TITLE

Role of the endothelium and nitric oxide synthases in modulating superoxide formation induced by endotoxin and cytokines in porcine pulmonary arteries

AUTHOR(S)
Muzaffar, S.; Jeremy, J.Y.; Angelini, G.D.; Stuart-Smith, K.; Shukla, N.
PUB. DATE
July 2003
SOURCE
Thorax;Jul2003, Vol. 58 Issue 7, p598
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Background: The interactive roles of cytokines, endotoxins, superoxide (O[sub 2, sup •-]) and nitric oxide (NO) in the pathogenesis of adult respiratory distress syndrome (ARDS) have not been fully elucidated. The effects of tumour necrosis factor-α (TNF-α), interleukin 1α (1L-1α), and lipopolysaccharide (LPS) and the role of NO and the endothelium in mediating O[sub 2, sup •-] formation were therefore investigated in intact porcine pulmonary arteries in vitro. Methods: Intrapulmonary artery (PA) segments were obtained from White Landrace pigs (25-35 kg) and incubated with LPS, IL-1α, and TNF-α and O[sub 2, sup •-] release was measured by the superoxide dismutase (SOD) inhibitable reduction of ferricytochrome c. The source of O[sub 2, sup •-] formation was determined using a number of enzyme inhibitors. The role of NO was explored using NO synthase (NOS) inhibitors and the distribution of NOS isoforms and peroxynitrite (ONOO[sup -], an index of NO-O[sub 2, sup •-] interactions) assessed by immunocytochemistry. Results: LPS, IL-1α, and TNF-α promoted the formation of O[sub 2, sup •-] from PA compared with untreated controls in a time and dose dependent manner, an effect markedly enhanced by removal of the endothelium but completely inhibited by the NADPH oxidase inhibitor diphenylene iodonium chloride (DPI). L-NAME and the eNOS inhibitor N[sup 5]-(1-iminoethyl)-ornithine (L-NIO) enhanced O[sub 2, sup •-] formation from PA (with endothelium) in response to IL-1α and TNF-α but had no effect on LPS mediated O[sub 2, sup •-] formation, whereas L-NAME and the iNOS inhibitor L-N[sup 6]-(1-iminoethyl)-lysine-HCl (L-NIL) enhanced O[sub 2, sup •-] formation only in response to LPS. Conclusions: LPS, IL-1α, and TNF-α promote O[sub 2, sup •-] formation through an upregulation of NADPH oxidase activity which is augmented by removal of the endothelium, as...
ACCESSION #
10595442

 

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