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Shock. 2019 Jan;51(1):78-87. doi: 10.1097/SHK.0000000000001127.

Protective Effects of the Complement Inhibitor Compstatin CP40 in Hemorrhagic Shock.

Author information

1
Experimental Trauma Surgery, Department of Trauma Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
2
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
3
Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
4
Institute of Clinical and Experimental Trauma-Immunology, University of Ulm, Ulm, Germany.
5
Institute for Anaesthesiological Pathophysiology and Process Development, University of Ulm, Ulm, Germany.
6
Department of Transplantation, Malmö University Hospital, Lund University, Lund, Sweden.
7
Simian Conservation Breeding and Research Center (SICONBREC), Makati City, Philippines.
8
Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany.
9
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

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 nonhuman primates (NHP; cynomolgus monkeys) received a pressure-controlled severe HS (60 min at mean arterial pressure 30 mmHg) with subsequent volume resuscitation. Thirty minutes 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.

PMID:
29461464
PMCID:
PMC6092248
DOI:
10.1097/SHK.0000000000001127

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