Immunopathology of Terminal Complement Activation and Complement C5
Blockade Creating a Prosurvival and Organ-protective Phenotype in Trauma
Abstract
Background and Purpose: Traumatic hemorrhage (TH) is the leading cause
of potentially preventable deaths that occur during the prehospital
phase of care. No effective pharmacological therapeutics are available
for critical TH patients yet. Here, we identify terminal complement
activation (TCA) as a therapeutic target in combat casualties and
evaluate the efficacy of TCA inhibitor (nomacopan) on organ damage and
survival in vivo. Experimental Approach: Complement activation products
and cytokines were analyzed in plasma from 54 combat casualties, and the
correlations between activated complement pathway(s) and the clinical
outcomes in trauma patients were assessed. Nomacopan was administrated
to rats subjected to lethal TH (blast injury and hemorrhagic shock).
Effects of nomacopan on TH were determined using survival rate, organ
damage, physiologic parameters, and laboratory profiles. Key Results:
Early TCA was found to be associated with systemic inflammatory
responses and clinical outcomes in this trauma cohort. Lethal TH in the
untreated rats induced early TCA that correlated with severity of tissue
damage and mortality. The addition of nomacopan to a damage control
resuscitation (DCR) protocol significantly inhibited TCA, decreased
local and systemic inflammatory responses, improved hemodynamics and
metabolism, attenuated tissue and organ damage, and increased survival.
Conclusion and Implications: Our findings reveal that early TCA
represents a rational therapeutic target for trauma patients; and
nomacopan as a prosurvival and organ-protective drug, could emerge as a
promising adjunct to DCR that may significantly reduce the morbidity and
mortality in severe TH patients while awaiting transport to critical
care facilities.