Dataset Information

Effects of the PPAR-?/? agonist GW0742 during resuscitated porcine septic shock.

ABSTRACT:

Background

In un-resuscitated rodent models of septic shock, the peroxisome proliferator-activated receptor-?/? (PPAR-?/?) 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-?/? receptor expression than in healthy animals.

Conclusions

In swine with pre-existing atherosclerosis, the PPAR-?/? 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.

SUBMITTER: Wepler M

PROVIDER: S-EPMC4796150 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Publications

Effects of the PPAR-β/δ agonist GW0742 during resuscitated porcine septic shock.

Wepler Martin M Hafner Sebastian S Scheuerle Angelika A Reize Matthias M Gröger Michael M Wagner Florian F Simon Florian F Matallo José J Gottschalch Frank F Seifritz Andrea A Stahl Bettina B Matejovic Martin M Kapoor Amar A Möller Peter P Calzia Enrico E Georgieff Michael M Wachter Ulrich U Vogt Josef A JA Thiemermann Christoph C Radermacher Peter P McCook Oscar O

Intensive care medicine experimental 20131029 1

<h4>Background</h4>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.<h4>Methods</h4>Six, 12, and 18 h after the induction of fecal peritonitis by inoculation of autologous feces, anesthetized, mechanically ventilated, and instrumented male ...[more]

PMID: 26266797

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