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Phosphodiesterase-4 inhibition with rolipram attenuates hepatocellular injury in hyperinflammation in vivo and in vitro without influencing inflammation and HO-1 expression.

Wollborn J, Wunder C, Stix J, Neuhaus W, Bruno RR, Baar W, Flemming S, Roewer N, Schlegel N, Schick MA - J Pharmacol Pharmacother (2015 Jan-Mar)

Bottom Line: In HepG2 cells TNF-α and LPS significantly reduced cell viability.The heme oxygenase 1 (HO-1) pathway did not induce the protective effect of PD-4-I.Intravenous PD-4-I treatment was effective in improving hepatic microcirculation and hepatic integrity, while it had a direct protective effect on HepG2 viability during inflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Anaesthesia and Critical Care, University Hospital Würzburg, Germany.

ABSTRACT

Objective: To investigate the impact of the phophodiesterase-4 inhibition (PD-4-I) with rolipram on hepatic integrity in lipopolysaccharide (LPS) induced hyperinflammation.

Materials and methods: Liver microcirculation in rats was obtained using intravital microscopy. Macrohemodynamic parameters, blood assays, and organs were harvested to determine organ function and injury. Hyperinflammation was induced by LPS and PD-4-I rolipram was administered intravenously one hour after LPS application. Cell viability of HepG2 cells was measured by EZ4U-kit based on the dye XTT. Experiments were carried out assessing the influence of different concentrations of tumor necrosis factor alpha (TNF-α) and LPS with or without PD-4-I.

Results: Untreated LPS-induced rats showed significantly decreased liver microcirculation and increased hepatic cell death, whereas LPS + PD-4-I treatment could improve hepatic volumetric flow and cell death to control level whithout influencing the inflammatory impact. In HepG2 cells TNF-α and LPS significantly reduced cell viability. Coincubation with PD-4-I increased HepG2 viability to control levels. The heme oxygenase 1 (HO-1) pathway did not induce the protective effect of PD-4-I.

Conclusion: Intravenous PD-4-I treatment was effective in improving hepatic microcirculation and hepatic integrity, while it had a direct protective effect on HepG2 viability during inflammation.

No MeSH data available.


Related in: MedlinePlus

Exemplary microscopic anatomy of the liver and hepatic injury scores: (a) control group, (b) LPS group with marked areas of vacuolization, (c) LPS + PD-4-I group with marked areas of inflammation. Graphs: (d) and (e) Total hepatic injury score (THIS), revealing no significant differences among the different groups. (n=5-6, P≤0.05, mean±SEM)
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Figure 6: Exemplary microscopic anatomy of the liver and hepatic injury scores: (a) control group, (b) LPS group with marked areas of vacuolization, (c) LPS + PD-4-I group with marked areas of inflammation. Graphs: (d) and (e) Total hepatic injury score (THIS), revealing no significant differences among the different groups. (n=5-6, P≤0.05, mean±SEM)

Mentions: In vivo fluorescent microscopy revealed an increased rate of hepatic cell death by LPS, whereas rolipram attenuated LPS-induced cell death in the in vivo fluorescent-microscopy [Figure 4]. Markers of liver injury were compared in order to prove liver injury following LPS treatment of animals. Serum glucose was significantly reduced in LPS animals. AST, ALP, and ALT were augmented compared to controls while liver synthesis parameter (INR, CHE, and albumin) were unchanged [Table 2]. In the LPS + PD-4-I group AST and ALP were even augmented compared to LPS treatment alone, while serum glucose levels reached control levels following PD-4-I treatments. In histopathological examination no significant differences were obvious [Figure 5].


Phosphodiesterase-4 inhibition with rolipram attenuates hepatocellular injury in hyperinflammation in vivo and in vitro without influencing inflammation and HO-1 expression.

Wollborn J, Wunder C, Stix J, Neuhaus W, Bruno RR, Baar W, Flemming S, Roewer N, Schlegel N, Schick MA - J Pharmacol Pharmacother (2015 Jan-Mar)

Exemplary microscopic anatomy of the liver and hepatic injury scores: (a) control group, (b) LPS group with marked areas of vacuolization, (c) LPS + PD-4-I group with marked areas of inflammation. Graphs: (d) and (e) Total hepatic injury score (THIS), revealing no significant differences among the different groups. (n=5-6, P≤0.05, mean±SEM)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4319242&req=5

Figure 6: Exemplary microscopic anatomy of the liver and hepatic injury scores: (a) control group, (b) LPS group with marked areas of vacuolization, (c) LPS + PD-4-I group with marked areas of inflammation. Graphs: (d) and (e) Total hepatic injury score (THIS), revealing no significant differences among the different groups. (n=5-6, P≤0.05, mean±SEM)
Mentions: In vivo fluorescent microscopy revealed an increased rate of hepatic cell death by LPS, whereas rolipram attenuated LPS-induced cell death in the in vivo fluorescent-microscopy [Figure 4]. Markers of liver injury were compared in order to prove liver injury following LPS treatment of animals. Serum glucose was significantly reduced in LPS animals. AST, ALP, and ALT were augmented compared to controls while liver synthesis parameter (INR, CHE, and albumin) were unchanged [Table 2]. In the LPS + PD-4-I group AST and ALP were even augmented compared to LPS treatment alone, while serum glucose levels reached control levels following PD-4-I treatments. In histopathological examination no significant differences were obvious [Figure 5].

Bottom Line: In HepG2 cells TNF-α and LPS significantly reduced cell viability.The heme oxygenase 1 (HO-1) pathway did not induce the protective effect of PD-4-I.Intravenous PD-4-I treatment was effective in improving hepatic microcirculation and hepatic integrity, while it had a direct protective effect on HepG2 viability during inflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Anaesthesia and Critical Care, University Hospital Würzburg, Germany.

ABSTRACT

Objective: To investigate the impact of the phophodiesterase-4 inhibition (PD-4-I) with rolipram on hepatic integrity in lipopolysaccharide (LPS) induced hyperinflammation.

Materials and methods: Liver microcirculation in rats was obtained using intravital microscopy. Macrohemodynamic parameters, blood assays, and organs were harvested to determine organ function and injury. Hyperinflammation was induced by LPS and PD-4-I rolipram was administered intravenously one hour after LPS application. Cell viability of HepG2 cells was measured by EZ4U-kit based on the dye XTT. Experiments were carried out assessing the influence of different concentrations of tumor necrosis factor alpha (TNF-α) and LPS with or without PD-4-I.

Results: Untreated LPS-induced rats showed significantly decreased liver microcirculation and increased hepatic cell death, whereas LPS + PD-4-I treatment could improve hepatic volumetric flow and cell death to control level whithout influencing the inflammatory impact. In HepG2 cells TNF-α and LPS significantly reduced cell viability. Coincubation with PD-4-I increased HepG2 viability to control levels. The heme oxygenase 1 (HO-1) pathway did not induce the protective effect of PD-4-I.

Conclusion: Intravenous PD-4-I treatment was effective in improving hepatic microcirculation and hepatic integrity, while it had a direct protective effect on HepG2 viability during inflammation.

No MeSH data available.


Related in: MedlinePlus