HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0900550v1 183/7/4764    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by He, S. Articles by Tomlinson, S. PubMed PubMed Citation Articles by He, S. Articles by Tomlinson, S.

A Role for Complement in the Enhanced Susceptibility of Steatotic Livers to Ischemia and Reperfusion Injury¹

Songqing He^2,*,, Carl Atkinson^2,*, Zachary Evans^*,, Justin D. Ellett^*,, Mark Southwood, Andrew Elvington^*, Kenneth D. Chavin^*, and Stephen Tomlinson^3,*

^* Department of Microbiology and Immunology, Children’s Research Institute and Surgery, Division of Transplant, Medical University of South Carolina, Charleston, South Carolina 29245; Hepatic Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China; and Department of Pathology, Papworth Hospital National Health Service Trust, Papworth Everard, Cambridge, United Kingdom

Hepatic steatosis typically renders the donor organ unusable, as donor organs with >30% steatosis are more likely to develop graft failure. The mechanisms leading to failure are not well defined, but steatosis enhances hepatic susceptibility to ischemia reperfusion injury (IRI). We investigated the role of complement in hepatic IRI in lean and steatotic (diet-induced) mice. Steatotic mice were significantly more susceptible to total warm hepatic IRI than lean mice as determined by serum alanine aminotransferase, histopathologically assessed damage, and 24-h survival. C3 deficiency protected both lean and steatotic mice from IRI, as determined by all measured outcomes. Furthermore, treatment of wild-type mice with the complement inhibitor CR2-Crry provided protection equivalent to that seen in C3-deficient mice. Importantly, although steatotic livers were much more susceptible to IRI than lean livers, by most measures there was no statistical difference between the level of IRI to steatotic or lean livers when complement was inhibited. To investigate the clinical relevance of these findings in the context of transplantation, we treated recipients of lean or steatotic liver grafts with saline or CR2-Crry. There was a marked reduction in graft inflammation and injury and significantly improved 7-day survival in CR2-Crry-treated recipients of either lean or steatotic grafts. These data indicate that complement plays a key role in the enhanced susceptibility of steatotic livers to IRI and suggest that complement inhibition represents a potential strategy to reduce the donor shortage by allowing the more routine use of marginal steatotic donor livers.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant R01 HL86576 and a scientist development grant from The American Heart Association (to C.A.).

² S.H. and C.A. contributed equally to the preparation of this manuscript.

³ Address correspondence and reprint requests to Dr. Stephen Tomlinson, Department of Microbiology and Immunology, Darby Children’s Research Institute, Medical University of South Carolina, Charleston, SC 29425. E-mail address: tomlinss{at}musc.edu

⁴ Abbreviations used in this paper: IRI, ischemia reperfusion injury; ALT, alanine aminotransferase; I/R, ischemia reperfusion; MPO, myeloperoxidase; wt, wild type.