Preclinical and clinical studies have shown that traumatic
hemorrhage (TH) induces early
complement cascade activation, leading to
inflammation-associated
multiple-organ dysfunction syndrome (
MODS). Several previous studies have demonstrated the beneficial effects of
complement inhibition in anesthetized (unconscious) animal models of
hemorrhage.
Anesthetic agents profoundly affect the immune response, microcirculation response, and coagulation patterns and thereby may confound the TH research data acquired. However, no studies have addressed the effect of
complement inhibition on
inflammation-driven
MODS in a conscious model of
hemorrhage. This study investigated whether early administration of
decay-accelerating factor (CD55/DAF, a
complement C3/C5 inhibitor) alleviates
hemorrhage-induced organ damage and how DAF modulates
hemorrhage-induced organ damage. DAF was administered to unanesthetized male Sprague Dawley rats subjected to pressure-controlled
hemorrhage followed by a prolonged (4 h) hypotensive
resuscitation with or without
lactated Ringer's (LR). We assessed DAF effects on organ protection, tissue levels of
complement synthesis and activation, T lymphocyte infiltration, fluid
resuscitation requirements, and
metabolic acidosis.
Hemorrhage with (HR) or without (H) LR
resuscitation resulted in significantly increased C3, C5a, and
C5b-9 deposition in the lung and intestinal tissues. HR rats had significantly higher tissue levels of complement activation/deposition (particularly C5a and C5b-9 in the lung tissues), a higher but not significant amount of C3 and
C5b-9 pulmonary microvascular deposition, and relatively severe injury in the lung and intestinal tissues compared to H rats. DAF treatment significantly reduced tissue
C5b-9 formation and C3 deposition in the H or HR rats and decreased tissue levels of C5a and C3
mRNA in the HR rats. This treatment prevented the injury of these organs, improved
metabolic acidosis, reduced fluid
resuscitation requirements, and decreased T-cell infiltration in lung tissues. These findings suggest that DAF has the potential as an organ-protective adjuvant treatment for TH during prolonged damage control
resuscitation.