C1-esterase inhibitor attenuates the inflammatory response during human endotoxemia

Dorresteijn, Mirrin J.; Visser, Tjaakje; Cox, Laura A.; Bouw, Martijn P.W.J.M.; Pillay, Janesh; Koenderman, Anky H. L.; Strengers, P. F. W.; Leenen, Luke P. H.; Hoeven, Johannes G. van der; Koenderman, Leo; Pickkers, Peter

doi:10.1097/ccm.0b013e3181f17be4

Cited by 36 publications

(21 citation statements)

References 42 publications

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“…C1 inhibitor has been reported to reduce the release of circulating TNF-! in human endotoxemia (33). In the current study, administration of 250 IU/kg C1-INH reduced circulating TNF-!…”

Section: Discussionmentioning

confidence: 95%

Effects of C1 Inhibitor on Tissue Damage in a Porcine Model of Controlled Hemorrhage

Lucca¹,

Li²,

Simovic³

et al. 2012

Shock

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Activation of the complement system has been associated with tissue injury after hemorrhage and resuscitation in animals. We investigated whether administration of recombinant human C1-esterase inhibitor (rhC1-INH), a regulator of complement and contact activation systems, reduces tissue damage and cytokine release and improves metabolic acidosis in a porcine model of hemorrhagic shock. Male Yorkshire swine were assigned to experimental groups and subjected to controlled, isobaric hemorrhage to a target mean arterial pressure of 35 mmHg. Hypotension was maintained for 20 min followed by a bolus intravenous injection of rhC1-INH or vehicle; animals were then observed for 3 h. Blood chemistry and physiologic parameters were recorded. Lung and small intestine tissue samples were subjected to histopathologic evaluation and immunohistochemistry to determine the extent of injury and deposition of complement proteins. Cytokine levels and quantitative assessment of renal and hepatic function were measured via enzyme-linked immunosorbent assay and chemistry analyzer, respectively. Pharmacokinetics of rhC1-INH revealed dose proportionality for maximum concentration, half-life, and the time span in which the functional C1-INH level was greater than 1 IU/mL. Recombinant human C1-INH significantly reduced renal, intestinal, and lung tissue damage in a dose-dependent manner (100 and 250 IU/kg). In addition, rhC1-INH (250 IU/kg) markedly improved hemorrhage-induced metabolic acidosis and circulating tumor necrosis factor α. The tissue-protective effects of rhC1-INH appear to be related to its ability to reduce tissue complement activation and deposition. Recombinant human C1-INH decreased tissue complement activation and deposition in hemorrhaged animals, improved metabolic acidosis, reduced circulating tumor necrosis factor α, and attenuated tissue damage in this model. The observed beneficial effects of rhC1-INH treatment on tissue injury 20 min into severe hypotension present an attractive model of low-volume resuscitation, particularly in situations with a restrictive medical logistical footprint.

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“…C1 inhibitor has been reported to reduce the release of circulating TNF-! in human endotoxemia (33). In the current study, administration of 250 IU/kg C1-INH reduced circulating TNF-!…”

Section: Discussionmentioning

confidence: 95%

Effects of C1 Inhibitor on Tissue Damage in a Porcine Model of Controlled Hemorrhage

Lucca¹,

Li²,

Simovic³

et al. 2012

Shock

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“…The sample size calculation is based on damping of the increase in serum IL-6 concentration by 30% in the C1-INH group, compared to the placebo group [21,30,31]. With an expected standard deviation of 50% [30,31] and a relevant decrease of IL-6 concentration of 30% [21,30,31], 35 patients in each sample-group (C1-INH or placebo) are needed to find a statistically significant difference (power 80%, Type 1 error rate 0.05).…”

Section: Methodsmentioning

confidence: 99%

“…With an expected standard deviation of 50% [30,31] and a relevant decrease of IL-6 concentration of 30% [21,30,31], 35 patients in each sample-group (C1-INH or placebo) are needed to find a statistically significant difference (power 80%, Type 1 error rate 0.05).…”

Section: Methodsmentioning

confidence: 99%

“…A promising intervention to attenuate the systemic innate immune response is the treatment with a high concentration of C1-esterase inhibitor (C1-INH) [21]. C1-INH is an acute phase protein, produced by the liver in response to inflammatory conditions.…”

Section: Introductionmentioning

confidence: 99%

“…Apart from the modulation of the these systems, C1-INH has also been shown to attenuate systemic inflammation independently of the activation of complement [24]. In fact, Dorresteijn et al showed that administration of C1-INH, in a 'human endotoxemia model', attenuates the release of pro-inflammatory cytokines, including IL-6, in healthy male volunteers [21]. This model evokes a systemic inflammatory response in the absence of complement activation [21,25].…”

Section: Introductionmentioning

confidence: 99%

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The effect of C1-esterase inhibitor on systemic inflammation in trauma patients with a femur fracture - The CAESAR study: study protocol for a randomized controlled trial

Heeres

Visser

Wessem

et al. 2011

Trials

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BackgroundSystemic inflammation in response to a femur fracture and the additional fixation is associated with inflammatory complications, such as acute respiratory distress syndrome and multiple organ dysfunction syndrome. The injury itself, but also the additional procedure of femoral fixation induces a release of pro-inflammatory cytokines such as interleukin-6. This results in an aggravation of the initial systemic inflammatory response, and can cause an increased risk for the development of inflammatory complications. Recent studies have shown that administration of the serum protein C1-esterase inhibitor can significantly reduce the release of circulating pro-inflammatory cytokines in response to acute systemic inflammation.ObjectiveAttenuation of the surgery-induced additional systemic inflammatory response by perioperative treatment with C1-esterase inhibitor of trauma patients with a femur fracture.MethodsThe study is designed as a double-blind randomized placebo-controlled trial. Trauma patients with a femur fracture, Injury Severity Score ≥ 18 and age 18-80 years are included after obtaining informed consent. They are randomized for administration of 200 U/kg C1-esterase inhibitor intravenously or placebo (saline 0.9%) just before the start of the procedure of femoral fixation. The primary endpoint of the study is Δ interleukin-6, measured at t = 0, just before start of the femur fixation surgery and administration of C1-esterase inhibitor, and t = 6, 6 hours after administration of C1-esterase inhibitor and the femur fixation.ConclusionThis study intents to identify C1-esterase inhibitor as a safe and potent anti-inflammatory agent, that is capable of suppressing systemic inflammation in trauma patients. This might facilitate early total care procedures by lowering the risk of inflammation in response to the surgical intervention. This could result in increased functional outcomes and reduced health care related costs.Trial registrationclinicaltrials.gov NCT01275976 (January 12th 2011)

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C1‐Inhibitor

Over

Kramer

Koenderman

et al. 2012

Production of Plasma Proteins for Therapeutic Use

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C1-esterase inhibitor attenuates the inflammatory response during human endotoxemia

Abstract: This study is the first to demonstrate that C1-esterase inhibitor exerts anti-inflammatory effects in the absence of classic complement activation in humans.

Cited by 36 publications

References 42 publications

Effects of C1 Inhibitor on Tissue Damage in a Porcine Model of Controlled Hemorrhage

Effects of C1 Inhibitor on Tissue Damage in a Porcine Model of Controlled Hemorrhage

The effect of C1-esterase inhibitor on systemic inflammation in trauma patients with a femur fracture - The CAESAR study: study protocol for a randomized controlled trial

C1‐Inhibitor

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