Detrimental effects of complement activation in hemorrhagic shock

Abstract

The complement system has been implicated in early inflammatory events and a variety of shock states. In rats, we measured complement activation after hemorrhage and examined the hemodynamic and metabolic effects of complement depletion before injury and worsening of complement activation after hemorrhage and resuscitation [with a carboxypeptidase N inhibitor (CPNI), which blocks the clearance of C5a]. Rats were bled to a mean arterial pressure of 30 mmHg for 50 min and were then resuscitated for 2 h. Shock resulted in significant evidence of complement consumption, with serum hemolytic activity being reduced by 33% (P < 0.05). Complement depletion before injury did not affect hemorrhage volume (complement depleted = 28 +/- 1 ml/kg, complement intact = 29 +/- 1 ml/kg, P = 0.74) but improved postresuscitation mean arterial pressure by 37 mmHg (P < 0.05) and serum bicarbonate levels (complement depleted = 22 +/- 3 meq/ml, complement intact = 13 +/- 8 meq/ml, P < 0.05). Pretreatment with CPNI was lethal in 80% of treated animals vs. the untreated hemorrhaged group in which no deaths occurred (P < 0.05). In this model of hemorrhagic shock, complement activation appeared to contribute to progressive hypotension and metabolic acidosis seen after resuscitation. The lethality of CPNI during acute blood loss suggests that the anaphylatoxins are important in the pathophysiological events involved in hemorrhagic shock.

Complement Component C5a Mediates Hemorrhage-Induced Intestinal Damage

“…In other animal models, C5a receptor antagonists attenuate the cobra venom factor mediated or xenotransplant induced blood pressure changes (40,41). However, in other hemorrhage studies, complement depletion did not significantly alter mean arterial pressures within the first 2 hr after hemorrhage (15). Thus, it is possible that administration of the C5 receptor antagonist prevents the hemorrhage-induced hypotension.…”

“…C5a in rat models of hemorrhage or hemorrhage with vascular clamping prevented decrease in mean arterial pressure and the appearance of acidosis, intestinal permeability and tissue damage (15,19). Our studies extend these observations and suggest the recorded beneficiary effects of complement inhibition on physiological parameters such as mean arterial blood pressure and acid-base balance are probably due to the preceding inhibition of the tissue inflammatory response and damage.…”

“…. Depletion of complement prevented clinical signs of hemorrhagic shock (15) and hemodynamic changes were prevented with complement inhibition with soluble complement receptor 1 (sCR1) (3,16) or C1-inhibitor (17). Recent studies showed that anti-C5 antibody treatment decreases the resuscitation fluid volume required to improve mean arterial pressure (18).…”

“…It is critical therefore, to identify the specific molecules involved in the complement mediated damage in order to achieve targeted complement inhibition. Excess of C5a is lethal in a rat hemorrhage model (15) and a C5a receptor antagonist decreased the inflammatory response within rat intestine and lungs in a model of intestinal ischemia with hemorrhage (19). However, it is unclear if inhibition of C5a activity is sufficient to prevent or attenuate intestinal damage and its sequelae.…”

Femoral Nailing-related Coagulopathy Determined by First-hit Magnitude

“…Hemorrhagic shock also activates the inflammatory system and is a well-known cofactor of lung injuries [3,16,28,29,47,60,68,77,79]. The effect of additional hemorrhage on the fat embolisminduced changes in the presence of a pulmonary contusion has not been investigated before.…”