Ibute to pain and inflammation in many connective tissues within the body [23]. PGE2 levels are reported to increase in the peri-tendinous space of the Achilles of healthy exercising human subjects [24] and in murine patellar and Achilles tendons following treadmill exercise [25], suggesting exercise can also induce tendon inflammation. These observations are supported by in vitro experiments whereby tendon fibroblasts in culture release PGE2 in response to repetitive cyclic strain [26?8]. Furthermore, prostaglandins regulate MMP production, partly via an IL-1b mediated mechanism in catabolism of cartilage, periodontal ligament [29,30] and tendon [20,22] contributing to degradation of the extracellular matrix (ECM). However the involvement of other prostaglandins such as those of the D series and their cyclopentanone 23115181 metabolites to the development of tendinopathy are not known. The receptors mediating prostaglandin effects are also cited as contributors to the pathogenesis of tendon injuries. A series of four EP receptor subtypes are responsible for the downstream effects of PGE2. The EP4 receptor is reported to mediate the IL-1b-induced catabolic metabolism via the p38 MAPK pathway in human tendon fibroblasts, implicating its role in the development of tendinopathy [31]. Regulation of mPGES-1 and PGDH enzymes controlling prostaglandin synthesis and the clearance mechanismsassociated with degradation have been described for burn related injuries and sepsis in human patients [32]. However, little is currently known about prostaglandin metabolism in flexor tendons that have sustained a natural injury, nor the effect of injury stage and age. In addition to prostaglandins, other products of the arachadonic acid pathway exert important roles in regulating inflammation. Lipoxin A4 (LXA4) is a Chebulagic acid web specialised pro-resolving mediator that selectively signals through the FPR2/ALX receptor providing endogenous stop signals for inflammation [33,34]. The ability to resolve inflammation after injury or sepsis is well documented for other body tissues [33,35,36], although knowledge of the anticipated roles of specialised pro-resolving mediators such as lipoxins is limited for tendon injuries. We recently described significantly increased expression of FPR2/ALX in sub-acutely injured equine tendons [16]; however expression appeared to be of insufficient duration and magnitude to TBHQ supplier suppress inflammation, which may potentiate development of chronic disease and fibrotic repair. Taking all these observation together, it is likely that additional factors play a role in repair-processes during tendon 1662274 injury. A reduced ability to respond to inflammation may be a contributing factor influencing the reduced efficacy of tendon repair. Inflammaging is a component of immunosenescence which is an age associated decline in immune function, whereby the major cell types of the immune system exhibit age-related changes, resulting in a diminished ability to cope with inflammation [37]. Although tendon pathology and incidence of injury are known to increase in aged individuals [18,38], the effect of age on the ability to resolve tendon inflammation and the contribution of immunosenescence to the development of disease are not understood. The aims of this study were to assess the temporal and differential alterations in prostaglandin and resolving lipid mediators in normal and naturally injured equine tendons throughout the stages of healing and to determine the effect of age a.Ibute to pain and inflammation in many connective tissues within the body [23]. PGE2 levels are reported to increase in the peri-tendinous space of the Achilles of healthy exercising human subjects [24] and in murine patellar and Achilles tendons following treadmill exercise [25], suggesting exercise can also induce tendon inflammation. These observations are supported by in vitro experiments whereby tendon fibroblasts in culture release PGE2 in response to repetitive cyclic strain [26?8]. Furthermore, prostaglandins regulate MMP production, partly via an IL-1b mediated mechanism in catabolism of cartilage, periodontal ligament [29,30] and tendon [20,22] contributing to degradation of the extracellular matrix (ECM). However the involvement of other prostaglandins such as those of the D series and their cyclopentanone 23115181 metabolites to the development of tendinopathy are not known. The receptors mediating prostaglandin effects are also cited as contributors to the pathogenesis of tendon injuries. A series of four EP receptor subtypes are responsible for the downstream effects of PGE2. The EP4 receptor is reported to mediate the IL-1b-induced catabolic metabolism via the p38 MAPK pathway in human tendon fibroblasts, implicating its role in the development of tendinopathy [31]. Regulation of mPGES-1 and PGDH enzymes controlling prostaglandin synthesis and the clearance mechanismsassociated with degradation have been described for burn related injuries and sepsis in human patients [32]. However, little is currently known about prostaglandin metabolism in flexor tendons that have sustained a natural injury, nor the effect of injury stage and age. In addition to prostaglandins, other products of the arachadonic acid pathway exert important roles in regulating inflammation. Lipoxin A4 (LXA4) is a specialised pro-resolving mediator that selectively signals through the FPR2/ALX receptor providing endogenous stop signals for inflammation [33,34]. The ability to resolve inflammation after injury or sepsis is well documented for other body tissues [33,35,36], although knowledge of the anticipated roles of specialised pro-resolving mediators such as lipoxins is limited for tendon injuries. We recently described significantly increased expression of FPR2/ALX in sub-acutely injured equine tendons [16]; however expression appeared to be of insufficient duration and magnitude to suppress inflammation, which may potentiate development of chronic disease and fibrotic repair. Taking all these observation together, it is likely that additional factors play a role in repair-processes during tendon 1662274 injury. A reduced ability to respond to inflammation may be a contributing factor influencing the reduced efficacy of tendon repair. Inflammaging is a component of immunosenescence which is an age associated decline in immune function, whereby the major cell types of the immune system exhibit age-related changes, resulting in a diminished ability to cope with inflammation [37]. Although tendon pathology and incidence of injury are known to increase in aged individuals [18,38], the effect of age on the ability to resolve tendon inflammation and the contribution of immunosenescence to the development of disease are not understood. The aims of this study were to assess the temporal and differential alterations in prostaglandin and resolving lipid mediators in normal and naturally injured equine tendons throughout the stages of healing and to determine the effect of age a.