Attenuation of the oxidative burst-induced DNA damage in human leukocytes by hyaluronan.
Oxidative burst provides the mechanism for specialized phagocytes, such as granulocytes or monocytes, to kill invading microorganisms through generation of superoxide anions. However, the oxidants generated during the burst damage DNA of the phagocytes and neighboring cells. Human blood leukocytes treated with phorbol myristate acetate (PMA) are considered to represent the experimental model of induction of oxidative burst. We recently reported that DNA damage in PMA-treated leukocytes is assessed by cytometric analysis of the induction of histone H2AX phosphorylation and Ataxia Telangiectasia Mutated (ATM) activation. In the present study we observed that hyaluronic acid (HA) of average molecular weight (MW) 5.4x10(6) and 2x10(6) at 0.1% (w/v) concentration significantly attenuated H2AX phosphorylation and ATM activation induced in leukocytes during oxidative burst. HA also reduced the intracellular level of PMA-induced reactive oxidants as measured by the ability of cells to oxidize 2',7'-dihydro-dichlorofluorescein-diacetate. No such effect was seen with HA of 6x10(4) MW. The data are consistent with earlier observations that HA of high MW protects DNA from oxidative damage induced by endo- or exogenous oxidants. The anti-oxidant effect of HA seen during oxidative burst also explains its anti-inflammatory effect when used to treat arthritic joints.
Brander Cancer Research Institute and Department of Pathology, New York Medical College, Valhalla, NY, 10595, USA.
H Dorota
HD
Halicka
Vadim
V
Mitlitski
Julie
J
Heeter
Endre A
EA
Balazs
Zbigniew
Z
Darzynkiewicz
D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005452:Fluoresceins / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism; D008970:Molecular Weight; D010766:Phosphorylation / Q000187:drug effects; D006656:Protamine Kinase / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects* / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
C110400:2',7'-dichlorodihydrofluorescein diacetate; D000975:Antioxidants; D005452:Fluoresceins; C468783:H2AX protein, human; D006657:Histones; D006820:Hyaluronic Acid; D006656:Protamine Kinase; D013755:Tetradecanoylphorbol Acetate