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Sci."],"abstract":"<jats:p><jats:bold>Objective:<\/jats:bold>To determine the symptomatic and disease-modifying capabilities of sEH and COX inhibitors during joint inflammation.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold>Using a blinded, randomized, crossover experimental design, 6 adult healthy horses were injected with lipopolysaccharide (LPS; 3 \u03bcg) from<jats:italic>E. coli<\/jats:italic>in a radiocarpal joint and concurrently received the non-selective cyclooxygenase (COX) inhibitor phenylbutazone (2 mg\/kg), the sEH inhibitor<jats:italic>t<\/jats:italic>-TUCB (1 mg\/kg) or both (2 mg\/kg phenylbutazone and 0.1, 0.3, and 1 mg\/kg<jats:italic>t<\/jats:italic>-TUCB) intravenously. There were at least 30 days washout between treatments. Joint pain (assessed<jats:italic>via<\/jats:italic>inertial sensors and peak vertical forces), synovial fluid concentrations of prostanoids (PGE<jats:sub>2<\/jats:sub>, TxB<jats:sub>2<\/jats:sub>), cytokines (IL-1\u03b2, IL-6, TNF-\u03b1) and biomarkers of collagen synthesis (CPII) and degradation (C2C) were measured at pre-determined intervals over a 48-h period. The anti-apoptotic effect of COX and sEH inhibitors was determined<jats:italic>via<\/jats:italic>ELISA technique in primary equine chondrocytes incubated with TNF-\u03b1 (10 ng\/ml) for 24 h. Apoptosis was also determined in chondrocytes incubated with sEH-generated metabolites.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold>Combined COX and sEH inhibition produced significantly better control of joint pain, prostanoid responses, and collagen synthesis-degradation balance compared to each compound separately. When administered separately, pain control was superior with COX<jats:italic>vs<\/jats:italic>. sEH inhibition. Cytokine responses were not different during COX and\/or sEH inhibition. In cultured chondrocytes, sEH inhibition alone or combined with COX inhibition, but not COX inhibition alone had significant anti-apoptotic effects. However, sEH-generated metabolites caused concentration-dependent apoptosis.<\/jats:p><jats:p><jats:bold>Conclusions:<\/jats:bold>Combined COX and sEH inhibition optimize pain control, attenuate loss of articular cartilage matrix during joint inflammation and cytokine-induced chondrocyte apoptosis.<\/jats:p>","DOI":"10.3389\/fvets.2021.685824","type":"journal-article","created":{"date-parts":[[2021,8,5]],"date-time":"2021-08-05T08:23:45Z","timestamp":1628151825000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Targeting Soluble Epoxide Hydrolase and Cyclooxygenases Enhance Joint Pain Control, Stimulate Collagen Synthesis, and Protect Chondrocytes From Cytokine-Induced Apoptosis"],"prefix":"10.3389","volume":"8","author":[{"given":"Laura","family":"Tucker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Troy N.","family":"Trumble","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna","family":"Groschen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Dobbs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline F.","family":"Baldo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Wendt-Hornickle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alonso G. 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