C5-blocking antibody reduces fluid requirements and improves responsiveness to fluid infusion in hemorrhagic shock managed with hypotensive resuscitation

Peckham, Russell M.; Handrigan, Michael; Bentley, Timothy B.; Falabella, Michael; Chrovian, Andrew D.; Stahl, Gregory L.; Tsokos, George C.

doi:10.1152/japplphysiol.00917.2006

Cited by 19 publications

(19 citation statements)

References 36 publications

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“…14 In this study, we demonstrate that infusion of DAF in swine after 20 minutes of severe hypotension mitigated gut and lung injury and reduced hyperkalemia. We propose that DAF infusion may represent a modality of pharmacologic resuscitation or adjunct to small volume fluid resuscitation.…”

Section: Introductionmentioning

confidence: 55%

“…15 Treatments are aimed at restoring intravascular volume and maintaining vital organ perfusion. 11 Complement activation has been implicated during hemorrhage shock in rats 14 and swine, 16 and it relates to morbidity and mortality of trauma patients due to severe inflammatory tissue destruction. 17 Previously we showed that complement inhibition decreased resuscitation fluid requirements in hemorrhagic shock in rats.…”

Section: Discussionmentioning

confidence: 99%

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Decay-Accelerating Factor Mitigates Controlled Hemorrhage-Instigated Intestinal and Lung Tissue Damage and Hyperkalemia in Swine

Lucca¹,

Simovic²,

Li³

et al. 2011

Journal of Trauma: Injury, Infection &Amp; Critical Care

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Background Activation of complement system has been associated with tissue injury after hemorrhage and resuscitation in rats and swine. This study investigated whether administration of human recombinant decay-accelerating factor (DAF; a complement regulatory protein that inhibits classical and alternative pathways) reduces tissue damage in a porcine model of hemorrhagic shock. Methods Male Yorkshire swine assigned to four groups were subjected to controlled, isobaric hemorrhage over 15 minutes to a target mean arterial pressure of 35 mmHg. Hypotension was maintained for 20 minutes followed by a bolus intravenous injection of DAF or vehicle then animals were observed for 200 minutes. Blood chemistry and physiological parameters were recorded. Tissue samples from lung and small intestine were subjected to histopathological evaluation and detection of tissue deposition of complement proteins by immunohistochemistry and Western blot analyses. Results Administration of DAF significantly reduced intestinal and lung tissue damage in a dose-dependent manner (5, 25, and 50 µg/kg). In addition, DAF treatment improved hemorrhage-induced hyperkalemia. The protective effects of DAF appear to be related to its ability to reduce tissue complement activation and deposition on affected tissues. Conclusions DAF treatment decreased tissue complement activation and deposition in hemorrhaged animals and attenuated tissue damage at 200 minutes post treatment. The observed beneficial effects of DAF treatment on tissue injury after 20 minutes of severe hypotension presents an attractive model of small volume resuscitation, particularly in situations with a restrictive medical logistical footprint such as far-forward access to first responders in the battlefield or in remote rural or mountainous environments.

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Section: Introductionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Decay-Accelerating Factor Mitigates Controlled Hemorrhage-Instigated Intestinal and Lung Tissue Damage and Hyperkalemia in Swine

Lucca¹,

Simovic²,

Li³

et al. 2011

Journal of Trauma: Injury, Infection &Amp; Critical Care

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“…Complement activation has been implicated during hemorrhage in rats (8) and swine (3,10) and relates to morbidity and mortality of trauma patients because of severe inflammatory tissue destruction (4). Peckham et al (8) showed that complement inhibition decreased resuscitation fluid requirements of hemorrhaged rats. We demonstrated that decayaccelerating factor attenuated C-reactive proteinYenhanced tissue damage in murine mesenteric ischemia/reperfusion (5) and protected neurons from hypoxia-mediated injury in vitro (11).…”

Section: Discussionmentioning

confidence: 99%

“…We have implicated complement activation in reperfusion-induced intestinal injury (5) as well as hemorrhage-induced inflammation and intestinal damage in mice (6). Complement inhibition has been shown to be an effective therapeutic strategy in mice for intestinal ischemia/ reperfusion (5, 7) as well as in rats for traumatic and hemorrhagic shock (8).…”

Section: Introductionmentioning

confidence: 99%

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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“…Previous studies showed that systemic blockade of central complement components, C3, C5 or C5a, attenuated hemorrhage-induced intestinal damage (3, 30-31). However, each of these systemic inhibitors increases the risk of sepsis by blocking multiple complement activation pathways.…”

Section: Discussionmentioning

confidence: 99%

Macrophage-Produced IL-12p70 Mediates Hemorrhage-Induced Damage in a Complement-Dependent Manner

Hylton

Hoffman²,

Rooijen³

et al. 2011

Shock

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Hemorrhage and hemorrhagic shock instigate intestinal damage and inflammation. Multiple components of the innate immune response, including complement and neutrophil infiltration, are implicated in this pathology. To investigate the interaction of complement activation and other components of the innate immune response during hemorrhage, we treated mice post-hemorrhage with CR2-fH, a targeted inhibitor of the alternative complement pathway and assessed intestinal damage and inflammation 2 h after hemorrhage. In wildtype mice, CR2-fH attenuated hemorrhage-induced, mid-jejunal damage and inflammation as determined by decreased mucosal damage, macrophage infiltration, LTB4, IL-12p40, and TNF-α production. The critical nature of intestinal macrophage infiltration and activation in the response to hemorrhage was further determined using mice pre-treated with clodronate containing liposomes. The absence of either macrophages or IL-12p70 attenuated intestinal damage. These data suggest that complement activation and macrophage infiltration with IL-12p70 production are critical to hemorrhage induced mid-jejunal damage and inflammation.

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C5-blocking antibody reduces fluid requirements and improves responsiveness to fluid infusion in hemorrhagic shock managed with hypotensive resuscitation

Cited by 19 publications

References 36 publications

Decay-Accelerating Factor Mitigates Controlled Hemorrhage-Instigated Intestinal and Lung Tissue Damage and Hyperkalemia in Swine

Decay-Accelerating Factor Mitigates Controlled Hemorrhage-Instigated Intestinal and Lung Tissue Damage and Hyperkalemia in Swine

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

Macrophage-Produced IL-12p70 Mediates Hemorrhage-Induced Damage in a Complement-Dependent Manner

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