Microhemodynamic and cellular mechanisms of activated protein C action during endotoxemia*

Hoffmann, Johannes N.; Vollmar, Brigitte; Laschke, Matthias W.; Inthorn, D.; Fertmann, Jan; Schildberg, F. W.; Menger, Michael D.

doi:10.1097/01.ccm.0000120058.88975.42

Cited by 137 publications

(93 citation statements)

References 39 publications

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“…Studies have also suggested that low PC levels are predictive of early death in a rat model of polymicrobial sepsis (14). Exogenous administration of activated PC (APC) has been shown to reduce ischemia-reperfusion-induced renal injury and to attenuate microcirculatory dysfunction (16,26). These studies support the significance of the PC pathway in reducing organ dysfunction, which is further exemplified by the efficacy of recombinant human APC in the treatment of severe sepsis (1).…”

mentioning

confidence: 65%

Activated protein C ameliorates LPS-induced acute kidney injury and downregulates renal INOS and angiotensin 2

Gupta

Rhodes

Berg³

et al. 2007

American Journal of Physiology-Renal Physiology

133

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Grinnell BW. Activated protein C ameliorates LPS-induced acute kidney injury and downregulates renal INOS and angiotensin 2. Am J Physiol Renal Physiol 293: F245-F254, 2007. First published April 4, 2007; doi:10.1152/ajprenal.00477.2006.-Endothelial dysfunction contributes significantly to acute renal failure (ARF) during inflammatory diseases including septic shock. Previous studies have shown that activated protein C (APC) exhibits anti-inflammatory properties and modulates endothelial function. Therefore, we investigated the effect of APC on ARF in a rat model of endotoxemia. Rats subjected to lipopolysaccharide (LPS) treatment exhibited ARF as illustrated by markedly reduced peritubular capillary flow and increased serum blood urea nitrogen (BUN) levels. Using quantitative two-photon intravital microscopy, we observed that at 3 h post-LPS treatment, rat APC (0.1 mg/kg iv bolus) significantly improved peritubular capillary flow [288 Ϯ 15 m/s (LPS) vs. 734 Ϯ 59 m/s (LPSϩAPC), P ϭ 0.0009, n ϭ 6], and reduced leukocyte adhesion (P ϭ 0.003) and rolling (P ϭ 0.01) compared with the LPS-treated group. Additional experiments demonstrated that APC treatment significantly improved renal blood flow and reduced serum BUN levels compared with 24-h post-LPS treatment. Biochemical analysis revealed that APC downregulated inducible nitric oxide synthase (iNOS) mRNA levels and NO by-products in the kidney. In addition, APC modulated the renin-angiotensin system by reducing mRNA expression levels of angiotensin-converting enzyme-1 (ACE1), angiotensinogen, and increasing ACE2 mRNA levels in the kidney. Furthermore, APC significantly reduced ANG II levels in the kidney compared with the LPS-treated group. Taken together, these data suggest that APC can suppress LPS-induced ARF by modulating factors involved in vascular inflammation, including downregulation of renal iNOS and ANG II systems. Furthermore, the data suggest a potential therapeutic role for APC in the treatment of ARF.two-photon intravital microscopy; endotoxin ACUTE RENAL FAILURE (ARF) is a common complication in septic patients, with an incidence reported to be ϳ20 -50% (35, 36). The mortality rate associated with ARF in septic patients is 75% compared with 45% in patients without sepsis (38). Despite advances in supportive care with appropriate antibiotic administration and maintenance of systemic hemodynamics, coupled with the lack of proven pharmacological intervention, mortality rates for ARF patients have remained unchanged (50).During sepsis, a broad array of soluble factors are altered including the serine protease, protein C (PC). Reduction in plasma levels of PC have been shown to be prognostic for sepsis and sepsis severity (reviewed in Ref. 11). Studies have also suggested that low PC levels are predictive of early death in a rat model of polymicrobial sepsis (14). Exogenous administration of activated PC (APC) has been shown to reduce ischemia-reperfusion-induced renal injury and to attenuate microcirculatory dysfunction (16,26). These studies support...

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mentioning

confidence: 65%

Activated protein C ameliorates LPS-induced acute kidney injury and downregulates renal INOS and angiotensin 2

Gupta

Rhodes

Berg³

et al. 2007

American Journal of Physiology-Renal Physiology

133

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“…11 Moreover, activated protein C has been shown to improve capillary perfusion and to protect from lipopolysaccharide-mediated microcirculatory dysfunction in animal models. 38 …”

Section: Treatment Effect Of Drotrecogin Alfa (Activated)mentioning

confidence: 99%

Prognostic Value of Plasma N-Terminal Pro-Brain Natriuretic Peptide in Patients With Severe Sepsis

et al. 2005

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Background-Increased plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) have been identified as predictors of cardiac dysfunction and prognosis in congestive heart failure and ischemic heart disease. In severe sepsis patients, however, no information is available yet about the prognostic value of natriuretic peptides. Therefore, the aim of the present study was to determine the role of the N-terminal prohormone forms of ANP (NT-proANP) and BNP (NT-proBNP) in the context of outcome of septic patients. Furthermore, the effect of treatment with recombinant human activated protein C [drotrecogin alfa (activated)] on plasma levels of natriuretic peptides in severe sepsis was evaluated. Methods and Results-Fifty-seven patients with severe sepsis were included. Levels of NT-proANP and NT-proBNP were measured on the second day of sepsis by ELISA. Septic patients with NT-proBNP levels Ͼ1400 pmol/L were 3.9 times more likely (relative risk [RR], 3.9; 95% CI, 1.6 to 9.7) to die from sepsis than patients with lower NT-proBNP values (PϽ0.01). NT-proANP levels, however, were not predictive of survival in our patient population. A highly significant correlation was found between troponin I levels and plasma concentrations of NT-proBNP in septic patients (rϭ0.68, PϽ0.0001). In addition, troponin I significantly accounted for the variation in NT-proBNP levels (PϽ0.0001), suggesting an important role for NT-proBNP in the context of cardiac injury and dysfunction in septic patients. Twenty-three septic patients who received treatment with drotrecogin alfa (activated) presented with significantly lower concentrations of NT-proANP, NT-proBNP, and troponin I compared with patients not receiving drotrecogin alfa (activated). Conclusions-NT-proBNP

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“…It is converted to the activated form (APC) under conditions of thrombotic and inflammatory stress by thrombin in complex with endothelial surface thrombomodulin. APC functions as a feedback inhibitor of thrombin generation (23) and has receptor-mediated anti-inflammatory and cytoprotective effects through interaction with the endothelial PC receptor (EPCR) (24 -26); recent studies have also shown that APC can inhibit leukocyte rolling and adhesion (27,28). APC plays a fundamental role in a coordinated system for controlling thrombosis, limiting inflammatory responses, and potentially decreasing endothelial cell apoptosis in response to inflammatory cytokines and ischemia (24).…”

mentioning

confidence: 99%

Role of Protein C in Renal Dysfunction after Polymicrobial Sepsis

Gupta

Berg²,

Gerlitz³

et al. 2007

Journal of the American Society of Nephrology

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Protein C (PC) plays an important role in vascular function, and acquired deficiency during sepsis is associated with increased mortality in both animal models and in clinical studies. This study explored the consequences of PC suppression on the kidney in a cecal ligation and puncture model of polymicrobial sepsis. This study shows that a rapid drop in PC after sepsis is strongly associated with an increase in blood urea nitrogen, renal pathology, and expression of known markers of renal injury, including neutrophil gelatinase-associated lipocalin, CXCL1, and CXCL2. The endothelial PC receptor, which is required for the anti-inflammatory and antiapoptotic activity of activated PC (APC), was significantly increased after cecal ligation and puncture as well as in the microvasculature of human kidneys after injury. Treatment of septic animals with APC reduced blood urea nitrogen, renal pathology, and chemokine expression and dramatically reduced the induction of inducible nitric oxide synthase and caspase-3 activation in the kidney. The data demonstrate a clear link between acquired PC deficiency and renal dysfunction in sepsis and suggest a compensatory upregulation of the signaling receptor. Moreover, these data suggest that APC treatment may be effective in reducing inflammatory and apoptotic insult during sepsis-induced acute renal failure.

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Microhemodynamic and cellular mechanisms of activated protein C action during endotoxemia*

Cited by 137 publications

References 39 publications

Activated protein C ameliorates LPS-induced acute kidney injury and downregulates renal INOS and angiotensin 2

Activated protein C ameliorates LPS-induced acute kidney injury and downregulates renal INOS and angiotensin 2

Prognostic Value of Plasma N-Terminal Pro-Brain Natriuretic Peptide in Patients With Severe Sepsis

Role of Protein C in Renal Dysfunction after Polymicrobial Sepsis

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