Countervailing influence of tumor necrosis factor-α and nitric oxide in endotoxemia

Edgar A. Jaimes, Domingo Del Castillo, Mark S. Rutherford, Leopoldo Raij

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


Tumor necrosis factor-α (TNF-α), a crucial mediator in sepsis, elicits multiple biologic effects, including intravascular thrombosis and circulatory shock. TNF-α exerts its biologic effects through two distinct cell surface receptors, TNF-R1 and TNF-R2. The pathophysiologic interaction between TNF-α and nitric oxide (NO) in glomerular thrombosis caused by endotoxemia in rats and wild-type mice (C57BL6) as well as in knockout mice that are deficient in TNF-R1 (R1 -/-), TNF-R2 (R2 -/-), or both receptors (R1R2 -/-) was studied. Administration of lipopolysaccharide (LPS; Escherichia coli endotoxin) resulted in increased NO and TNF-α production but failed to induce glomerular thrombosis. Concomitant administration of LPS + NG-nitro-L-arginine methyl ester (L-NAME; an NO synthesis inhibitor) resulted in glomerular thrombosis in rats and in wild-type mice. Intraperitoneal administration of pentoxifylline before LPS inhibited TNF-α synthesis and prevented glomerular thrombosis in rats given LPS + L-NAME. In contrast to the results observed in rats and wild-type mice, administration of LPS + L-NAME did not result in glomerular thrombosis in knockout mice with either single or double TNF-α receptor deletion. Thus, during endotoxemia, (1) TNF-α fosters glomerular thrombosis if there is deficiency of NO synthesis and (2) both TNF-α receptors are necessary for TNF-α's prothrombogenic action. Clinically, these novel studies suggest that in gram-negative endotoxemia, inhibition of NO synthesis and selective blockade of TNF-α receptors may provide unique therapeutic approaches for mitigation of glomerular thrombosis and restitution of vascular tone.

Original languageEnglish (US)
Pages (from-to)1204-1210
Number of pages7
JournalJournal of the American Society of Nephrology
Issue number6
StatePublished - Jun 2001


Dive into the research topics of 'Countervailing influence of tumor necrosis factor-α and nitric oxide in endotoxemia'. Together they form a unique fingerprint.

Cite this