Delayed activation of PPAR-β/δ improves long-term survival in mouse sepsis: effects on organ inflammation and coagulation

• Published in: Innate immunity (London, England) England), 2018-05, Vol.24 (4), p.262-273
• Main Authors: Busch, Daniel, Kapoor, Amar, Rademann, Pia, Hildebrand, Frank, Bahrami, Soheyl, Thiemermann, Christoph, Osuchowski, Marcin F
• Format: Article
• Language: English
• Subjects: Alanine; Alanine transaminase; Animals; Biochemical markers; Blood Coagulation - drug effects; Cecum; Chemokines; Clotting; Coagulation; Creatine; Creatine kinase; Creatinine; Cytokines - blood; Endotoxemia; Female; Fibrinogen; Inflammation - drug therapy; L-Lactate dehydrogenase; Lactic acid; Mice; Monocyte chemoattractant protein; Monocyte chemoattractant protein 1; Monocytes; Original; Peroxisome proliferator-activated receptors; Plasminogen activator inhibitors; PPAR delta - agonists; PPAR delta - metabolism; PPAR-beta - agonists; PPAR-beta - metabolism; Sepsis; Sepsis - blood; Sepsis - drug therapy; Sepsis - mortality; Sulfones - pharmacology; Survival; Thiazoles - therapeutic use; Thiophenes - pharmacology; Thrombin; Triglycerides; Urea; γ-Interferon
• ISSN: 1753-4259; 1753-4267
• DOI: 10.1177/1753425918771748

Activation of peroxisome proliferator-activated receptor (PPAR)-β/δ reduces tissue injury in murine endotoxemia. We hypothesized that the PPAR-β/δ-agonist GW0742 improves long-term outcome after sepsis caused by cecal ligation and puncture (CLP). Fifty-one CD-1 female mice underwent CLP and received either vehicle (control), GW0742 (0.03 mg/kg/injection; five post-CLP i.v. injections), GSK0660 (PPAR-β/δ-antagonist) or both and were monitored for 28 d. Another 20 CLP mice treated with GW0742 and vehicle were sacrificed 24 h post-CLP to assess coagulopathy. Compared to vehicle, survival of CLP-mice treated with GW0742 was higher by 35% at d 7 and by 50% at d 28. CLP mice treated with GW0742 had 60% higher IFN-γ but circulating monocyte chemoattractant protein-1 and chemokine ligand were lower at 48 h post-CLP. Compared to vehicle, CLP mice treated with GW0742 exhibited a 50% reduction in the circulating plasminogen activator inhibitor-1 associated with an increase in platelet number at 24 h post-CLP (but no changes occurred in anti-thrombin-III, plasminogen, fibrinogen and clotting-times). CLP mice treated with GW0742 exhibited a similar increase in most of the biochemical markers of organ injury/dysfunction (lactate dehydrogenase, alanine aminotransferase, creatine kinase, creatinine, blood urea nitrogen, and triglycerides) measured. Treatment with GW0742 consistently improved long-term survival in septic CD-1 mice by partially modulating the post-CLP systemic cytokine response and coagulation systems.