Wynik wyszukiwania w bazie Polska Bibliografia Lekarska GBL

Zapytanie: TARNOW-MORDI
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Tytuł oryginału: Immunopharmacological potential of selective phosphodiesterase inhibition.[P.] 1: Differential regulation of lipopolysaccharide-mediated proinflammatory cytokine (interleukin-6 and tumor necrosis factor-ŕ) biosynthesis in alveolar epithelial cells.
Autorzy: Haddad John J., Land Stephen C., Tarnow-Mordi William O., Zembala Marek, Kowalczyk Danuta, Lauterbach Ryszard
Źródło: J. Pharmacol. Exp. Ther. 2002: 300 (2) s.559-566, il., bibliogr. s. 565-566
Sygnatura GBL: 310,547

Hasła klasyfikacyjne GBL:
  • farmacja

    Typ dokumentu:
  • praca doświadczalna
  • praca opublikowana za granicą
  • tytuł obcojęzyczny

    Wskaźnik treści:
  • zwierzęta
  • szczury
  • in vitro

    Streszczenie angielskie: In an attempt to elaborate in vitro on a therapeutic strategy that countracts an inflammatory signal, we previously reported a novel immunopharmacological potential of glutathione, an antioxidant thiol, in regulating inflammatory cytokines. In the present study, we investigated the hypothesis that selective regulation of phosphodiesterases (PDEs), a family of enzymes that controls intracellular cAMP/cGMP degradation, differentially regulates proinflammatory cytokines. Selective PDE1 inhibition (8-methoxymethyl-3-isobutyl-1-methylxanthine) blockaded lipopolysaccharide-endotoxin (LPS)-mediated biosynthesis of interleukin (IL)-6, but this pathway had no inhibitory effect on tumor necrosis factor-ŕ (TNF-ŕ). Furthermore, inhibition of PDE3 (amrinone) abolished the effect of LPS on IL-6, but attenuated TNF-ŕ production. Reversible competitive inhibition of PDE4 (rolipram) exhibited a potent inhibitory effect on IL-6 and a dual, biphasic (excitatory/inhibitory) effect on TNF-ŕ secretion. Blockading PDE5 (4-[3',4'-(methylenediox)benzyl]amino-6-methoxyquinazoline) showed a high potency in reducing IL-6 production, but in a manner similar to the inhibition of PDE4, exhibited a biphasic effect on TNF-ŕ biosynthesis. Simultaneous inhibition of PDE5, 6 and 9 (zaprinast), purported to specifically elevate intracellular cGMP, reduced, in a doseindependent manner, IL-6 and TNF-ŕ biosynthesis. Finally, nonselective inhibition of PDE by pentoxyfylline suppressed LPS-mediated secretion of IL-6 and TNF-ŕ. The involvement of specific PDE isoenzymes in differentially regulating LPS-mediated inflammatory cytokine biosynthesis indicates a novel approach to unravel the potential therapeutic targets that these isozymes constitute during the progression of inflammation within the respiratory epithelium.

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    Tytuł oryginału: Immunopharmacological potential of selective phosphodiesterase inhibition. [P.] 2: Evidence for the involvement of an inhibitory-kB/nuclear factor-kB-sensitive pathway in alveolar epithelial cells.
    Autorzy: Haddad John J., Land Stephen C., Tarnow-Mordi William O., Zembala Marek, Kowalczyk Danuta, Lauterbach Ryszard
    Źródło: J. Pharmacol. Exp. Ther. 2002: 300 (2) s.567-576, il., tab., bibliogr. s. 575-576
    Sygnatura GBL: 310,547

    Hasła klasyfikacyjne GBL:
  • farmacja

    Typ dokumentu:
  • praca doświadczalna
  • praca opublikowana za granicą
  • tytuł obcojęzyczny

    Wskaźnik treści:
  • zwierzęta
  • szczury

    Streszczenie angielskie: In this report we investigated the immunopharmacological role of selective and nonselective phosphodiesterase (PDE) inhibition in regulating the inhibitory-kB (IkB-ŕ)/nuclear factor-kB (NF-kB) signally transduction pathway. In fetal alveolar type II epithelial cells, PDE blockade at the level of the diverging cAMP/cGMP pathways differentially regulated the phosphorylation and degradation of IkB-ŕ, the major cytosolic inhibitor of NF-kB. Whereas selective inhibition of PDEs 1, 3, and 4, by the action of 8-methoxymethyl-3-isobutyl-1-methylxanthine, amrinone, and rolipram, respectively, exhibited a tendency to augment the translocation of NF-kB1 (p50), RelA (p65), RelB (p68), and c-Rel (p75), selective blockade of PDE 5, 6, and 9, by the action of 4-[3',4'=(methylenedioxy)benzyl]amino)-6-methoxyquinazoline and zaprinast, attenuated lipopolysaccharide-endotoxin (LPS)-mediated NF-kB translocation. Pentoxifilline, a nonspecific PDE inhibitor, reversed the excitatory effect of LPS on NF-kB subunit nuclear localization, in a dosedependent manner. Furthermore, analysis of NF-kB activation under the same conditions revealed a biphasic effect mediated by LPS. PDEs 1, 3, and 4 inhibition was associated with upregulating NF-kB transcriptional activity. In contrast, blockading the activity of PDEs 5, 6, and 9 negatively attenuated LPS-mediated NF-kB activation, similar to the effect of 3,7-dihydro-3,7-dimethyl-1-(5-oxohexyl)-1H-purine-2,6-dione (pentoxifulline). These results indicate that selective and nonselective interference with the control of the dynamic equilibrium of cyclic nucleotides via PDE isoenzyme regulation represents an immunoregulatory mechanism that requires the differential, biphasic targeting of the IkB-ŕ/NF-kB pathway.

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