Activated protein C improves the visceral microcirculation by attenuating the leukocyte-endothelial interaction in a rat lipopolysaccharide model

Iba, Toshiaki; Kidokoro, Akio; Fukunaga, Masaki; Nagakari, Kunihiko; Shirahama, Akihiko; Ida, Yukiko

doi:10.1097/01.ccm.0000153415.04995.88

Cited by 83 publications

(53 citation statements)

References 26 publications

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“…The effect of rhaPC on microcirculation in vivo was recently demonstrated in a rat model utilizing intravital microscopy following LPS versus LPS plus rhaPC injection [31]. At one, two, and three hours post-injection of LPS alone or LPS plus either low or high-dose rhaPC, the mesenteric microcirculation was examined under intravital microscopy.…”

Section: Introductionmentioning

confidence: 99%

The Apoptotic Pathway as a Therapeutic Target in Sepsis

Wesche-Soldato¹,

Swan²,

Chung³

et al. 2007

CDT

139

114

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Recent research has yielded many interesting and potentially important therapeutic targets in sepsis. Specifically, the effects of antagonistic anti-cytokine therapies (tumor necrosis factor-alpha [TNF-α], interleukin-1 [IL-1]) and anti-endotoxin strategies utilizing antibodies against endotoxin or endotoxin receptor/carrier molecules (anti-CD14 or anti-LPS-binding protein) have been studied. Unfortunately, these approaches often failed clinically, and in many cases, the efficacy of these treatments was dependent on the severity of sepsis. Recently, clinical trials using insulin to lock blood glucose levels and activated protein C treatment have showed that while they provided some survival benefit, their efficacy does not appear to be predicated solely upon anti-inflammatory effects. Here, we will review work done in animal models of polymicrobial sepsis and clinical findings that support the hypothesis that apoptosis in the immune system is a pathologic event in sepsis that can be a therapeutic target. In this respect, experimental studies looking at the septic animal suggest that loss of lymphocytes during sepsis may be due to dysregulated apoptosis and that this appears to be brought on by a variety of mediators effecting 'intrinsic' as well as 'extrinsic' cell death pathways. From a therapeutic perspective this has provided a number of novel targets for clinically successful current, as well as future therapies, such as caspases (caspase inhibition/protease inhibition), pro-apoptotic protein-expression (via administration and/or over-expression of Bcl-2) and the death receptor family Fas-FasL (via. FasFP [fas fusion protein] and the application of siRNA against a number proapoptotic factors).

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Section: Introductionmentioning

confidence: 99%

The Apoptotic Pathway as a Therapeutic Target in Sepsis

Wesche-Soldato¹,

Swan²,

Chung³

et al. 2007

CDT

139

114

View full text Add to dashboard Cite

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“…Although our study does not allow any conclusions regarding the risk of hemorrhage and the safety of rhAPC in septic neonates because of a limited number of animals and a short observation period, we speculate that potential differences in bleeding events may have been due to the different APC dosing regimen employed in our study (infusion of 24 µg/kg/h) versus a bolus of 2 and 5 mg/kg used by Iba and colleagues. 16 This regimen has been described by Russo and colleagues 24 who treated pediatric cancer patients with severe ongoing sepsis with 24 µg/kg/h. Although these patients had a low platelet count (mean 9000/nl), none of them experienced bleeding events during treatment.…”

Section: Discussionmentioning

confidence: 99%

“…The release of these pro-inflammatory mediators can result in a vasodilatory/vasoconstrictory imbalance and subsequent microcirculatory impairment that improves after the application of rhAPC in an animal model of septic shock. 16 Since microcirculation is one of the aspects of sepsis that has received less attention than others, we designed a study which focused on the important pathophysiological problem of microcirculatory impairment during septic shock. We hypothesized that treatment with rhAPC at least partly reverses these deleterious effects of endotoxemia.…”

Section: Introductionmentioning

confidence: 99%

Protein C preserves microcirculation in a model of neonatal septic shock

Fischer

Nold

Nold-Petry

et al. 2009

VHRM

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Objectives: Sepsis remains a disease with a high mortality in neonates. Microcirculatory impairment plays a pivotal role in the development of multiorgan failure in septic newborns. The hemodynamic effects of recombinant activated protein C (rhAPC) were tested in an animal model of neonatal septic shock focusing on intestinal microcirculation. Materials and methods: Endotoxic shock was triggered by intravenous application of Escherichia coli lipopolysaccarides in newborn piglets. Thereafter, five animals received a continuous infusion of 24 µg/kg/h rhAPC, and five received vehicle for control. Over the course of three hours, intestinal microcirculation was assessed by intravital microscopy every 30 min. Macrocirculation and blood counts were monitored simultaneously. Results: After a short hypotensive period in all animals, the arterial blood pressure returned to baseline in the rhAPC-treated piglets, whereas the hypotension became increasingly severe in the controls. By 90 min, mean blood pressure in the controls was significantly lower than in the treatment group. Similar observations were made regaring microcirculation. After an early impairment in all study animals, functional capillary density and intestinal microcirculatory red blood cell velocity and red blood cell flow recovered in the rhAPC group, but deteriorated further in the control piglets. Conclusion: Recombinant activated protein C protects macro-and microcirculation from endotoxic shock.

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“…To be consistent with reference literature and our previous experiments, APC was given as a bolus instead of an infusion. 6,9 Intravital fluorescence microscopy We performed intravital fluorescence microscopy at zero, one, and two hours following endotoxin/ placebo (saline) administration (for details of the experimental settings please refer to our previous study). 10 The examination was directed to one venule of the mesentery of the terminal ileum.…”

Section: General Protocolmentioning

confidence: 99%

Effects of activated protein C on the mesenteric microcirculation and cytokine release during experimental endotoxemia

Lehmann

Scheibe

Schade

et al. 2008

Can J Anesth/J Can Anesth

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Purpose: Activated protein C (APC) is the first anti-inflammatory drug to be approved for the treatment of severe sepsis. However, the underlying mechanisms are not completely elucidated. Therefore, the aim of our study was to evaluate the effects of APC on the microcirculation (mesenteric leukocyteendothelial interaction, plasma extravasation) using intravital microscopy (IVM) and on cytokine release during experimental endotoxemia in rats. Methods: We divided forty, male, Lewis rats into four groups (n = 10 per group): Controls, LPS (15 mg·kg -1 lipopolysaccharide iv), APC (2 mg·kg -1 APC iv), and LPS+APC. We determined mesenteric leukocyte-endothelial interactions and plasma extravasation at zero, one and two hours following administration of LPS and APC by IVM. Plasma levels of tumour necrosis factor-α, IL-1β, interleukin (IL)-6, and IL-10 were measured at zero and at two hours.Results: Leukocyte adherence (-74%) and plasma extravasation (-28%) during endotoxemia were diminished significantly following APC treatment, compared to untreated LPS animals (P = 0.0001 and P = 0.0004, respectively). Interleukin-1ß release was also significantly reduced by APC treatment (2567.4 ± 320.9 pg·mL -1 in the LPS group vs 1626.1 ± 427.2 pg·mL -1 in the LPS+APC group; P = 0.001). Conclusion:These rodent experiments showed that APC treatment significantly attenuated deterioration of the mesenteric microcirculation and systemic IL-1ß release caused by endotoxin challenge. Because of the crucial role of the microcirculation in ongoing sepsis pathogenesis and multiple organ dysfunction syndrome, these effects may be of clinical importance.

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Activated protein C improves the visceral microcirculation by attenuating the leukocyte-endothelial interaction in a rat lipopolysaccharide model

Abstract: Recombinant human activated protein C demonstrated a protective effect on microcirculation through the inhibition of leukocyte-endothelial interaction and suppression of inflammatory cytokine production.

Cited by 83 publications

References 26 publications

The Apoptotic Pathway as a Therapeutic Target in Sepsis

The Apoptotic Pathway as a Therapeutic Target in Sepsis

Protein C preserves microcirculation in a model of neonatal septic shock

Effects of activated protein C on the mesenteric microcirculation and cytokine release during experimental endotoxemia

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