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Protective Effects of the Complement Inhibitor Compstatin CP40 in Hemorrhagic Shock

van Griensven, Martijn and Ricklin, Daniel and Denk, Stephanie and Halbgebauer, Rebecca and Braun, Christian K. and Schultze, Anke and Hönes, Felix and Koutsogiannaki, Sofia and Primikyri, Alexandra and Reis, Edimara and Messerer, David and Hafner, Sebastian and Radermacher, Peter and Biglarnia, Ali-Reza and Resuello, Ranillo R. G. and Tuplano, Joel V. and Mayer, Benjamin and Nilsson, Kristina and Nilsson, Bo and Lambris, John D. and Huber-Lang, Markus. (2019) Protective Effects of the Complement Inhibitor Compstatin CP40 in Hemorrhagic Shock. Shock, 51 (1). pp. 78-87.

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Official URL: https://edoc.unibas.ch/64239/

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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.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molekulare Pharmazie (Ricklin)
UniBasel Contributors:Ricklin, Daniel
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Lippincott, Williams & Wilkins
ISSN:1073-2322
e-ISSN:1540-0514
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:09 Sep 2020 11:15
Deposited On:09 Sep 2020 11:15

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