ABSTRACT: Sepsis and sepsis-induced organ dysfunction remain lethal and common conditions among intensive care patients. Accumulating evidence suggests that the matricellular Cyr61/CCN1 (cysteine-rich, angiogenic-inducer, 61) protein is involved in the regulation of inflammatory responses and possesses organ-protective capabilities in diseases of an inflammatory etiology. However, its regulation in sepsis remains largely unexplored. The present study provides a comprehensive description of CCN1 regulation in the circulation and vital organs during experimentally induced sepsis with developing organ dysfunction. Female CD-1 mice served as baseline controls or were subjected to cecal ligation and puncture (CLP) for 18 to 96 h, and CCN1 regulation was analyzed in selected organs and in the circulation. A 5-, 5-, and 3-fold increases in circulating CCN1 protein were observed at 18, 48, and 96 h after CLP, respectively. Hepatic and pulmonary CCN1 mRNA expression was down-regulated by 80%, 60%, and 55% and 85%, 80%, and 65% at 18, 48, and 96 h after CLP and undetectable in circulating white blood cells. To identify a potential source for the circulating protein, mouse and human platelets were explored and revealed to contain CCN1. Human platelets were stimulated by thrombin and a specific PAR1 agonist (SFLLRN) in vitro. Both agonists induced an instant CCN1 release, and the effect of SFLLRN was blocked by the specific antagonist RWJ56110. The current study demonstrates that experimental sepsis is associated with a robust increase in circulating CCN1 protein levels and a paradoxical downregulation of CCN1 mRNA expression in vital organs. It provides evidence that CCN1 is released from activated platelets, suggesting that platelets constitute a novel source for CCN1 release to the circulation during sepsis.
*Institute for Surgical Research, Oslo University Hospital HF–Rikshospitalet; †Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; and ‡Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria
Received 3 Aug 2013; first review completed 22 Aug 2013; accepted in final form 2 Dec 2013
Address reprint requests to Claus Vinter B. Hviid, MD, Institute for Surgical Research, Oslo University Hospital–Rikshospitalet, P.O box 4950 Nydalen, 0424 Oslo, Norway. E-mail: Claus.email@example.com.
The work conducted in Vienna was supported by the Vienna Science and Technology Fund (LS07-065) and Marie Curie International Reintegration Grant (203685). The work conducted in Oslo received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The funders had no role in study design, data collection and analysis, decision to publish, or manuscript preparation.
The authors declare that there are no conflicts of interest.
C.V.B.H. and J.S.E. contributed equally to this manuscript.
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