Differential release of matrix metalloproteinase‐9 and nitric oxide following infusion of endotoxin to human volunteers

Albert, Johanna; Radomski, Anna; Soop, Anne; Sollevi, Alf; Frostell, Claes; Radomski, Marek W.

doi:10.1034/j.1399-6576.2003.00059.x

Cited by 44 publications

(35 citation statements)

References 24 publications

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“…This finding is in agreement with previous human endotoxemia studies (35,36). Increased NO production in our study with septic patients and previous studies (37,38) may be explained by a much higher degree of inflammation, ongoing LPS release, and impaired renal clearance of NO metabolites during septic shock compared with the mild inflammatory response of a single bolus injection of LPS that does not severely impair renal function during experimental endotoxemia.…”

Section: Discussionsupporting

confidence: 83%

Upregulation of Renal Inducible Nitric Oxide Synthase during Human Endotoxemia and Sepsis Is Associated with Proximal Tubule Injury

Heemskerk

Pickkers

Bouw

et al. 2006

Clinical Journal of the American Society of Nephrology

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The incidence and the mortality of septic acute kidney injury are high, partly because the pathogenesis of sepsis-induced renal dysfunction is not clear. The objective of this study was to investigate the upregulation of renal inducible nitric oxide synthase (iNOS) in human endotoxemia and sepsis and the effect of NO on tubular integrity. Septic patients and endotoxemia that was induced by a bolus injection of 2 ng/kg Escherichia coli LPS in human volunteers were studied. In addition, the effect of co-administration of the selective iNOS inhibitor aminoguanidine was evaluated. The urinary excretion of the cytosolic glutathione-S-transferase-A1 (GSTA1-1) and GSTP1-1, markers for proximal and distal tubule damage, respectively, was determined. In septic patients, an almost 40-fold induction of iNOS mRNA in cells that were isolated from urine was found accompanied by a significant increase in NO metabolites in blood. The mRNA expression of iNOS was induced 34-fold after endotoxin administration. LPS-treated healthy volunteers showed a higher urinary excretion of NO metabolites compared with control subjects. Urinary NO metabolite excretion correlated with urinary GSTA1-1 excretion, indicating proximal tubule damage, whereas no distal tubular damage was observed. Co-administration of aminoguanidine reduced the upregulation of iNOS mRNA, urinary NO metabolite, and GSTA1-1 excretion, indicating that upregulation of iNOS and subsequent NO production may be responsible for renal proximal tubule damage observed.

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Section: Discussionsupporting

confidence: 83%

Upregulation of Renal Inducible Nitric Oxide Synthase during Human Endotoxemia and Sepsis Is Associated with Proximal Tubule Injury

Heemskerk

Pickkers

Bouw

et al. 2006

Clinical Journal of the American Society of Nephrology

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“…The increased expression of MMPs after an LPS challenge suggests that these proteases may influence the pathogenesis of endotoxemia. MMP-9 is released after infusion of bacterial LPS in healthy human volunteers (2). Accordingly, increased levels of pro-MMP-9 and pro-MMP-2, as well as activated forms of MMP-9, were found in the plasma of two patients with gram-negative sepsis.…”

Section: Expression Of Mmps During Sepsis and Endotoxemiamentioning

confidence: 98%

Matrix Metalloproteinases as Drug Targets in Infections Caused by Gram-Negative Bacteria and in Septic Shock

2009

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SUMMARY The mammalian immune system is optimized to cope effectively with the constant threat of pathogens. However, when the immune system overreacts, sepsis, severe sepsis, or septic shock can develop. Despite extensive research, these conditions remain the leading cause of death in intensive care units. The matrix metalloproteinases (MMPs) constitute a family of proteases that are expressed in developmental, physiological, and pathological processes and also in response to infections. Studies using MMP inhibitors and MMP knockout mice indicate that MMPs play essential roles in infection and in the host defense against infection. This review provides a brief introduction to some basic concepts of infections caused by gram-negative bacteria and reviews reports describing MMP expression and inhibition, as well as studies with MMP-deficient mice in models of infection caused by gram-negative bacteria and of septic shock. We discuss whether MMPs should be considered novel drug targets in infection and septic shock.

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“…We have investigated the interactions between iNOS, COX-2, and MMP-9, three pro-inflammatory enzymes that are induced in the vasculature during acute inflammatory reactions such as septicemia and septic shock (Beckman et al, 1990;Gomez-Jimenez et al, 1995;Beckman and Koppenol, 1996;Szabo et al, 1996;Pugin et al, 1999;Titheradge, 1999;Ermert et al, 2000;Fischer et al, 2000;Strong et al, 2000;Opdenakker, 2001;Dubois et al, 2002;Albert et al, 2003). We have studied these interactions using rat smooth muscle vascular cells, which were induced by LPS, IFN-␥, and PMA.…”

Section: Discussionmentioning

confidence: 99%

“…Reactive oxygen species produced by the same cell type lead to the chemical activation of MMP-9, and as a consequence, degradation of the vascular wall takes place (Opdenakker, 2001). Other lines of evidence from mice and humans have also correlated MMP-9 levels with shock conditions (Pugin et al, 1999;Dubois et al, 2002;Albert et al, 2003).…”

mentioning

confidence: 99%

“…Moreover, COX-2 up-regulation leads to overproduction of thromboxane and prostaglandin E 2 (PGE 2 ), which have been implicated in the pathogenesis of septic shock (Ermert et al, 2000;Fischer et al, 2000;Strong et al, 2000). In the presence of LPS, cells like neutrophils secrete considerable amounts of latent MMPs, including MMP-9 (Albert et al, 2003). Reactive oxygen species produced by the same cell type lead to the chemical activation of MMP-9, and as a consequence, degradation of the vascular wall takes place (Opdenakker, 2001).…”

mentioning

confidence: 99%

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Nitric Oxide and Cyclic GMP Increase the Expression of Matrix Metalloproteinase-9 in Vascular Smooth Muscle

Marcet‐Palacios¹,

Graham²,

Cass³

et al. 2003

J Pharmacol Exp Ther

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Interactions and possible cross talk between inducible nitricoxide synthase (iNOS), cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9), were studied in rat aortic vascular smooth muscle cells stimulated with bacterial lipopolysaccharide (LPS), interferon-␥ (IFN-␥), and phorbol 12-myristate13-acetate (PMA). The expression and activity of iNOS, COX-2, and MMP-9 were characterized at the transcriptional, protein, and enzyme activity levels. The NOS inhibitor N -nitro-L-arginine methyl ester (L-NAME) was used to investigate the effects of NO on COX-2 and MMP-9 at the transcriptional level. The measurements of mRNAs for these enzymes using realtime polymerase chain reaction (PCR) showed that COX-2 mRNA was up-regulated 2.3-fold, whereas MMP-9 mRNA upregulation was 11.7-fold in the presence of LPS, IFN-␥, and PMA. Real-time PCR results indicated that L-NAME exerted an inhibitory effect on COX-2 and MMP-9 mRNA synthesis. Both superoxide dismutase (SOD) and the SOD mimetic Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (MnTMPyP) did not modify significantly the up-regulation of these enzymes, indicating that neither superoxide nor peroxynitrite are involved in this mechanism. Furthermore, NO-mediated up-regulation of MMP-9 was cGMP-dependent since 1H-[1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase, blocked, in a concentration-dependent manner, the increased expression of MMP-9, an effect reversed by 8-bromocGMP, a soluble analog of cGMP. Our findings suggest that NO and cGMP are necessary to up-regulate the expression of MMP-9.

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Differential release of matrix metalloproteinase‐9 and nitric oxide following infusion of endotoxin to human volunteers

Abstract: The release of MMP-9, but not MMP-2 or NO, is a sensitive index of endotoxaemia in humans. MMP-9 release may contribute to the pathogenesis of sepsis via its pro-inflammatory effects on the vasculature.

Cited by 44 publications

References 24 publications

Upregulation of Renal Inducible Nitric Oxide Synthase during Human Endotoxemia and Sepsis Is Associated with Proximal Tubule Injury

Upregulation of Renal Inducible Nitric Oxide Synthase during Human Endotoxemia and Sepsis Is Associated with Proximal Tubule Injury

Matrix Metalloproteinases as Drug Targets in Infections Caused by Gram-Negative Bacteria and in Septic Shock

Nitric Oxide and Cyclic GMP Increase the Expression of Matrix Metalloproteinase-9 in Vascular Smooth Muscle

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