it was analyzed the distribution and expression of alpha smooth muscle cell (αSMA) and collagen type I (Col Type I) by immunofluorescence. TGFβ1 produced de novo formation of αSMA fibers and Col Type I that were inhibited by Omegaven® (1/100) but not by Lipofundin MCT/LCT®, SMOFlipid® and ClinOleic® (Fig. 9A). Similar results were observed at the level of gene expression. Omegaven® and in a lesser extent SMOFlipid® dose-dependently inhibited the increase of αSMA and Col Type I gene expression induced by TGFβ1 (Fig. 9B). In contrast, Lipofundin MCT/LCT® and ClinOleic® increased the αSMA and Col Type I gene expression per se and in cells stimulated with TGFβ1 (Fig. 9B). According to these observations, TGFβ1 significantly decreased the expression of epithelial markers E-cadherin and ZO-1, both tight and adherent junctions implicated in the epithelial barrier conformation (Figs. 10A and B). Unlike other lipid emulsions studied, Omegaven® was able to increase E-cadherin and ZO-1 expression to control levels (Figs. 10A and B). In other experiments, only Omegaven® was able to decrease vimentin expression as well as mesenchymal transcription factors Snail and Slug increased by TGFβ1 (Fig. 11).

Bottom Line: However, its clinical effectiveness in adults has been scarcely reported.The effect was maintained during the treatment course but impaired when conventional lipid emulsions were reintroduced.Omegaven® improves clinical, anti-inflammatory and anti-fibrotic parameters in adults with long-term home PNALD.

View Article: PubMed Central - PubMed

Affiliation: Hospital Pharmacy, Clinical Nutrition Unit, University General Hospital Consortium, Valencia, Spain.

ABSTRACT
Home parenteral nutrition (PN) is associated with many complications including severe hepatobiliary dysfunction. Commercial ω-6 fatty acid-soybean based-lipid emulsions in PN may mediate long term PN associate liver disease (PNALD) whereas ω-3-fish oil parenteral emulsions have shown to reverse PNALD in children. However, its clinical effectiveness in adults has been scarcely reported. In this work, we study the role of soybean and fish oil lipid commercial emulsions on inflammatory and profibrotic liver markers in adults with long term PNALD and in in vitro cellular models. Inflammatory and profibrotic markers were measured in serum of ten adults with long term PNALD and in culture supernatants of monocytes. Liver epithelial to mesenchymal transition (EMT) was induced by transforming growth factor beta 1 (TGFβ1) to evaluate in vitro liver fibrosis. Omegaven®, a 100% fish oil commercial emulsion, was infused during four months in two patients with severe long term PNALD reversing, at the first month, the inflammatory, profibrotic and clinical parameters of PNALD. The effect was maintained during the treatment course but impaired when conventional lipid emulsions were reintroduced. The other patients under chronic soybean oil-based PN showed elevated inflammatory and profibrotic parameters. In vitro human monocytes stimulated with lipopolysaccharide induced a strong inflammatory response that was suppressed by Omegaven®, but increased by soybean emulsions. In other experiments, TGFβ1 induced EMT that was suppressed by Omegaven® and enhanced by soybean oil lipid emulsions. Omegaven® improves clinical, anti-inflammatory and anti-fibrotic parameters in adults with long-term home PNALD.

No MeSH data available.


Related in: MedlinePlus