Protective Effects of the Complement Inhibitor Compstatin CP40 in Hemorrhagic Shock

Abstract

Trauma-induced hemorrhagic shock (HS) plays a decisive role in the development of immune, coagulation, and organ dysfunction often resulting in a poor clinical outcome. Imbalanced complement activation is intricately associated with the molecular danger response and organ damage after HS. Thus, inhibition of the central complement component C3 as turnstile of both inflammation and coagulation is hypothesized as a rational strategy to improve the clinical course after HS.Applying intensive care conditions, anaesthetized, monitored, and protectively ventilated non-human primates (NHP; cynomolgus monkeys) received a pressure-controlled severe HS (60 min at MAP 30 mmHg) with subsequent volume resuscitation. Thirty min after HS, animals were randomly treated with either an analog of the C3 inhibitor compstatin (i.e., Cp40) in saline (n = 4) or with saline alone (n = 4). The observation period lasted 300 min after induction of HS.We observed improved kidney function in compstatin Cp40-treated animals after HS as determined by improved urine output, reduced damage markers and a tendency of less histopathological signs of acute kidney injury. Sham-treated animals revealed classical signs of mucosal edema, especially in the ileum and colon reflected by worsened microscopic intestinal injury scores. In contrast, Cp40-treated HS animals exhibited only minor signs of organ edema and significantly less intestinal damage. Furthermore, early systemic inflammation and coagulation dysfunction were both ameliorated by Cp40.The data suggest that therapeutic inhibition of C3 is capable to significantly improve immune, coagulation and organ function and to preserve organ-barrier integrity early after traumatic HS. C3-targeted complement inhibition may therefore reflect a promising therapeutic strategy in fighting fatal consequences of HS.

Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock

“…Of note, traumatic HS-induced upregulated renal TNK1 was inhibited by blockade of the central complement component C3. As recently reported, C3 blockade by the small peptide inhibitor Cp40 was able to prevent signs of lung, intestinal, and kidney injury and to inhibit the systemic inflammatory response after (traumatic) HS (13). Here, it seems that Cp40 was capable of inhibiting upregulation of TNK1 expression and induction of apoptosis in the kidneys.…”

Inflammation, Thrombosis, and Destruction: The Three-Headed Cerberus of Trauma- and SARS-CoV-2-Induced ARDS

“…In a model of trauma-induced HS in nonhuman primates, the PaO 2 in blood-gas analyses was improved as well as the associated systemic inflammatory cytokine response by blockade of the central complement component C3 (by a compstatin analog), indicating some improvement in the pulmonary blood-gas exchange (42). In murine trauma studies, a significant increase in C5a plasma levels was observed within 24 h after blunt chest trauma.…”

Does Complement-Mediated Hemostatic Disturbance Occur in Traumatic Brain Injury? A Literature Review and Observational Study Protocol

“…Strengthening the hypothesis that complement activation leads to increased platelet activity, other studies have demonstrated that there is a correlation between MAC levels and plasma concentrations of prothrombin fragments 1 and 2, which are produced upon thrombin generation, in trauma patients with low C3a levels [27]. Treatment with a C3 inhibitor in primates with traumatic shock also results in reduced coagulation [28].…”