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

Martin Wepler,José Matallo,Oscar Mccook,Christoph Thiemermann,Florian Simon,Matthias Reize,Frank Gottschalch,Andrea Seifritz,Michael Georgieff,Florian Wagner,Ulrich Wachter,Michael Gröger,Peter Radermacher,Amar Kapoor,Enrico Calzia,Angelika Scheuerle,Peter Möller,Bettina Stahl,J Vogt ,Martin Matějovič ,Sebastian Häfner

doi:10.1186/2197-425x-1-9

Abstract

BackgroundIn 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.MethodsSix, 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.ResultsDespite 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.ConclusionsIn 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.Electronic supplementary materialThe online version of this article (doi:10.1186/2197-425X-1-9) contains supplementary material, which is available to authorized users.

Highlights

In un-resuscitated rodent models of septic shock, the peroxisome proliferator-activated receptor-β/δ (PPAR-β/δ) agonist GW0742 improved visceral organ function
Ample evidence is available that the activation of the peroxisome proliferator-activated receptors (PPAR), ligand-activated transcription factors of the nuclear hormone receptor family, presenting as PPAR-α, PPAR-γ, and PPAR-β/δ, has beneficial effects in various shock models
One animal in the control group died 15 h after the induction of peritonitis; data at the end of the experiment originate from 11 vehicle-treated animals only

Summary

Introduction

In un-resuscitated rodent models of septic shock, the peroxisome proliferator-activated receptor-β/δ (PPAR-β/δ) agonist GW0742 improved visceral organ function. The highly selective synthetic PPAR-β/δ agonist GW0742 [1] blunted shock-induced organ injury as a result of attenuated inflammation and oxidative and nitrosative stress and decreased activation of the nuclear transcription factor κB (NF-κB) [2,3,4,5,6,7,8] These organ-protective properties were present in animals with obesity [9] and diabetes [10], most likely as a result of enhanced insulin sensitivity and, improved glucose utilization [11], as well as attenuated endothelial dysfunction [12]. Given the beneficial effects of GW0742 on glucose homoeostasis [11] and vascular function [12], we investigated swine with hyperlipidemia and ubiquitous atherosclerosis [15]

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Results

Discussion

Conclusion