AIMS: We studied the new anti-inflammatory effects of non-specific phosphodiesterase (PDE) inhibitor pentoxifylline (PTX) on ischaemia-reperfusion injury and postconditioning of the lower extremities. We aimed to examine the oxidative stress parameters (OSP), the inflammatory response and the changes in structure of skeletal muscle after revascularization surgery.
METHODS: 50 Wistar rats in five groups underwent a 60 min infrarenal aortic cross clamping. After the ischaemia in IR+PC group ischemic postconditioning was performed, intermittent 15 seconds reperfusion, 15 seconds ischaemic periods were applied four times. The ischemic phase was followed by a 120 min of reperfusion. In IR+PTX group the animals were treated with PTX. In IR+PC+PTX group both ischemic postconditioning and PTX treatment were performed. Blood samples and biopsy from quadriceps muscle were collected. Plasma malondialdehyde, reduced glutathione, -SH-groups, TNF-alpha, IL-6 concentrations and superoxide dismutase enzyme activity were measured.
RESULTS: The levels of OSP and the inflammatory proteins were significantly higher in the IR group. PTX treatment and PC could significantly decrease the levels of OSP and inflammatory proteins. When the animals were co-treated with PTX and PC the results were even better.
CONCLUSIONS: Inhibition of PDE by PTX could markedly decrease the inflammatory response and moderate the ischaemia-reperfusion damages after lower limb ischemia and reperfusion. Administration of PTX could potentiate the beneficial effects of PC.
Abdel-SalamO.M., BaiuomyA.R., El-ShenawyS.M. and ArbidM.S., The anti-inflammatory effects of the phosphodiesterase inhibitor pentoxifylline in the rat, Pharmacol Res47(4) (2003), 331–340.
2.
AbegunewardeneN., KreitnerK.F., OberholzerK., VosselerM., SchmidtK.H., WimmerE., ElsäßerA., GoriT., DüberC., MünzelT. and HorstickG., Serial assessments of microvascular obstruction by contrast-enhanced magnetic resonance predict contractile recovery and clinical outcome after reperfused acute myocardial infarction, Clin Hemorheol Microcirc62(4) (2015), 345–357.
3.
AnS., HishikawaY., LiuJ. and KojiT., Lung injury after ischemia-reperfusion of small intestine in rats involves apoptosis of type II alveolar epithelial cells mediated by TNF-alpha and activation of Bid pathway, Apoptosis12(11) (2007), 1989–2001. doi: 10.1007/s10495-007-0125-1
4.
BaldwinA.S., The transcription factor NFkB and human disease, J Clin Invest107 (2001), 3–6.
5.
DunzendorferS., SchratzbergerP., ReinischN., KahlerC.M. and WiedermannC.J., Pentoxifylline differentially regulates migration and respiratory burst activity of the neutrophil, ANN NY Acad Sci15 (1997), 330–340.
6.
El-GhoneimiA., CursioR., Schmid-AllianaA., ToveyM., LasfarA., MichielsJ.F., et al., Pentoxifylline inhibits liver expression of tumor necrosis factor alpha mRNA following normothermic ischemia-reperfusion, HPB (Oxford)9 (2007), 112–119.
7.
FlynnW.J., CryerH.G. and GarrisonR.N., Pentoxifylline restores in-testinal microvascular blood flow during resuscitated hemor-rhagic shock, Surgery110 (1991), 350–356.
8.
FuldaS. and DebatinK.M., Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy, Oncogene25(34) (2006), 4798–811. doi: 10.1038/sj.onc.1209608
9.
GrauM., KollikowskiA. and BlochW., Remote ischemia preconditioning increases red blood cell deformability through red blood cell-nitric oxide synthase activation, Clin Hemorheol Micricirc63(3) (2016), 185–197.
10.
HaddadJ.J., LandS.C., Tarnow-MordiW.O., ZembalaM., KowalczykD. and LauterbachR., Immunopharmacological potential of selective phosphodiesterase inhibition: II – evidence for the involvement of an inhibitory-kappaB/nuclear factor kappaB-sensitive pathway in alveolar epithelial cells, J Pharmacol Exp Ther300 (2002), 567–576.
11.
HernándezE., BucioL., SouzaV., EscobarM.C., Gómez-QuirozL.E., FarfánB., et al., Pentoxifylline downregulates alpha (I) col-lagen expression by the inhibition of Ikappabalpha degrada-tion in liver stellate cells, Cell Biol Toxicol24 (2008), 303–314.
12.
KishiM., TanakaH., SeiyamaA., TakaokaM., MatsuokaT., YoshiokaT., et al., Pentoxifylline attenuates reperfusion injury in skeletal muscle after partial ischemia,, Am J Physiol274 (1435), H1435–H1442.
13.
LuS.C., Regulation of glutathione synthesis, Curr Top Cell Regul36 (2000), 95–116.
14.
MarziI., MaierM., HerzogC. and BauerM., Influence of pentoxifyl-line and albifylline on liver microcirculation and leukocyte adhe-sion after hemorrhagic shock in the rat, J Trauma40 (1996), 90–96.
15.
ModzelewskiB. and JaniakA., Pentoxiphilline as a cyclooxygenase (cox-2) inhibitor in experimental sepsis, Med Sci Monit10(7) (2004), BR233–BR237.
16.
NemethN., FurkaI. and MikoI., Hemorheological changes in ischemia-reperfusion: An overview on our experimental surgical data, Clin Hemorheol Microcirc57(3) (2014), 215–225.
17.
NemethN., KissF., KlarikZ., TothE., MesterA., FurkaI. and MikoI., Simultaneous investigation of hemodynamic, microcirculatory and arterio-venous micro-rheological parameters in infrarenal or suprarenal aortic cross-clamping model in the rat, Clin Hemorheol Microcirc57(4) (2014), 339–353.
18.
PlacerZ.A., CushmanL.L. and JohnsonB.C., Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems, Anal Biochem16(2) (1966), 359–364.
19.
PorterJ.M., CutlerB.S., LeeB.Y., et al., Pentoxifylline efficacy in the treatment of intermittent claudication: Multicenter controlled double-blind trial with objective assessment of chronic occlusive arterial disease patients, Am Heart J104 (1982), 66–72.
20.
PorterJ.M., CutlerB.S., LeeB.Y., et al., Pentoxifylline efficacy in the treatment of intermittent claudication: Multicenter controlled double-blind trial with objective assessment of chronic occlusive arterial disease patients, Am Heart J104 (1982), 66–72.
21.
ReffelmannT. and KlonerR.A., The “no-reflow” phenomenon: Basic science and clinical correlates, Heart87 (2002), 162–168.
22.
SchreckR., AlbermannK. and BaeuerleP.A., Nuclear factor kappa B: An oxidative stress-responsive transcription factor of eukariotic cells, Free Radical Res Commun17 (1992), 221–237.
23.
SedlakJ. and LindsayR.H., Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent, Anal Biochem25(1) (1968), 192–205.
24.
StrieterR.M., RemickD.G., WardP.A., et al., Cellular and molecular regulation of tumor necrosis factor-alpha production by pentoxifylline, Biochem Biophys Res Commun155 (1988), 1230–1236.
25.
TsangA., HausenloyD.J., MocanuM.M. and YellonD.M., Postconditioning: A form of “modified reperfusion” protects the myocardium by activating the phosphatidylinositol 3-kinase-Akt pathway, Circ Res95(3) (2004), 230–232.
26.
WangP., BaZ.F., MorrisonM.H., AyalaA. and ChaudryI.H., Mecha-nism of the beneficial effects of pentoxifylline on hepatocel-lular function after trauma hemorrhage and resuscitation, Surgery112 (1992), 451–458.
27.
WangW., TamW.F., HughesC.C.W., RathS. and SenR., c-Rel is a target of pentoxifylline-mediated inhibition og T lymphocyte activation, Immunity6 (1997), 165–174.
ZsoltS., RobertK., FerencK., ZoltanK., JanosP., IstvanF., PeterS., IrenM., KatalinP. and NorbertN., Effects of various drugs (flunixin, pentoxifylline, enoxaparin) modulating micro-rheological changes in cerulein-induced acute pancreatitis in the rat, Clinical Hemorheology and Microcirculation57(4), 303–314.
