Activities of superoxide dismutases and NADPH oxidase in neutrophils obtained from asthmatic and normal donors.
PMN obtained from asthmatic subjects demonstrate a heightened respiratory burst with increased superoxide generation compared to normals. This enhanced superoxide anion generation could be secondary to increased activity of the respiratory burst NADPH oxidase or diminished metabolism of superoxide via superoxide dismutase (SOD). The two forms of SOD expressed in PMN, CuZnSOD expressed constitutively in the cytosol and inducible mitochondrial MnSOD, were investigated in asthmatics. Resting PMN from asthmatics (N = 9) contained significantly less MnSOD activity compared to controls (0.46 +/- 0.16 vs. 0.79 +/- 0.17 units/10(7) PMN, respectively; P = 0.0002). As several cytokines including interleukins (IL) -1, -4, and -6 as well as granulocyte macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF) enhance the PMN respiratory burst and are synthesized in the asthmatic lung, their effects on PMN MnSOD activity were assayed. In contrast to its effects on lymphocytes, both IL-1 and IL-6 significantly inhibited in a dose-dependent fashion the induction of MnSOD in PMN from normals (0.42 +/- 0.12 and 0.45 +/- 0.05 units/10(7) PMN, respectively, at 10 units/ml of each cytokine; P = 0.02 compared to resting cells) but failed to further modulate MnSOD production in asthmatic PMN. IL-4 and GM-CSF had no effect on MnSOD production, and TNF effects could not be studied because of its effects on cell viability. There were no differences in the activity of CuZnSOD (N = 9) or NADPH oxidase (N = 4) in the two groups. Inhibition of MnSOD activity in PMN secondary to cytokine exposure in the asthmatic lung could explain, at least in part, the increased generation of superoxide from PMN obtained from asthmatics. This would promote the presence and severity of inflammation in the asthmatic lung. These data further support a role for IL-1 and IL-6 in allergic inflammation.
Joseph
B Z
BZ
Department of Medicine, National Jewish Center for Immunology and Respiratory Medicine, University of Colorado Health Sciences Center, Denver.
Routes
J M
JM
Borish
L
L
D001249:Asthma / Q000201:enzymology*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007378:Interleukins / Q000494:pharmacology; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D019255:NADPH Oxidases; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology*; D016897:Respiratory Burst / Q000187:drug effects; D013482:Superoxide Dismutase / Q000145:classification / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013482:Superoxide Dismutase; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases