Effects of the PPAR-β/δ agonist GW0742 during resuscitated porcine septic shock.
BACKGROUND
In un-resuscitated rodent models of septic shock, the peroxisome proliferator-activated receptor-β/δ (PPAR-β/δ) agonist GW0742 improved visceral organ function. Therefore, we tested the hypothesis whether GW0742 would attenuate kidney injury during long-term, resuscitated, porcine polymicrobial septic shock.


METHODS
Six, 12, and 18 h after the induction of fecal peritonitis by inoculation of autologous feces, anesthetized, mechanically ventilated, and instrumented male pigs with pre-existing atherosclerosis resulting from familial hypercholesteremia and atherogenic diet randomly received either vehicle (dimethyl sulfoxide, n = 12) or GW0742 (n = 10). Resuscitation comprised hydroxyethyl starch and norepinephrine infusion titrated to maintain mean arterial pressure at baseline values.


RESULTS
Despite aggressive fluid resuscitation, fecal peritonitis was associated with arterial hypotension requiring norepinephrine infusion, ultimately resulting in progressive lactic acidosis and acute kidney injury. GW0742 did not beneficially affect any parameter of systemic and regional hemodynamics, gas exchange, metabolism, or organ function. The parameters of inflammation, oxidative and nitrosative stress, and organ injury (post-mortem analysis for histomorphology and markers of apoptosis) were not influenced either. Immunohistochemistry of pre-shock kidney biopsies from a previous study in this swine strain showed markedly lower PPAR-β/δ receptor expression than in healthy animals.


CONCLUSIONS
In swine with pre-existing atherosclerosis, the PPAR-β/δ agonist GW0742 failed to attenuate septic shock-induced circulatory failure and kidney dysfunction, most likely due to reduced receptor expression coinciding with cardiovascular and metabolic co-morbidity.
Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Klinik für Anästhesiologie, Universitätsklinikum, Helmholtzstrasse 8-1, Ulm, 89081, Germany, martin@wepler.de.
Martin
M
Wepler
Sebastian
S
Hafner
Angelika
A
Scheuerle
Matthias
M
Reize
Michael
M
Gröger
Florian
F
Wagner
Florian
F
Simon
José
J
Matallo
Frank
F
Gottschalch
Andrea
A
Seifritz
Bettina
B
Stahl
Martin
M
Matejovic
Amar
A
Kapoor
Peter
P
Möller
Enrico
E
Calzia
Michael
M
Georgieff
Ulrich
U
Wachter
Josef A
JA
Vogt
Christoph
C
Thiemermann
Peter
P
Radermacher
Oscar
O
McCook