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

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.

• Authors: Michael A Flierl, Philip F Stahel, Daniel Rittirsch, Markus Huber-Lang, Andreas D Niederbichler, L Marco Hoesel, Basel M Touban, Steven J Morgan, Wade R Smith, Peter A Ward, Kyros Ipaktchi
• Journal: Critical care (London, England) (Crit Care) Vol. 13 Issue 1 Pg. R12 ( 2009) ISSN: 1466-609X [Electronic] England
• PMID: 19196477 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Immunoglobulin G
• Receptor, Anaphylatoxin C5a
• Complement C5a

Topics

• Animals
• Blood-Brain Barrier (drug effects, metabolism)
• Complement C5a (antagonists & inhibitors, immunology)
• Immunoglobulin G (pharmacology, therapeutic use)
• Male
• Pituitary Diseases (metabolism, physiopathology, prevention & control)
• Rats
• Rats, Sprague-Dawley
• Receptor, Anaphylatoxin C5a (antagonists & inhibitors, biosynthesis)
• Sepsis (complications, drug therapy, metabolism)