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

Abstract

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.

Complement depletion protects lupus-prone mice from ischemia-reperfusion-initiated organ injury

“…Consistent with previous studies (11,55), we showed that complement-depleted mice are also protected from remote lung damage after mesenteric IR. In particular, we demonstrate that intestinal tissue damage is significantly reduced in complement-depleted MRL/lpr compared with complement-sufficient MRL/lpr mice.…”

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

“…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). We also found that decay-accelerating factor mitigates hemorrhage-associated intestinal and lung tissue damage and hyperkalemia in a controlled hemorrhage swine model (3).…”

“…Treatments are aimed at restoring intravascular volume and maintaining vital organ perfusion (1). 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.…”

“…This vasoconstriction also drives blood away from the intestines causing functional intestinal ischemia (3), triggering immuneinflammatory responses rendering the body particularly susceptible to deleterious complications (1). Morbidity and mortality following hemorrhage result from the involvement of multiple inflammatory pathways, including complement.…”

last Overpressure Induced Pulmonary and Intestinal Damage is Ameliorated by Post-injury Decay Accelerating Factor Injection

“…Blast overpressure; Complement activation; Decay accelerating factor; Lung; Rat James E Campbell 1 , Thomas Oh 1 , Brady J Hurtgen 1 , Debra M Niemeyer 1 , Forest R Sheppard 2 and Jurandir J Dalle Lucca 1 * integrity, reducing tau phosphorylation and decreasing cytotoxic edema [16]. DAF administration following hemorrhage and/or I/R also has been shown to limit lung and intestine tissue damage, decrease complement activation and tissue deposition, decrease IL-6 production and improve survival chances [17][18][19][20]. We therefore hypothesized that DAF administration would ameliorate pulmonary and intestinal damage commonly produced by blast injury.…”