Research

Inhibition of complement C5a prevents breakdown of the blood-brain barrier and pituitary dysfunction in experimental sepsis

Michael A Flierl¹ , Philip F Stahel¹ , Daniel Rittirsch^2,5 , Markus Huber-Lang³ , Andreas D Niederbichler⁴ , L Marco Hoesel⁵ , Basel M Touban¹ , Steven J Morgan¹ , Wade R Smith¹ , Peter A Ward⁵ and Kyros Ipaktchi¹

¹Department of Orthopaedic Surgery, Denver Health Medical Center, University of Colorado School of Medicine, 777 Bannock Street, Denver, CO 80204, USA

²Department of Trauma Surgery, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland

³Department of Trauma, Hand-, Plastic-, and Reconstructive Surgery, University Hospital Ulm, Steinhövelstrasse 9, 89075 Ulm, Germany

⁴Department of Plastic, Hand, and Reconstructive Surgery, University Medical Center Hannover (MHH), Carl-Neuberg-Strasse 1, 30625 Hannover, Germany

⁵Department of Pathology, University of Michigan Medical School, 1301 Catherine Road, Ann Arbor, MI 48109, USA

author email corresponding author email

Critical Care 2009, 13:R12doi:10.1186/cc7710

Published:	6 February 2009

See related commentary by Annane, http://ccforum.com/content/13/2/135

Abstract

Introduction

Septic encephalopathy secondary to a breakdown of the blood-brain barrier (BBB) is a known complication of sepsis. However, its pathophysiology remains unclear. The present study investigated the effect of complement C5a blockade in preventing BBB damage and pituitary dysfunction during experimental sepsis.

Methods

Using the standardised caecal ligation and puncture (CLP) model, Sprague-Dawley rats were treated with either neutralising anti-C5a antibody or pre-immune immunoglobulin (Ig) G as a placebo. Sham-operated animals served as internal controls.

Results

Placebo-treated septic rats showed severe BBB dysfunction within 24 hours, accompanied by a significant upregulation of pituitary C5a receptor and pro-inflammatory cytokine expression, although gene levels of growth hormone were significantly attenuated. The pathophysiological changes in placebo-treated septic rats were restored by administration of neutralising anti-C5a antibody to the normal levels of BBB and pituitary function seen in the sham-operated group.

Conclusions

Collectively, the neutralisation of C5a greatly ameliorated pathophysiological changes associated with septic encephalopathy, implying a further rationale for the concept of pharmacological C5a inhibition in sepsis.