518


EQUINE VETERINARY EDUCATION / AE / SEPTEMBER 2017


resolution response to inflammation. However, activation of these proresolving pathways is not sustained in advanced stage tendon disease. Furthermore, the persistence of inflammatory cells in advanced disease suggests failure of the tendon to return to normal and the development of chronic inflammation. Age is cited as an important factor contributing to the development of tendon injuries (Jarvinen et al. 2005; Dudhia et al. 2007). It is known that the ability of an individual to mount an effective response to inflammation reduces with age, a term coined ‘inflamm-ageing’ (Franceschi et al. 2000). A reduced ability to respond to inflammation may be a contributing factor influencing the reduced efficacy of tendon repair. A recent study demonstrated an age- associated decline in expression of an inflammation-resolving protein, FRP2/ALX in diseased equine SDFTs (Dakin et al. 2012a). This finding suggests aged horses have a reduced capacity to resolve tendon inflammation, which may present as a potential mechanism for the development of chronic inflammation and reinjury. Resident stromal cells are also known to play a prominent


role in the development of chronic inflammation (Buckley et al. 2001; Douglas et al. 2002). However, the inter- relationships between infiltrating inflammatory cells and resident tendon stromal cells are poorly understood. A recent laboratory study showed human tendon-derived stromal cells adopt a proinflammatory phenotype after stimulation with proinflammatory mediators. Furthermore, cells isolated from diseased tendons were primed for responding to inflammatory stimuli compared with cells isolated from healthy tendons (Dakin et al. 2015). These findings suggest that tendon stromal cells are an important niche that may contribute to the development of chronic inflammation.


The inflammation-fibrosis link


With time, injured tendons repair and remodel by the formation of scar tissue. Such fibrotic tissue is significantly different to functional and elastic tendon. This is exemplified by marked differences in the proteomic composition of diseased compared with healthy tendons (Dakin et al. 2014b). The quality of the repair scar is inferior in structure and function compared with healthy tendon tissue. In vivo limb stiffness has been shown to reduce immediately following SDFT injury and increase during the convalescent period, approximating that of the contralateral limb by 7 months post injury (Dakin et al. 2011). The mechanical properties of the repair scar are functionally inferior to healthy tendons. The transitional interface between the site of injury and healthy tissue is particularly predisposed to recurrent injury due to segmental change in tendon structural stiffness at the site of injury (Crevier-Denoix et al. 1997). Fibrosis is defined as the hardening or scarring of tissues


and is attributed to excess deposition of extracellular matrix components. These include increased production of proteoglycans, glycosaminoglycans and collagen type 3, which are associated with matrix disorganisation at the macroscopic and ultrastructural level. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including tissue injury (Wynn 2004). Whilst injured


tendons show evidence of inflammation and fibrotic repair, fibrotic pathways are poorly studied in diseased equine and human tendons. Furthermore, there is a gap in our


© 2016 EVJ Ltd


knowledge of understanding the inflammation-fibrosis link and how we might therapeutically exploit this to improve the quality of tendon repair. Studies of inflammation driven fibrosis in other connective tissues might yield valuable insights into the mechanisms of disease. Chronic inflammation is known to drive fibrosis in diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis and progressive renal disease, and treatment typically involves targeting the inflammatory response (Wynn 2004). Important regulators of fibrosis include Th2 cytokines such as IL-13 and TGF-b1, angiogenic factors (VEGF), growth factors (PDGF) and caspases which have been investigated as potential targets of anti-fibrotic drugs (Wynn 2003, 2004; Li et al. 2006; Parsons et al. 2007). Further studies are required to improve understanding of the mechanisms driving fibrosis in diseased tendons to inform therapeutic target discovery.


Therapeutic rationale: the future of treating tendinopathy


Recent work has highlighted the importance of inflammatory and fibrotic processes in healing tendons. The persistence of chronic inflammation in diseased equine and human tendons suggests inflammation and inflammation-resolving pathways are potential therapeutic targets. Improved


understanding of the complexities of inflammatory and fibrotic processes is pivotal to promote restoration of normal tendon function after injury. Complete inflammatory blockade may be potentially deleterious given that inflammation has beneficial components and is necessary for the debridement of tissues and recruitment of immune cells to the injured area. Inflammation also stimulates resolution, which promotes the restoration of tissue homeostasis after injury (Serhan et al. 1984). COX-2 selective nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to diminish endogenous resolution responses (Gilroy et al. 1999, 2004), which may impair the tissues’ innate ability to heal. Furthermore, prolonged use of NSAIDs is known to have a deleterious effect on collagen synthesis (Christensen et al. 2011), which is likely to influence tendon repair processes. An alternative approach of moderating inflammation,


whilst simultaneously potentiating resolution, may have therapeutic benefit for cases with tendinopathy (Dakin et al. 2014a). Low dose aspirin works via a different mechanism to conventional NSAIDs, resulting in the release of stable aspirin triggered isoforms of proresolving mediators, which potentiate resolution of inflammation (Serhan et al. 2000; Morris et al. 2009). Stable isoforms of aspirin have shown efficacy in chronic inflammatory diseases such as murine models of pulmonary inflammation (Levy et al. 2007) and in the treatment of infantile eczema (Wu et al. 2013). An in vitro model of inflammation using diseased human tendon stromal cells suggests stable isoforms of aspirin may be therapeutically beneficial for resolving tendon inflammation (Dakin et al. 2015). As chronic inflammation is known to drive the formation of scar tissue, preventing its development may also improve the quality of the repair of injured tendon tissue. Whilst inflammation-resolving mediators may hold therapeutic promise, many of these compounds are still in the research development phase and randomised controlled clinical trials are necessary to determine their plasma half-lives and therapeutic potential in vivo.


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88