Inhibition of complement C5a prevents breakdown of the blood-brain barrier and pituitary dysfunction in experimental sepsis.
BACKGROUND
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.
Flierl
Michael A
MA
Department of Orthopaedic Surgery, Denver Health Medical Center, University of Colorado School of Medicine, Denver, CO 80204, USA. michael.flierl@dhha.org
Stahel
Philip F
PF
Rittirsch
Daniel
D
Huber-Lang
Markus
M
Niederbichler
Andreas D
AD
Hoesel
L Marco
LM
Touban
Basel M
BM
Morgan
Steven J
SJ
Smith
Wade R
WR
Ward
Peter A
PA
Ipaktchi
Kyros
K
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D015936:Complement C5a / Q000037:antagonists & inhibitors* / Q000276:immunology*; D007074:Immunoglobulin G / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D010900:Pituitary Diseases / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018805:Sepsis / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*
D007074:Immunoglobulin G; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a