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Peroxynitrite Modulates Manganese-Containing Superoxide Dismutase Gene Expression in Lung Epithelial Cells*

Robert M. Jackson, MD; G. Parish; E. Helton
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*From the Birmingham Veterans Affairs Medical Center, Birmingham, AL, and University of Alabama at Birmingham, Birmingham, AL.

Correspondence to: Robert M. Jackson, MD, Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Alabama at Birmingham, 215 Tinsley Harrison Tower, 1900 University Blvd, Birmingham, AL 35294-0015



Chest. 1999;116(suppl_1):100S-101S. doi:10.1378/chest.116.suppl_1.100S
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Extract

Peroxynitrite (ONOO) is a strong oxidant derived from nitric oxide (NO) and superoxide, reactive nitrogen and oxygen species present in inflamed tissue. Other oxidant stresses, eg, tumor necrosis factor-α and hyperoxia, induce mitochondrial, manganese-containing superoxide dismutase (MnSOD) gene expression. Because ONOO occurs in ARDS lungs, these experiments tested whether ONOO regulated MnSOD gene expression in human lung epithelial (A549) cells. MnSOD message expression was assessed by reverse transcriptase-polymerase chain reaction and Northern blots 4 h after exposure to reactive nitrogen species in vitro. 3-morpholinosydnonimine · HCl (SIN-1) (10 or 1000 μM) increased MnSOD messenger RNA (mRNA), but did not detectably change hypoxanthine guanine phosphoribosyl transferase (HPRT) mRNA. Authentic ONOO (100 to 500 μM) also increased MnSOD mRNA, but did not detectably change constitutive HPRT mRNA expression. We also tested effects of ONOO on cells transiently transfected with an MnSOD promoter-luciferase reporter construct. ONOO stimulated luciferase gene expression driven by a 2.5-kb fragment of the rat MnSOD gene 5′ promoter region. MnSOD gene induction due to ONOO was inhibited effectively by L-cysteine (10 mM) and partially inhibited by N-acetyl cysteine (50 mM) or pyrrole dithiocarbamate (10 mM). NO from 1-propanamine, 3-(2-hydroxy-2-nitroso-1-propylhydrazine (100 or 1,000 μM) did not change MnSOD or HPRT mRNA levels in epithelial cells. Neither H2O2 nor NO2, breakdown products of SIN-1 and ONOO, had any affect on MnSOD mRNA expression. ONOO and SIN-1 did not increase MnSOD protein content appreciably on western blots, nor did they increase MnSOD enzymatic activity. Increased steady state superoxide in the presence of NO yields ONOO, and ONOO has direct, stimulatory effects on MnSOD transcript expression. However, any anti-inflammatory effects of ONOO may be due to other mechanisms, including nuclear factor-κ B activation, which occurs variably after SIN-1 and ONOO exposure of epithelial cells.


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