Increased nitric oxide formation in recurrent thrombotic microangiopathies: a possible mediator of microvascular injury.
The term thrombotic microangiopathy (TMA) has been used extensively to encompass hemolytic uremic syndrome and thrombotic thrombocytopenic purpura, two syndromes of hemolytic anemia, and thrombocytopenia associated with renal or brain involvement or both. There is evidence that endothelial damage is a crucial feature in the sequence of events that precedes the development of microvascular lesions. More recent studies would suggest that endothelial dysfunction could be a consequence of neutrophil activation. Activated neutrophils generate superoxide anions (O2-) that, combining with endothelial-derived nitric oxide (NO), form the highly cytotoxic hydroxyl radical. Seven patients with recurrent forms of TMA and seven healthy volunteers were studied. Plasma concentrations of the NO metabolites, nitrites/nitrates, were elevated in the acute phase of TMA, indicating an increased NO synthesis in vivo. In addition, elevated serum concentrations of tumor necrosis factor, a potent inducer of endothelial NO synthase, were found in acute TMA. Serum from patients with acute TMA induced NO synthesis in cultured endothelial cells more than normal serum. Enhanced stimulatory activity was no longer found in the recovery phase. Release of O2- by neutrophils ex vivo was higher than normal in patients with acute TMA, but decreased in the recovery phase. Exactly the same trend was observed for plasma malondialdehyde and conjugated dienes, indicating that excessive oxygen radical formation in acute TMA is associated with increased lipid peroxidation. Thus, in recurrent forms of TMA, NO formation was increased as compared with controls. This was associated with signs of lipid peroxidation, likely the consequence of the interaction of NO with neutrophil-derived oxygen products.
Noris
M
M
Mario Negri Institute for Pharmacological Research, Ospedali Riuniti diBergamo, Rome, Italy.
Ruggenenti
P
P
Todeschini
M
M
Figliuzzi
M
M
Macconi
D
D
Zoja
C
C
Paris
S
S
Gaspari
F
F
Remuzzi
G
G
D015104:3,4-Methylenedioxyamphetamine / Q000378:metabolism; D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D001120:Arginine / Q000097:blood; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005260:Female; D006463:Hemolytic-Uremic Syndrome / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000096:biosynthesis*; D009573:Nitrites / Q000097:blood; D011697:Purpura, Thrombotic Thrombocytopenic / Q000378:metabolism* / Q000473:pathology; D012008:Recurrence; D013481:Superoxides / Q000378:metabolism; D013927:Thrombosis / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D009569:Nitric Oxide; D015104:3,4-Methylenedioxyamphetamine; D001120:Arginine