3-nitrotyrosine and Anaphylaxis

Reactive oxygen species produced during allergic inflammation are key players of the pathophysiology of asthma, leading to oxidative tissue injury and inactivation of endogenous manganese superoxide dismutase (MnSOD). On this ground, removal of excess superoxide anion by scavenger molecules would be beneficial and protective. Here we show that a novel manganese(II)-containing polyamine-polycarboxylic compound, termed Mn(II)(Me(2)DO2A), with potent superoxide dismuting properties decreases the respiratory and histopathological lung abnormalities due to allergen inhalation in a model of ovalbumin (OA)-induced allergic asthma-like reaction in sensitized guinea pigs. Severe respiratory dysfunction in response to OA aerosolic challenge arose rapidly in the sensitized animals and was accompanied by bronchoconstriction, alveolar hyperinflation, mast cell activation, increased leukocyte infiltration (evaluated by myeloperoxidase assay), oxidative lung tissue injury (evaluated by the thiobarbituric-acid-reactive substances and nitrotyrosine immunostaining), decay of endogenous MnSOD activity, production of pro-inflammatory prostaglandins, and lung cell apoptosis. Treatment with Mn(II)(Me(2)DO2A) (15mg/kg, given 1h before allergen challenge), but not the inactive congener Zn(II)(Me(2)DO2A) lacking redox-active metal site, significantly attenuated all the above functional, histopathological and biochemical parameters of allergic inflammation and restored the levels of MnSOD activity. In conclusion, our findings support the potential therapeutic use of Mn(II)(Me(2)DO2A) as novel superoxide scavenger drug in asthma and anaphylactic reactions.

Topics: Allergens; Anaphylaxis; Animals; Anti-Asthmatic Agents; Apoptosis; Asthma; Bronchoconstriction; Caspase 3; Free Radical Scavengers; Guinea Pigs; Male; Mast Cells; Organometallic Compounds; Ovalbumin; Peroxidase; Superoxides; Thiobarbituric Acid Reactive Substances; Tyrosine

The participation of apoptotic cell death of neutrophils in the development of skin lesions of patients with anaphylactoid purpura was examined by the in situ specific labeling of fragmented DNA. In the early stage of the skin lesions, there were few positively stained nuclei in infiltrating cells. The number of positive cells increased markedly in the fully developed stage of the lesions. A number of neutrophils were stained positively. Finally, a few fragmented nuclei were still positive in the late stage of the lesions. It was therefore suggested that fragmentation of neutrophils in the skin lesions from the patients might be due to apoptosis. Inducible nitric oxide synthase and nitrotyrosine were detected in infiltrates, and interleukin-8 was also detected in vascular endothelial cells in those skin lesions. The roles of nitric oxide and interleukin-8 in the apoptosis of neutrophils are discussed.

Topics: Adolescent; Adult; Aged; Anaphylaxis; Apoptosis; Cell Nucleus; Child; Child, Preschool; DNA Fragmentation; Endothelium, Vascular; Female; Humans; Interleukin-8; Leukocyte Count; Male; Middle Aged; Neutrophils; Nitric Oxide Synthase; Purpura; Skin Diseases; Tyrosine