Oxidative stress induces protein and DNA radical formation in follicular dendritic cells of the germinal center and modulates its cell death patterns in late sepsis.

National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Free Radical Biology and Medicine (Impact Factor: 5.27). 04/2011; 50(8):988-99. DOI: 10.1016/j.freeradbiomed.2010.12.037
Source: PubMed

ABSTRACT Profound depletion of follicular dendritic cells (FDCs) is a hallmark of sepsis-like syndrome, but the exact causes of the ensuing cell death are unknown. The cell death-driven depletion contributes to immunoparalysis and is responsible for most of the morbidity and mortality in sepsis. Here we have utilized immuno-spin trapping, a method for detection of free radical formation, to detect oxidative stress-induced protein and DNA radical adducts in FDCs isolated from the spleens of septic mice and from human tonsil-derived HK cells, a subtype of germinal center FDCs, to study their role in FDC depletion. At 24h post-lipopolysaccharide administration, protein radical formation and oxidation were significantly elevated in vivo and in HK cells as shown by ELISA and confocal microscopy. The xanthine oxidase inhibitor allopurinol and the iron chelator desferrioxamine significantly decreased the formation of protein radicals, suggesting the role of xanthine oxidase and Fenton-like chemistry in radical formation. Protein and DNA radical formation correlated mostly with apoptotic features at 24h and necrotic morphology of all the cell types studied at 48h with concomitant inhibition of caspase-3. The cytotoxicity of FDCs resulted in decreased CD45R/CD138-positive plasma cell numbers, indicating a possible defect in B cell differentiation. In one such mechanism, radical formation initiated by xanthine oxidase formed protein and DNA radicals, which may lead to cell death of germinal center FDCs.


Available from: Ronald P Mason, Apr 01, 2015
1 Bookmark
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although highly active antiretroviral therapy (HAART) has succeeded in many cases in suppressing ongoing viral replication, the HIV-infected cells are not eradicated by this therapy. In this article, the author proposes a new treatment protocol based on administration of radiophosphorus 32 (32P) with HAART combination. The proposed new protocol consists of the following steps: HAART keeps viral replication below the level of detection. Then, 32P is administered for the removal of the “residual disease”. By its beta emission, incorporated 32P to viral RNA or proviral DNA may kill free virions and productively infected cells, reactivates latently infected cells and makes them vulnerable to immune competent cells and antiretroviral therapy. This new combination may exhibit synergistic interactions between virostatic effects of antiretroviral molecules and radiobiological effect of internal radiotherapy and provide a new tool to purge the viral reservoirs.
    Medecine Nucleaire 10/2011; 35(10):545-552. DOI:10.1016/j.mednuc.2011.07.004 · 0.16 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: An overproduction of corticosterone during severe sepsis results in increased apoptosis of immune cells, which may result in relative immunosuppression and an impaired ability to fight infections. We have previously demonstrated that administration of tubastatin A, a selective inhibitor of histone deacetylase-6 (HDAC6), improves survival in a lethal model of cecal ligation and puncture (CLP) in mice. The purpose of this study was to characterize the effects of this treatment on sepsis-induced stress responses and immune function.
    Surgery 06/2014; 156(2). DOI:10.1016/j.surg.2014.03.033 · 3.37 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective: To study the phytochemical and biological properties (antioxidant, and thrombolytic) of methanolic extracts of Enhydra fluctuans Lour, a plant bel oanngtihnegl mtoi ntthiec Asteraceae family. Methods: The phytochemical evaluation was carried out by qualitative analysis. In vitro raendtuiocxtiidona,n tt oataclt ipvihteyn oofl eaxntdr atcott awl aflsa vstoundoiiedd c uonsitneng tsfr edee treardmiicnaalt isocna vaesnsagyins.g Tahses aayn, thabelimlitiyn toicf athcrtoivmitbyo lwyatisc daectteivrimtyi nbeyd c ulosti ndgis rpuapratiloyns iass saanyd. death time of phertima posthuma (earthworm) and Results: The phytochemical evaluation showed significant presence of flavonoids, triterpenes, caacrtibvoihtyy dwraast ef,o urenddu sciignngi fsiucgaanrts [,I Csaponins, phenols, diterpenes, protein and tannin. The antioxidant 50=(135.20依0.56) μg/mL] as compared to ascorbic acid [(130.00±0.76) μg/mL]. The reducing power was increased with concentration. Total phenol and total flavonoid dcoenatthe nttims ew eorf ee a(1r5th3w.0o8r依m0s.3 f8o) rm dgif/fmerLe natn cdo n(1c7e2n.t0r4a依ti0o.n5s6 ) omf egx/mtraLc tr ewsepreec tdievteelrym. iTnhede apnadra clyosmisp aarnedd awlibthen adlabzeonldea. zAodled.i tTiohnea rlelys,u tlhtse schrouwdeed e txhtraat c1t0 s mhogw/medL ao fc tohnec ecnrutrdaeti oenx tdraecpte hnadde ds irmelialatiro nefsfheicpt wwiitthh isttsr eapntothkeinlmasine’tsic c lporto lpyesritsy (.4 0T.h13e clot lysis activity of crude extract was compared to the standard %) activity and found significant (31%). Conclusions: The study proves that the crude methanolic extract of Enhydra fluctuans Lour hphasy tosicghneimfiiccaanlst .antioxidant
    Asian Pacific Journal of Tropical Biomedicine 04/2014; DOI:10.12980/APJTB.4.2014C677