Effects of the PPAR-β/δ agonist GW0742 during resuscitated porcine septic shock View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2013-12

AUTHORS

Martin Wepler, Sebastian Hafner, Angelika Scheuerle, Matthias Reize, Michael Gröger, Florian Wagner, Florian Simon, José Matallo, Frank Gottschalch, Andrea Seifritz, Bettina Stahl, Martin Matejovic, Amar Kapoor, Peter Möller, Enrico Calzia, Michael Georgieff, Ulrich Wachter, Josef A Vogt, Christoph Thiemermann, Peter Radermacher, Oscar McCook

ABSTRACT

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. More... »

PAGES

9

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/2197-425x-1-9

DOI

http://dx.doi.org/10.1186/2197-425x-1-9

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1022965438

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/26266797


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