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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: 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.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

Microhemodynamics: (a) Sinusoidal microcirculation, arrows indicate areas of non-perfused sinusoids (b) Volumetric flow in perfused sinusoids, revealing significantly higher volumetric flow in PD-4-I treated animals (c) Sinusoidal diameters show significantly dilated sinusoids in the LPS + PD-4-I compared to control and LPS (d) Number of continuously (CPS), intermittently (IPS), and non-perfused sinusoids (NPS) demonstrating a significantly higher count of CPS in PD-4-I treated animals compared to the LPS group. (*vs. Control, #vs. LPS, §vs. LPS + PD-4-I, n = 5-6, P ≤ 0.05, mean ± SEM)
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Figure 4: Microhemodynamics: (a) Sinusoidal microcirculation, arrows indicate areas of non-perfused sinusoids (b) Volumetric flow in perfused sinusoids, revealing significantly higher volumetric flow in PD-4-I treated animals (c) Sinusoidal diameters show significantly dilated sinusoids in the LPS + PD-4-I compared to control and LPS (d) Number of continuously (CPS), intermittently (IPS), and non-perfused sinusoids (NPS) demonstrating a significantly higher count of CPS in PD-4-I treated animals compared to the LPS group. (*vs. Control, #vs. LPS, §vs. LPS + PD-4-I, n = 5-6, P ≤ 0.05, mean ± SEM)

Mentions: Lipopolysaccharide significantly decreased sinusoidal volumetric flow (12.94 ± 0.6 μm3/ms), whereas PD-4-I (16.8 ± 0.7 μm3/ms) stabilized hepatic microcirculation to control levels (16.26 ± 1.0 μm3/ms; Figure 3b). Additionally, rolipram significantly increased sinusoidal diameter (11.4 ± 0.1 control; 11.57 ± 0.1 LPS; 12.1 ± 0.1 LPS + PD-4-I [μm]) and functional sinusoidal density (37.1 ± 2.1 control; 21.8 ± 1.3 LPS; 27.2 ± 1.5 LPS + PD-4-I [perfused sinusoids/0.4 mm2]) illustrating a protective effect for sinusoidal microhemodynamics in endotoxemia [Figure 3a and c and d].


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)

Microhemodynamics: (a) Sinusoidal microcirculation, arrows indicate areas of non-perfused sinusoids (b) Volumetric flow in perfused sinusoids, revealing significantly higher volumetric flow in PD-4-I treated animals (c) Sinusoidal diameters show significantly dilated sinusoids in the LPS + PD-4-I compared to control and LPS (d) Number of continuously (CPS), intermittently (IPS), and non-perfused sinusoids (NPS) demonstrating a significantly higher count of CPS in PD-4-I treated animals compared to the LPS group. (*vs. Control, #vs. LPS, §vs. LPS + PD-4-I, 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 4: Microhemodynamics: (a) Sinusoidal microcirculation, arrows indicate areas of non-perfused sinusoids (b) Volumetric flow in perfused sinusoids, revealing significantly higher volumetric flow in PD-4-I treated animals (c) Sinusoidal diameters show significantly dilated sinusoids in the LPS + PD-4-I compared to control and LPS (d) Number of continuously (CPS), intermittently (IPS), and non-perfused sinusoids (NPS) demonstrating a significantly higher count of CPS in PD-4-I treated animals compared to the LPS group. (*vs. Control, #vs. LPS, §vs. LPS + PD-4-I, n = 5-6, P ≤ 0.05, mean ± SEM)
Mentions: Lipopolysaccharide significantly decreased sinusoidal volumetric flow (12.94 ± 0.6 μm3/ms), whereas PD-4-I (16.8 ± 0.7 μm3/ms) stabilized hepatic microcirculation to control levels (16.26 ± 1.0 μm3/ms; Figure 3b). Additionally, rolipram significantly increased sinusoidal diameter (11.4 ± 0.1 control; 11.57 ± 0.1 LPS; 12.1 ± 0.1 LPS + PD-4-I [μm]) and functional sinusoidal density (37.1 ± 2.1 control; 21.8 ± 1.3 LPS; 27.2 ± 1.5 LPS + PD-4-I [perfused sinusoids/0.4 mm2]) illustrating a protective effect for sinusoidal microhemodynamics in endotoxemia [Figure 3a and c and d].

Bottom Line: 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.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